New platinum antitumor complexes

Critical

Review

in

ONCOLOGY/ HEMA TOLOG Y Critical

Reviews

in Oncology/Hematology

I5 ( 1993) I91 -2 19

New platinum antitumor complexes Lloyd R. Kelland Section

of Drug Development,

The Institute

of Cancer

Research,

(Accepted

15 Cotswold

2 June

Road, Belmont.

Sutton,

Surrey.

SM2

5NG.

1993)

Contents I.

Historical aspects ............................................. 1.1. The limitations of cisplatin ............................... 1.2. The development of carboplatin ...........................

2.

A strategy for the discovery of broad-spectrum platinum-based drugs ..................... 2.1. Preclinical tumor models ...................................................... 2.2. Mechanism of action of cisplatin ............................................... 2.2.1. Relative effects of &-versus transplatin ..................................

2.3.

2.2.2. Cell killing by cisplatin ................................................ 2.2.3. Damage-recognition proteins ............................................ Mechanisms of resistance to cisplatin/carboplatin ................................. 2.3.1. Decreased accumulation ............................................... 2.3.2.

2.3.3. 2.3.4. 2.3.5. 2.3.6.

3.1.

4.

1040-8428/93/%24.00 SSDI

,193 ,193 ,195 195

,195 195

,197 ,197 ,198 ,198

Increased intracellular detoxification .................................... 2.3.2.1. GSH ....................................................... ..I9 9 2.3.2.2. MTs ...................................................... ,199 Increased DNA repair/tolerance ........................................ 200 2.3.3.1. Cellular sensitivity of testicular tumors .......................... The possible involvement of proto-oncogenes in platinum tumor cell ..2 . resistance ........................................................... The involvement of signal transduction pathways in cisplatin-induced ..2 . cytotoxicity ......................................................... ..20 I Summary ...........................................................

Platinum drugs currently in clinical trial ..................... lproplatin (Chip) .................................... 3.2. Diaminocyclohexane and related platinum complexes 3.2.1. Tetraplatin (ormaplatin, NSC3638 12) ........... 3.2.2. Oxaliplatin (I-OHP) ......................... 3.3. ‘Carboplatin-like’ agents ............................. 3.3. I Zeniplatin and enloplatin ..................... 3.3.2. DWA2114R ................................. 3.3.3. 254-S (NSC 375101D) ........................ 3.3.4. Cl-973 (NKl21) ............................. 3.3.5. Lobaplatin (D19466) ......................... 3.3.6. Cycloplatam ................................ 3.3.7. Summary ...................................

3.

192 192 192

201 ,201 . . .._702 __.,.,._._ 702 204 __.,.,.___ 705 205 . . . . .._706 ,._...._._ ‘07 . . .._707 . . . . . . . ..i 707 208 . . . . . . . 208

Future approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...208 4.1. Amminelamine platinum (IV) dicarboxylates . . . .208 4.1. I. Bis-acetate-ammine-dichloro-cyclohexylamine platinum (IV) JM216; an orally active platinum drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...209 4. I .2. Preclinical toxicology .2 IO 4.1.3. In vivo antitumor activity .. ,210 4.1.4. Circumvention of transport-determined resistance to cisplatin by JM216. ,210 0

1993 Elsevier Scientific

1040-8428(93)00083-R

Publishers

Ireland

Ltd. All rights

reserved.

UK

L. R. Kelland/ Crit. Rev. Oncol. Hematol. 15 (1993)

192

4.2. 4.3. 5. 6. 7. 8. 9.

.21I ,211

Bis-platinum complexes and trans platinum complexes ............................ Additional synthetic approaches ................................................

Summary ......................................................................... Acknowledgements ................................................................ Biography ........................................................................ Reviewer ......................................................................... References .......................................................................

1. Historical aspects The current widespread use of the neutral, square planar, coordination complex cisplatin [CDDP, cisdiamminedichloroplatinum(II)] in the chemotherapeutic treatment of cancer emanates from a well-documented modern-day case of serendipity in research. The compound, whose chemical identity was originally established over 100 years previously in 1845 (and known as Peyrone’s chloride) was first shown to possess potential antitumor properties by Barnett Rosenberg in the mid 1960s while performing studies designed to test the effect of electric fields on bacteria [ 1, for a review]. Within the remarkably short time of only 5 years (1971) cisplatin was introduced into clinical practice. Undoubtedly the most dramatic effect of the drug has been on the long-term survival of patients presenting with advanced testicular cancer. Although this is a relatively uncommon tumor, the average age of sufferers is only 30 years. Before the introduction of cisplatin, the cure rate for this tumor was only 5- lo”/0whereas following its introduction by Einhorn and Donohue into a regime also containing vinblastine and bleomycin (PVB regime) over 80% of patients can now expect to survive long-term, free of disease [2, for a review]. In addition, largely as a result of the pioneering clinical studies of Wiltshaw and colleagues at the Royal Marsden Hospital (London) cisplatin was also observed to confer significant antitumor activity against advanced ovarian cancer [3]. Combination regimes including cisplatin typically produce clinical complete remissions in over 50% of patients presenting with advanced disease [4, for a review]. Moreover, recently accrued long-term survival data for this disease from the Netherlands indicates that combination chemotherapy with cisplatin can enhance survival by more than 10% at 5 or 10 years post diagnosis compared with the best available treatment of the precisplatin era [5]. Cisplatin is also recognized to confer a substantial palliative effect in patients presenting with other tumor types; e.g., small cell lung cancer, bladder carcinoma, head and neck carcinoma and cervical carcinoma [2]. Furthermore, there have been some recent clinical stud-

191-219

..212 ..212 ..212 ..212 ..212

ies suggesting that cisplatin may offer benefit in the tirstline treatment of advanced breast cancer [6]. I. 1. The limitations of cisplatin

Despite the impressive antitumor activity of cisplatin in testicular and ovarian cancer, two major limitations of the drug were soon recognised: (i) its severe sideeffects (especially nephrotoxicity, nausea and vomiting, ototoxicity and peripheral neuropathy) and (ii) its relatively poor activity (intrinsic resistance) against some more common tumor types (e.g., colorectal and non-small cell lung cancers) combined with the drug’s inability to confer lasting remissions in a proportion of responding tumor types (especially ovary) due to the emergence of (acquired) drug resistance. These limitations have resulted in a great deal of effort having been expended into structural modifications of cisplatin. The drug’s severe side-effects were a major consideration in early analogue development. 1.2. The development of carboplatin

In a collaborative research program between the Drug Development Section of The Institute of Cancer Research (Sutton, UK) and the Johnson Matthey Company, whose goal was to discover a less toxic but equally efficacious platinum-based analogue, over 300 complexes were studied during the 1970s. The result was carboplatin [7, for a review] (Fig. 1 for comparative structure with cisplatin). Carboplatin [CBDCA,

‘43N\

oco

“3N

P

‘P’

H 3 N’

H N’pt\c,

3

CISPLATIN (CDDP,

CARBOPLATIN

Neoplatin)

Fig. 1. Chemical

‘OCO

(CBDCA, structures

of cisplatin

Paraplatin, and carboplatin.

JM8)

L.R. Kelland/ Crit. Rev. Oncol. Hemaiol. I5 (1993)

191-219

paraplatin; cis-diammine, 1,l -cyclobutane dicarboxylato platinum (II)] is currently the only additional platinum complex to date which has received worldwide registration and acceptance. From the results of numerous clinical trials with carboplatin, three principal conclusions may be drawn. Firstly, the major toxicities of cisplatin listed above have been substantially reduced in carboplatin where myelosuppression (predominantly thrombocytopenia) is dose-limiting [8,9, for a review]. Secondly, where randomised studies of cisplatin versus carboplatin have been performed (particularly in advanced ovarian cancer and testicular cancer) the two drugs appear broadly comparable in terms of response rates and disease-free intervals [lo- 121. Thirdly, cross-over studies have revealed that the two drugs essentially share cross-resistance with one another [13-141. Thus, while carboplatin unequivocally offers patients a more acceptable level of morbidity compared to cisplatin, the clinically significant problems of intrinsic and acquired cisplatin resistance persist. The purpose of this review is to summarize current and possible future efforts relating to the development of new, more effective, platinum-based drugs. In particular, a strategy for the discovery of broad-spectrum platinum drugs is presented based on refinements to preclinical tumor models for agent evaluation and rationally-driven synthetic chemistry through integration of recently accrued knowledge of tumor resistance mechanisms to cisplatin/carboplatin. In addition, the current clinical status of a number of platinum complexes which are presently in clinical trial is discussed. 2. A strategy

for the discovery platinum-based drugs

of broad-spectrum

Since the initial high level of patient morbidity associated with platinum-based chemotherapy has now been greatly alleviated through the use of carboplatin (and/or through hydration and antiemetic supportive measures with cisplatin) it is incontrovertible that future platinum drug development should focus predominantly on the circumvention of cisplatin/carboplatin resistance. However, before setting out to accomplish this goal it is appropriate to perform a critical assessment of the preclinical tumor models traditionally used in platinum drug development and to ask the question; ‘do such models require refinement’? 2.1. Preclinical tumor models Unquestionably, the successful discovery of improved platinum drugs is particularly dependent on the predictiveness of preclinical screening models. The traditional approach to preclinical antitumor evaluation of potential anticancer drugs (including platinum-based) has

193

generally involved screening for activity against rapidly growing transplantable murine tumor lines such as the L1210 and P388 leukemias [15, for a review]. In our previous platinum discovery programs, which culminated in the discovery of carboplatin and iproplatin, much emphasis was placed upon activity determinations against the highly cisplatin-sensitive murine ADJ/PC6 plasmacytoma [7]. Subsequently an extension of the L1210 and P388 models was provided through the establishment of variants possessing acquired resistance to cisplatin. The use of such models led to the discovery containing either 1,2of platinum complexes diaminocyclohexane (DACH) or 1,2-diaminocycloheptane ligands; complexes of this class were shown by Burchenal and colleagues to retain activity in L1210 cells with acquired resistance to cisplatin [16]. Indeed, some DACH-containing platinum complexes are presently undergoing clinical evaluation (see section 3). However, an important caveat concerning the adoption of a single acquired resistant murine tumor model for platinum drug development has been emphasized by our own observations using the DACH complex, tetraplatin (ormaplatin). While this agent conferred significant activity against cisplatin-resistant L1210 tumors (thus agreeing with other published studies) it was inactive against a cisplatin-resistant variant of the murine ADJ/PC6 model [ 171. During the 1980s disaffection with the general strategy of using murine leukemia-based prescreens increased, since, in addition to the existence of such model inconsistencies, it was recognized to have failed to reveal compounds possessing selective activity against the commoner, generally slower-growing, human malignancies. This has culminated in a general departure from the use of rapidly growing murine tumors in recent years to human tumor panels that conceptually might offer better predictiveness of the target disease in man. In accordance with this strategy, the entire anticancer drug-screening program at the National Cancer Institute has switched to the use of multiple panels of in vitro human tumor cell lines [ 18, for a review]. Our strategy for the discovery of novel broadspectrum platinum drugs has been to adopt a diseaseoriented, mechanism-directed, approach primarily involving human ovarian cancer; a disease where both intrinsic and acquired resistance to cisplatin/carboplatin severely limits a successful clinical outcome [4]. Keeping in mind the need to obtain an early indicator of therapeutic index for novel complexes [ 191we have established both in vitro [20,21] and parallel in vivo [22-241 panels of human ovarian cancers. Importantly, the panels contain examples of both intrinsic and acquired resistance to cisplatin; where possible, the mechanisms underlying resistance/sensitivity in these models has been determined (see section 2.3.). Details of the evaluation cascade currently employed in a collaborative ven-

L.R. Kelland/Crit.

194

/y_/--- - _= SYNTHETC CHEMISTRY ,* / /@ / ’ ,’ / /’ 1’ I

/

/

// I

I I I I I I I \ \ \

/ / I I I I I I I \

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Rev. Oncol. Hematol. 15 (1993) 191-219

‘-._

I’

I

-PRMARY HUMAN OVARLAN SECONDARY CELL CARCINOMA CELL LINE PANEL-LINE PANELS (LUNG, CERVlX, TESTICULAR CANCERS)

I \

IN WV0 MURINE ADJIPCG PLASMACMOMA (DOSE FINDING/ACUTE TOXCll’Yj \

\

\

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-.

-_

-----PRMARYHUMANOVARlAN XENOGRAFT PANEL

\ \

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SECONDARY XENOGRAFT PANEL

\SIMPLE MOUSE TOXICOLOGY (HEMATOLOGY; HISTOPATHOLOGY LNER ENZYMES; URINE DIPSTlCK)

-----+ Fig. 2. Preclinical

evaluation

STRUCTURE-ACTlVlTYREFlNEMENT cascade

for the discovery

ture between the Drug Development Section of the Institute of Cancer Research (Sutton, UK) the Johnson Matthey Technology Center and Bristol Myers Squibb is shown in Fig. 2. The cascade depicts several important features. Firstly, all compounds are initially evaluated against an in vitro panel of 8 human ovarian carcinoma cell lines; two representative of intrinsic resistance to cisplatin (HX/62 and SKOV-3) having been established from patients who had not previously received platinum-based chemotherapy, and three pairs of cell lines (parent and variant with acquired resistance to cisplatin). The live parent cell lines exhibit a large (over loo-fold in terms of ICSO values) range in sensitivity to cisplatin [20]. Compounds

of novel platinum-based

anticancer

drugs.

which show either a retention of activity against the acquired cisplatin-resistant lines and/or a decreased range in ICsO values across the panel are then selected for further study. This involves additional in vitro cytotoxicity assessments using panels of cervical and testicular cancer cell lines and small cell lung cancer (in collaboration with Dr. Peter Twentyman, Cambridge, UK, described in [25]) and an initial in vivo evaluation using the murine ADJ/PC6 tumor. Maximum tolerated doses of compounds are determined from the ADJ/PC6 test and all compounds are then evaluated against a panel of human ovarian carcinoma xenografts. The primary xenograft panel is comprised principally of lines parallel to the cell lines (e.g., xenograft counter-

L.R. Kelland/Crit.

Rev. Oncol. Hematol. 15 (1993)

191-219

195

parts of the HX/62 and SKOV-3 cell lines and three pairs of parent and acquired cisplatin resistant lines). An analysis of results obtained for eight companion lines has shown a statistically significant positive correlation between in vitro cytotoxicity and in vivo responsiveness for cisplatin (correlation coefficient r of 0.88) and carboplatin (r = 0.7) [24]. Significantly, the HX/62 and SKOV-3 lines are intrinsically resistant to cisplatin both in vitro and in vivo [24], and the acquired cisplatin resistant cell lines retain their resistance to cisplatin in vivo [23]. Compounds exhibiting a minimum of 3.32 x specific growth delay (an estimate of the number of volume doubling times by which tumor growth is delayed and approximating to one log cell kill) in any of the xenografts within the primary panel are then evaluated against further pairs of cisplatin-sensitive and -resistant tumors. Notably, the cascade also includes a simple mouse toxicology evaluation to enable an early indication of dose-limiting toxicity to be determined. 2.2. Mechanism of action of cisplatin In addition to tumor model considerations, a logical prerequisite to the development of additional platinum drugs capable of circumventing resistance to cisplatin is to gain a detailed understanding at the cellular and molecular level of precisely how cisplatin exerts its antitumor efficacy. Following activation via intracellular aquation reactions, the cytotoxic effects of cisplatin (and carboplatin) appear to be due to the formation of a variety of stable bifunctional adducts on DNA (see Fig. 3). Regardless of the fact that less than 10% of intracellular platinum binds to DNA, support for the notion that DNA is the critical target for the antitumor activity of cisplatin is compelling [reviewed in 261. For example, cells from patients with diseases where DNA repair processes are deficient (e.g., Xeroderma pigmentosum) are hypersensitive to cisplatin [27]. Secondly, following exposure to cisplatin, inhibition of DNA synthesis has been observed in various cells [28] and DNA in vitro [29]. Thirdly, correlations have been reported between levels of platinum-DNA adducts in leukocytes and disease response in patients receiving cisplatin or carboplatin [30-3 I], The nature and proportions of cisplatin-induced DNA adducts is shown in Fig. 3 [32-331. The major adduct involves binding to the N7 position of adjacent deoxyguanosines on the same strand of DNA. Once bound to DNA in equal amounts, cisplatin and carboplatin cause approximately equal adducts and cytotoxicity. The large difference in concentrations required to produce these effects reflect the very much faster aquation rate for cisplatin [34]. 2.2. I, Relative effects of c&versus transplatin The inactive trans isomer of cisplatin (transplatin)

is

sterically unable to form the major d(GpG) and d(ApG) intrastrand adducts formed by cisplatin. The lack of activity of transplatin may be associated with the formation of a high proportion of DNA monoadducts (up to 85% of adducts following a I-2-hour drug incubation with DNA; [35]. The monofunctional adducts would then be mainly detoxified through rapid reaction with glutathione. A minority slowly rearrange to form bifunctional 1,3 or 1,4 guanine-guanine intrastrand cross links or DNA interstrand cross-links. Additionally, it appears that these DNA-adducts induced by transplatin may be selectively removed (repaired) compared to cisplatin-induced adducts [36-371. 2.2.2. Cell killing by cisplatin It remains unclear exactly which of the above described platinum-DNA adducts are responsible for the drug’s cytotoxic effects. Furthermore, the mechanism(s) involved in cisplatin-induced cell killing have not been fully elucidated. While inhibition of DNA synthesis has been assumed to be a logical prerequisite to cytotoxicity (leading to a blocking of replication and transcription) cells exposed to cisplatin have been shown to arrest in the G2 phase of the cell cycle rather than the S phase [38]. A proportion of these Gz-arrested cells then appear to undergo a programmed cell death (apoptosis) involving DNA endonuclease-mediated production of DNA double strand breaks [39, for a review]. Experiments involving both bacterial enzymes (Escherichia coli UVRABC nuclease [40]) and mammalian cell extracts [37] indicate that platinum-DNA adducts are removed from DNA by nucleotide excision repair. The E. coli UVRABC nuclease has been shown to incise the 8th phosphodiester bond 5’ and the 4th bond 3 ’ to GG intrastrand crosslinks, thereby excising an oligomer containing the adduct [40]. Recent results indicate that the major intrastrand d(GpG) adduct induced by cisplatin is poorly repaired compared to d(GpXpG) and monofunctional adducts [41,42]. While the degree of DNA bending associated with each of these types of adduct appears similar (32-35”(Z) differences in repair may be associated with differences in the degree of DNA unwinding caused by each of the adducts (whereas both the GG and AC intrastrand adducts have been shown to unwind DNA by 13”, the GXG (1,3) intrastrand adduct unwinds DNA by 23”) [43]. Thus, there is increasing evidence that the antitumor efficacy of cisplatin (and the inactivity of transplatin) correlates with the production of 1,2 (GG and AC) intrastrand crosslinks, although a role for interstrand crosslinks cannnot be excluded. 2.2.3. Damage-recognition proteins Recently, proteins have been identified in mammalian cells which bind specifically to the two major types of platinum-DNA intrastrand crosslinks formed by cispla-

L.R. Kelland/Crit.

196

-I

. *___________ H,N’

++ 1 IS (1993)

191-219

CYTOPLASMlC COMPARTMENT

DECREASED DRUG UPTAKE @

H,N\Pt,Cl

Rev. Oncol. Hematol.

’ Cl

H3N\Pt/H20 ‘H

H3 N’

0

J

GLUTATHIONE 8 - detoxification

t

METALLOTHIONENS

t I

2

NUCLEAR COMPARTMENT NH3,

/NH,

NH3

NH3 lpt

/Pt\

-

-c-c-

-T-C-

.

A

(6065%)

-

G-X-G

G-

.

ipt

- \ C-

c-

/NH3

Pt\ / G - C

/ -G

.

(56%) ““‘3,

/NH3

.

c-x-c

(20-25%) NH3

ENHANCED DNA REPAIR/ TOLERANCE

‘Pt’ /\

/\

-G-G-

NH3

/NH3

k-

2-3%

interstrand (24%)

Fig. 3. Binding

of cisplatin

to DNA and mechanisms

tin [44-45). Notably, these proteins do not bind to adducts produced by the inactive transplatin [45]. A gene that encodes one protein of molecular weight of approximately 8 1 kDa (termed structure-specific recognition protein, SSRPl) has been cloned and sequenced and shares a region of sequence homology with the high mobility group protein, HMGl [46]. The SSRPl protein complex has recently been shown to contain human single-stranded binding protein (HSSB) [47]; a protein known to be involved in an early stage of the in vitro repair synthesis assay of mammalian excision repair [48]. Another protein complex of approximately 28 kDa has been shown to possess an identical amino acid sequence

of tumor

cell resistance.

to HMGl itself [49,50]. The HMG proteins are an abundant family of low molecular weight chromatin proteins thought to play a critical role in the bending or looping of DNA [51]. Further studies have suggested an essential role for thiol groups (primarily cysteine residues) in the binding of the HMG proteins to cisplatin-induced DNA adducts and, perhaps surprisingly, a lower extent of binding of HMG2 to DNA modified with carboplatin compared to cisplatin [52]. The exact function of these damage recognition proteins, however, is presently unknown. It has been postulated that they may either be involved in blocking access of repair enzymes to damaged DNA, or

L.R. Keliand/Crir.

Rev. Oncol. Hematol. 15 (1993)

191-219

197

somewhat contrary, in the repair of cisplatin-damaged DNA. Some support for the repair supposition is provided by observations that some cisplatin-resistant tumor cell lines, which have an increase in DNA repair capacity, also exhibit an increase in damage recognition proteins [53-541. However, studies using other cell lines with resistance to cisplatin have found no obvious differences in levels of damage recognition proteins [55-561. 2.3. Mechanisms of resistance to cisplatinkarboplatin Although the discovery of cisplatin itself was through serendipity, it might be argued that an additional crucial prerequisite to the development of additional platinum drugs capable of overcoming resistance to cisplatin is to gain a detailed understanding of the mechanisms underlying resistance. This has been addressed over recent years by numerous laboratory-based studies. Typically, these studies have used pairs of cell lines (sensitive parent line and variant with acquired resistance to cisplatin) of both murine and, latterly, more commonly, human origin. Such investigations allude to a multifocal basis for resistance involving one or more of three major mechanisms (Fig. 3): (i) decreased drug accumulation, (ii) increased intracellular detoxification (through elevated levels of glutathione and/or metallothioneins) and (iii) increased DNA repair/tolerance. As some comprehensive reviews of platinum drug resistance mechanisms have been published previously

Table 1 Pairs of cisplatin-sensitive

and resistant

cell lines where reduced

[see 57-591 this section will focus mainly on the latest developments subsequent to these reviews. 2.3.1. Decreased accumulation The majority of in vitro-derived cell lines with acquired cisplatin resistance exhibit some reduction in platinum accumulation compared to their parent line. A summary of some of these cell lines and their accumulation properties is shown in Table 1. Not all cell lines with cisplatin resistance, however, show a difference in acccumulation (e.g., GLC,-CDDP human small cell lung carcinoma [60] and our CHlcisR human ovarian carcinoma [21]). In one study using the COL0316 human ovarian carcinoma pair of lines [61] reduced uptake was a feature of acquired cisplatin resistance after resistance was generated by acute drug exposure but not after chronic drug exposure. Using two human ovarian carcinoma xenografted lines, resistance due at least partially to reduced drug accumulation has also been reported in vivo [62,63]. Moreover, studies using our panel of human ovarian carcinoma cell lines (see above) have shown that reduced cisplatin accumulation plays a major role in determining intrinsic resistance to cisplatin in some cell lines (e.g. HX/62) [64]. Perhaps surprisingly, it is still largely obscure whether cisplatin enters cells by passive diffusion or whether a carrier system is at least partly involved. For the cell lines listed in Table 1, few studies have addressed the underlying causative mechanism(s) of the reduced drug uptake. Probably the most studied pair of cell lines to

accumulation

plays a role in determining

resistance

Cell line pair

Tumor

type

o/u accumulation”

Resistance

Ll210 L1210 P388 RI.1

Mouse Mouse Mouse Mouse

leukemia leukemia leukemia lymphoma

36 34 51 66

18 14 24 23.5

[I591 It601

2008 COV 413B COLO 316 PC-9 see-25 KFr MCF-7 SW2 G3661 SL6

Ovarian Ovarian Ovarian Non-small Head and Ovarian Breast Small cell Melanoma Large cell

42 50 30 52 20 23 50 70 64 56 72

40 3.3 7.9 3.5 7.1 30 5.1 6.5 3.3 9.2 3.5

I751 1651 1741 (611 [2361 1731 [631 12371

41M HXl155 GCT27 MOR A2780

Ovarian Cervical Testicular Adenocarcinoma Ovarian

24 42 62 50 40

4.1 8.6 5.6 3.5 15.7

I211

cell lung neck

lung lung

lung

“% Accumulation in resistant relative to parent line after cisplatin bResistance factor : IC,, resistant line/ICso parent line.

exposure.

factorb

Reference

1951 1961 [251 Kelland.

unpublished

L.R. Kelland/ Crit. Rev. Oncol. Hematol. 15 (1993) 191-219

198

date has been the the 2008 human ovarian carcinoma model. In this pair of lines a component (about 50%) of the decreased accumulation appears to be energy dependent as it was inhibitable by dinitrophenol (an inhibitor of oxidative phosphorylation) combined with iodoacetate (an inhibitor of glycolysis) [65]. Furthermore, ouabain (an inhibitor of the Na+,K+-ATPase) inhibited cisplatin accumulation by approximately 50% [66] and cisplatin-resistant 2008 cells were also cross-resistant to ouabain (2.3-fold). Also in the 2008 pair of lines, elevations in plasma membrane and mitochondrial membrane potentials have been reported in the resistant cells [67-681. Interestingly, a gene encoding the carboxy terminal of a mitochondrial PI 60 kDa chaperonin heat shock protein (hsp 60) has been isolated from a 2008 derived cell line with acquired resistance to cisplatin [69]. Moreover, a correlation has been observed between elevated mRNA expression of hsp60 and poor prognosis in ovarian cancer patients [70]. It is presently unclear if these observations are a general feature of all cell lines with acquired cisplatin resistance exhibiting reduced drug influx. While cross-resistance to ouabain (2.6-fold), has also been observed in R1.l murine lymphoma cells selected for resistance to cisplatin [71] in our acquired cisplatin resistant 41 M cell line (where reduced drug influx plays a major role in the resistance) no cross-resistance to ouabain was observed [72]. As opposed to the membrane p-glycoproteinmediated multidrug resistance observed for other commonly used anticancer drugs (e.g., adriamycin, vincristine, etoposide, taxol) which occurs through enhanced drug efflux, reduced platinum influx rather than enhanced efflux is a general feature of acquired cisplatin resistance [63,65,71,72]. Furthermore, no overexpression of p-glycoprotein has been observed in any of our cisplatinresistant cell lines (S. Loh, pers. commun.) or in other cisplatin resistant cells [60,74]. Recently, however, there have been occasional reports of changes in membrane proteins associated with acquired cisplatin resistance

Table 2 Pairs of cisplatin-sensitive

and resistant

cell lines where increased

Cell line pair

Tumor

L1210 2008 COLO 316 PC-9 BE GLC4 PE04 MCF-7 SL6

Mouse leukemia Ovarian Ovarian Non-small cell lung Colon Small cell lung Ovarian Breast Large cell lung

A2780

Ovarian

“Resistance

factor:

IC,,

resistant

type

Fold increase GSH 6.8 2.0 2.3 3.0 3 2.5 2.0 2.8 3.3 13, 22, 48

line/lCsa

glutathione

parent

line.

[75-771. In a series of cisplatin-resistant murine lymphoma cell lines (R 1.1 line) the level of resistance (which paralleled reduced drug accumulation) correlated with increased levels of a 200-kDa membrane glycoprotein (CPR-200) [75]. To date, however, the CPR-200 protein has not been reported in any additional platinumresistant cell lines. In another cisplatin-resistant cell line (SCC-25 human head and neck squamous carcinoma) where a 3-fold reduction in cisplatin accumulation was observed, levels of a 48-kDa membrane protein recognised by monoclonal antibody SQMl were approximately 5-fold reduced [76]. Further confusion to this area have been provided by another preliminary study in which levels of a 55-kDa membrane protein were reduced in one cisplatin-resistant human ovarian carcinoma cell line (A2780) but enhanced in cisplatinresistant KB human mouth carcinoma cells [77]. Therefore, at present, it is difficult to ascertain the role (if any) of these various membrane proteins in conferring cisplatin resistance via reduced accumulation. 2.3.2 Increased intracellular detoxification Cisplatin is known to react avidly with sulfur ligands. Both glutathione (GSH, the major intracellular nonprotein thiol) and metallothioneins (MTs and the major fraction of intracellular protein thiols) have been implicated to play a role in acquired cisplatin resistance. 2.3.2.1. GSH. Cell lines where elevations in GSH have been reported are shown in Table 2. Note that some of these lines with acquired cisplatin resistance (e.g., A2780 and PC-9) also showed reduced platinum influx (see Table 1). Interestingly, the PE04 ovarian carcinoma cell line was derived from a patient after a second relapse to a platinum-based chemotherapeutic regime and showed two-fold higher levels of GSH compared to a cell line (PEOl) derived from the same patient at the time of first relapse [78]. Recent studies have implicated a role for GSH in high levels of resistance to cisplatin (> lOOfold) in human ovarian carcinoma cell lines [79]. How-

plays a role in determining

resistance

Resistance

Reference

factor”

14 15 I3 7.1 5 6.4 2.0 6.5 3.5 29, 530, 1080

[2381 1591 1611 12391 [16tl [6Ol 1781 12371 1791

L.R. Kelland/

Crit. Rev. Oncol. Hematol.

1.5 (1993)

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ever, as for reduced accumulation, while some cell lines with acquired cisplatin resistance clearly possess elevated levels of GSH and/or MTs, others do not. Increased GSH levels may also play a role in determining intrinsic resistance to cisplatin. In our own studies, intracellular GSH levels showed a significant (P = <0.05) correlation (r = 0.91) with cisplatin I& values across eight human ovarian carcinoma cell lines; the intrinsically cisplatin resistant SKOV-3 cell line contained 4-fold higher levels than the sensitive 41 M cell line [80]. Glutathione-S-transferase (GST) activity, however, showed no correlation with I& values. These data are in agreement with other recently published lindings [81,82]. For example, using human cell lines of varying origin, correlation coefficients of 0.79 (P = ~0.05) for cisplatin versus GSH levels (based on 11 lines) and only 0.04 for cisplatin versus GST activity (based on 6 lines) were obtained [81]. Furthermore, it has been postulated that GSH may also be involved in the repair of platinum-DNA adducts as depletion of GSH with buthionine sulfoximine (BSO), a specific inhibitor of y-glutamyl cysteine synthetase, partially inhibited DNA repair activity [83]. While GSH appears to play a role in determining resistance to cisplatin in at least some cell lines, any role for GST activity is more equivocal. Importantly, two recent studies using clinical biopsy material from ovarian cancer patients undergoing platinum-based chemotherapy have both shown no indication for a role for GST in determining response [84,85]. Moreover, in a panel of three lung cell lines, acquired cisplatin resistance did not correlate with GST levels [86]. Furthermore, ethacrynic acid, a putative inhibitor of GST activity, did not alter the cisplatin dose-response curves for these cell lines. Nevertheless, there are some preclinical data to support a role for GST activity; some cell lines with acquired resistance to cisplatin (including SCC-25 head and neck 1731)and Chinese hamster ovary cells [87] have been shown to possess higher levels of (GST) activity; a comparison of the PE04 and PEOl cell lines (see above) revealed 2.9-fold higher GST activity in PE04 cells [88]; levels of GST II mRNA in a panel of human small cell versus non-small cell lung cancer cell lines correlated with resistance to cisplatin and carboplatin [89]. 2.3.2.2. MTs. Metallothioneins comprise a class of cysteine-rich isoproteins (molecular weight 6000-7000) which are involved in heavy metal detoxification and zinc homeostasis. The possible importance of MTs in acquired cisplatin resistance has been highlighted by studies using five human tumor cell lines with acquired cisplatin resistance where four were shown to contain 2-5.1-fold higher levels of MTs [90]. Moreover, cells transfected with an expression vector containing DNA encoding human metallothionein-II* were resistant to cisplatin. In another study, the level of resistance to cis-

199

platin correlated with increased MT content in a series of H69 human small cell lung cell lines [91]. Also, induction of MT by dexamethasone conferred a transient resistance to cisplatin in non-transformed rat kidney cells [92]. Other studies, however, have shown no causal relationship between MT expression and cisplatin resistance; e.g., in a series of human ovarian carcinoma cell lines with intrinsic and acquired cisplatin resistance [93]. Moreover, no difference in levels of MTs was observed between ovarian tumor biopsies taken from untreated patients versus from patients who had completed therapy on a platinum-based regime [94]. Intriguingly, MT content was significantly higher in ovarian tumors as compared to normal ovaries. In our own studies using live human tumor cell lines with acquired resistance to cisplatin (and using sensitivity to cadmium chloride as an indirect measure of MT content) levels appeared to be raised in three (GCT27, testis, 1.6-fold; HX/l55 cervical, 1.9-fold; A2780 ovarian, 2.7-fold) but not in the 41M and CHl ovarian cell lines [21,95,96]. 2.3.3. Increased DNA repair/tolerance Cisplatin resistant cell lines where enhanced DNA repair has been demonstrated (either by adduct removal, unscheduled DNA synthesis, repair synthesis or host cell reactivation of cisplatin-damaged plasmid DNA) include the murine L1210 leukemia [97], the rat ovarian carcinoma cell line (ROT 68/Cl) [98], the human ovarian carcinoma cell lines A2780 [99-1021, PE04 [99], and our own CHl line [ 1031, our testicular teratoma cell line GCT27cisR [96] and the HeLa cervical carcinoma cell line [ 1041. Increased tolerance of certain platinum-DNA adducts may also contribute to resistance in some cell lines [105]; this could presumably occur through either adduct bypass and/or postreplication repair. Alternatively, as the majority of techniques used in DNA repair studies measure adducts as an average over the total genome, repair in specific genomic regions could provide the explanation. In Chinese hamster ovary cells, the major intrastrand DNA crosslinks induced by cisplatin have been shown to be removed faster from transcribed genes (dihydrofolate reductase and c-myc genes) than from non-coding fragments [106]. Perhaps the most compelling data, to date, implicating the possible clinical relevance of enhanced DNA repair of platinum adducts arises from experiments measuring the expression of the ERCCl human DNA repair gene in biopsy material [ 1071. Ovarian cancer patients who were clinically resistant to platinum-based therapy exhibited a 2.6-fold increase in average expression of the ERCCI gene in their tumor tissue compared to responding patients (P = 0.015). Other support for a role for enhanced DNA repair in acquired cisplatin resistance has been provided by determinations of the levels of some enzymes involved in excision repair. In

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200

cisplatin resistant human colon carcinoma HCT8 cells around a 2-fold increase in DNA polymerases (Yand 0 was reported, (as well as increased expression of genes encoding thymidylate synthase and dihydrofolate reductase) [108]. DNA polymerase /3 was raised 5-fold in cisplatin resistant P388 murine leukemia cells [ 1091. 2.3.3.1. Cellular sensitivity of testicular tumors. Recent evidence suggests that the exquisite clinical sensitivity of testicular tumors to cisplatinicarboplatin might be related to defective removal of platinum-DNA adducts. Cell lines derived from testicular tumors have been shown to be hypersensitive to platinum drugs [ 1 10,l 1 11. Our own studies using a human testicular nonseminomatous germ cell line (GCT27) and a variant with S-fold acquired resistance to cisplatin, have revealed that, while the resistant line removed DNAplatinum adducts at a rate comparable to most other mammalian cell lines (removal half time of 32 h) the removal half time for the parent line was much slower (67 h) [96]. Therefore, the parent line appears to possess a defective ability to remove platinum adducts from its DNA and acquired resistance in this case could more accurately be described as acquired loss of sensitivity. There is also supportive evidence that some other testicular teratoma cell lines derived from tumors from untreated patients exhibit deficient removal of the major platinum-DNA intrastrand cross-links i 112,113]. 2.3.4. The possible involvement of proto-oncogenes platinum tumor cell resistance

in

Two independent studies have shown that transformation of NIH3T3 mouse fibroblasts with ras oncogenes produces a marked increase in cisplatin resistance; from 4.5-8-fold [114] and 8.2-fold [115]. In the second study, induction of c-Ha-ras oncogene (which led to over a IO-fold increase in levels of mutant p21 ras protein) was also associated with a 40% reduction in platinum accumulation and a 3.3-fold increase in MT content. Other studies, however, also using 3T3 cells, have not been able to reproduce these findings [ 116,117]. The expression of the c-myc oncogene may also play a role in the acquisition of cisplatin resistance: NIH3T3 cells transfected with c-myc exhibited a 2. l-fold increase in ICSO to cisplatin [117] and using murine Friend erythroleukemia cells, cisplatin I& values were 3-fold higher for cells expressing amplified c-myc in the ‘sense’ versus ‘antisense’ orientation [118]. As c-myc transcript level had no effect on ionizing radiation response, the increase in resistance to cisplatin does not appear to be due to a general mechanism that alters cellular ability to deal with toxic insult [118]. Increased expression of the immediate early response oncogenes c-fos and c-jun may also be involved in the acquisition of cisplatin resistance [119,120]. Using a 13fold cisplatin-resistant A2780 human ovarian carcinoma cell line (compared to parental line) as well as cell lines developed from patients failing cisplatin-based chemo-

191-219

therapy, a 3-6-fold elevation of mRNA expression for the c-fos (and c-H-ras) oncogenes has been reported [121]. Interestingly, exposure of cisplatin resistant cells to cyclosporin A prior to cisplatin abolished the increase in c-fos and c-H-ras expression and conferred a 6-fold enhancement in sensitivity to cisplatin [122]. Furthermore, the transfection of DNA encoding a ribozyme (catalytic RNA) against c-fos RNA into cisplatinresistant A2780 cells also restored sensitivity to cisplatin to that of the parental line [123]. It has been suggested that the increase in c-jun expression is mediated by a protein kinase C (PKC)-dependent pathway [ 1201. 2.3.5. The involvement of signal transduction pathways in cisplatin-induced cytotoxicity

Signal transduction pathways are known to play a key role in the regulation of many vital cellular processes including cell growth, differentiation, receptor interactions and gene expression. It is now apparent that, in addition to the ras-mediated pathway discussed above, modulation of many signal transduction pathways, including those mediated by protein kinase C (PKC), the epidermal growth factor (EGF) receptor and protein kinase A (PKA), may influence cellular sensitivity to cisplatin [ 124,125 for reviews]. The large family of calcium- and phospholipiddependent PKC enzymes (which play a pivitol role in transmembrane signalling) are activated through the hydrolysis of inositol phospholipids to transiently produce diacylglycerol [126, for a review]. The importance of PKC modulation in relation to the cytotoxic effects of cisplatin was initially suggested by experiments (using Walker rat carcinoma cells) which showed the synergistic enhancement of cytotoxicity of cisplatin by inhibitors of PKC (quercetin, staurosporine, tamoxifen and the ether lipid analogue BM41440) [ 127,128]. In addition, these studies showed a similar enhancement using a prolonged exposure to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), which produces down-regulation of PKC. Two subsequent studies with TPA, indicate that PKC activation rather than down-regulation is the causative factor in the enhancement of cisplatin-induced cytotoxicity [129,130]. The TPA effects appeared to be both cell line and drug specific; enhancement was observed for the HeLa cell line but not for A253 human head and neck carcinoma cells and with cisplatin and (to a much lesser extent) with melphalan but not with doxorubicin or vincristine. The cisplatin effects were associated with a 2-fold increase in platinum uptake. The PKC activation hypothesis is supported by experiments using more specific PKC activators such as analogues of lyngbyatoxin A (where a 9-fold sensitization of HeLa cells was observed [ 13l] and, significantly, bryostatin 1, which is currently in phase I clinical trial in the United Kingdom [ 1321. The possible involvement of other signalling

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pathways (EGF- and PKA-mediated) in modulating the cytotoxicity of cisplatin have been highlighted in reports showing that around a 3-fold enhancement in cisplatin cytotoxicity was obtainable by adding EGF itself [ 1331 and by adding a combination of forskolin and 3isobutyl- 1-methyl-xanthine (where the effect was associated with a 2-fold increase in platinum uptake [ 1341. Notably, in both cases, the enhancement was obtained in a parent human ovarian carcinoma cell line (2008) but not in a subline selected for cisplatin acquired resistance. At present, attempts to modulate the cytotoxic effects of cisplatin through manipulation of signaling pathways is an area of active study. It is now important to determine whether these approaches are also able to modulate cisplatin activity in vivo without increasing toxicity or whether the in vitro effects are dependent on the nature of the platinum complex itself. 2.3.6. Summary In many in vitro derived models of acquired cisplatin resistance, the mechanism of resistance is not due to a single factor but rather one or more of decreased platinum influx, enhanced intracellular detoxification through increased levels of GSH and/or MTs, or enhanced DNA repair. In vitro, typical levels of resistance of 4-8-fold have been obtained. Although these levels of resistance may appear low when compared to those obtainable with other classes of anticancer drug (e.g., adriamycin, methotrexate) such levels are probably clinically relevant and, parenthetically, may also allude to the approximate fold-increase in dose intensity of cisplatin/carboplatin required to provide significant clinical benefit in currently resistant disease. In vitro studies have paid relatively little attention to understanding the underlying causative mechanisms of intrinsic cisplatin resistance; it is uncertain whether intrinsic resistance and acquired resistance are due to similar or dissimilar mechanisms. To date, relatively little work has been performed to assess the relative importance in vivo of each of the mechanisms of resistance described above either using human tumour xenografts transplanted in mice or directly from clinical material. This may have signiticance as, in one study, using EMT-6 murine mammary tumours, high levels of resistance to cisplatin developed through mechanisms expressed only in vivo [ 1351. Interestingly, in a recent follow up study, the expression of this ‘in vivo’ resistance could be fully regained in vitro when the EMT-6 cells were grown as three-dimensional multicellular tumor spheroids [ 1361. Our recent establishment of a number of human ovarian tumor xenografts where acquired resistance to cisplatin/carboplatin has been generated in vivo [23] will now allow us to determine the general relevance of mechanisms expressed only in vivo. Compared to only 5 years ago, we now know considerably more about how cisplatin exerts its cytotoxic

effects and how tumor cells become resistant to this drug. While there is still much to learn at the mechanistic level, the immediate urgent task is to develop strategies to circumvent resistance to cisplatin and carboplatin in the clinic. Apart from the traditional approach of combination chemotherapy which has met with limited success (although taxol does appear to exhibit some activity in platinum refractory disease [ 1371) one may envisage this being achievable through three possible routes; design of novel platinum-based agents, modulation of the above described mechanisms of resistance and administering higher doses of cisplatin/carboplatin (dose intensification). A number of modulators of cisplatin resistance have been reported including membrane active agents e.g., modulators of signal transduction pathways, calcium channel blockers [124,125,127-134,138-1411 modulators of glutathione biosynthesis (particularly using buthionine sulfoximine [e.g., 80,821) and DNA repair inhibitors [e.g., aphidicolin, lOO,lOl]. For further information, the reader is referred to an excellent recent review jl42]. Similarly, readers are referred to a recent review of the potential clinical role of high-dose platinum-based chemotherapy [ 1431; such studies appear better suited to carboplatin using dosage calculation based on renal function [144] rather than cisplatin (where dose-limiting neurotoxicity is apparent). The next section of this review focuses on those platinumbased drugs currently in clinical trial. In particular, the possible contribution of each agent in relation to circumvention resistance is of cisplatin/carboplatin discussed. 3. Platinum drugs currently in clinical trial

,

Since the introduction of cisplatin, over 23 different cisplatin analogs have been tested in cancer patients. Many of the early attempts at analog development were unsuccessful because of problems relating to poor aqueous solubility, formulation difficulties or severe and/or unpredictable toxic effects. Past clinical trials of these platinum drugs which are no longer of clinical interest (e.g., the platinum uracil blues, ethylenediamine(malonato)platinum(II) (JM40) and DACH-containing and related complexes such as JM82, PHIC and TN06) have been the subject of previous reviews [145-1471. At present, only carboplatin has received world-wide registration and acceptance. 3.1. Iproplatin (Chip) One of the most studied analogs has been Iproplatin (CHIP; cis-dichloro-trans-dihydroxy-bis [isopropylamine]platinum(IV)) . Iproplatin, like carboplatin, was selected for development on the basis of an improvement in therapeutic index (particularly less nephrotoxicity)

202

compared to cisplatin in preclinical models [see 148, for a review]. However, clinical trials in advanced ovarian [ 1491 cervical [ 1501 and non-small cell lung cancer [ 151,152] suggest that the activity of iproplatin is inferior to that of carboplatin, whilst inducing more severe gastrointestinal and hematological (predominantly thrombocytopenia) toxicity. For example, in a randomised trial of carboplatin versus iproplatin in advanced ovarian cancer (120 patients) response rates were 63% (median survival 114 weeks) for carboplatin and 38% (median survival 68 weeks) for iproplatin (P = 0.008) [149]. Moreover, other clinical studies indicate that iproplatin (like carboplatin) shares almost complete cross-resistance with cisplatin [ 153,154]. These data suggest that iproplatin offers no advantage over carboplatin and hence is unlikely to play any significant role in the future. A summary of the structures of platinum-based complexes currently in clinical trial is shown in Fig. 4. Apart from the novel ammine/amine platinum (IV) dicarboxylate, JM216 (see below), two major structural themes are apparent. Somewhat disappointingly, the majority of the complexes are essentially carboplatin ‘me-too’s’ with oxygenated leaving groups conferring generally good aqueous solubility and greater stability than the dichlorides of cisplatin. The second class of complex is those based on the 1,2 diaminocyclohexane (DACH) (or related) carrier ligand (e.g., tetraplatin, ormaplatin and oxaliplatin) with non-cross resistance properties in experimental cisplatin-resistant murine leukemias.

3.2. Diaminocyclohexane and relatedplatinum complexes (see Fig. 4 for structures) As described in section 3.1, interest in DACHcontaining platinum complexes was originally stimulated some 15 years ago by Burchenal and colleagues discovery of complete lack of cross-resistance by 1,21,2-diaminocycloheptane diaminocyclohexane and derivatives in a 50-fold cisplatin-resistant L1210 leukemia subline (induced by repetitive in vivo treatments) [ 161. Activity against resistant L1210 tumors was also observed in vivo [16]. Clinical trials of past DACHrelated platinum complexes (e.g. JM82 and TNO-6) were curtailed at an early stage mainly because of poor solubility and unpredictable and severe toxicities [ 145- 1471. Chemical refinement, primarily to improve aqueous solubility, has resulted in tetraplatin (ormaplatin) and oxaliplatin, both of which have recently entered clinical studies. 3.2.1. Tetraplatin (ormaplatin, NSC363812) Tetraplatin is a racemic mixture of the I-trans- and dtrans- enantiomers of tetrachloro( 1,2-diaminocyclo-

hexane)platinum (IV) [ 1551. The spectrum of activity in

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mouse tumor models (B16 melanoma, M5076 sarcoma, L1210 leukemia, P388 leukemia, MX-1 human breast cancer xenograft) was largely similar to that of cisplatin with the notable exception of lack of cross-resistance in cisplatin-resistant variants of the L1210 and P388 leukemias [ 155,156]. Tetraplatin has also been shown to be less nephrotoxic than cisplatin in rats [ 1551. The parent platinum (IV) complex is rapidly reduced to the corresponding dichloro( 1,2-diaminocyclohexane)platinum (II) species, both in tissue culture medium [157] and in vivo [158] suggesting that this biotransformation product is the major biologically active species. Our own studies with tetraplatin have confirmed its activity against cisplatin-resistant murine L 1210 tumors [ 171. Interestingly, reduced cisplatin accumulation appears to be the predominant mechanism conferring resistance in these cells [ 159,160]. However, tetraplatin was found to be completely cross-resistant in another murine tumor possessing acquired resistance to cisplatin (the ADJ/PC6). A survey of the in vitro activity of tetraplatin against human tumor cells with acquired resistance to cisplatin reveals that tetraplatin generally shares at least partial cross-resistance with cisplatin; in 3 (GLC, small cell lung, BE colon and HX/155 cervical) of 8 lines full cross-resistance was observed [21,60,82,95,96,161-1631. Furthermore, across sixteen human ovarian carcinoma xenografts, only two were sensitive to tetraplatin, those being the same tumors which were particularly sensitive to cisplatin and carboplatin [22]. In contrast, seven of the sixteen were sensitive to cisplatin and carboplatin [22]. To date, where evaluated, tetraplatin has not demonstrated significant activity in vivo against human tumor xenografts possessing acquired resistance to cisplatin/carboplatin [23,164]. Using plasmid DNA, no significant effects of the DACH ligand on the types or sites of platinum adduct formation were observed compared to adducts formed by an ethylenediamine carrier ligand [41]. Clinical trials with tetraplatin began in 1990. The status of live ongoing phase I clinical studies of tetraplatin, involving three different schedules (q 28 days, days 1 and 8 q 28 days and daily x 5 q 28 days) as reported in May 1992, is shown in Table 3. The maximally tolerated dose has been reached in one trial, that being 90 mg/m2 using a single dose schedule repeated every 4 weeks, where thrombocytopenia was doselimiting [ 1651. While emesis and myelosuppression have been reported with all schedules, perhaps the most problematic toxicity has been peripheral neuropathy (predominantly affecting sensory function) which has been recorded in all live trials. With the single dose schedule repeated every 4 weeks, clinical evidence of sensory neuropathy was observed in six of seven patients given a total dose of 150 mg/m2 or more [ 1651. With the same schedule at a second center, neuropathy developed in three of 23 patients treated with 50 mg/mz or more

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203

OH (CH,),CH-NH,,

1 /Cl Pt

Tetraptatin (Ormaptatin) tproplatin (CHIP, JM9)

Entoplatin (CL287, 1 IO)

Oxatiptatin (I-OHP)

-

DWA2114R

Zeniptatin (CL286,558)

H3N\/ oco \ ‘_,

3

N~Pt\O/CH2 254-S

D

CC973 (NK121)

H2N\ /°Co’C+O~ <~)t$ H N/Pt\oC()2 3

CH3

Lobaplatin (D-l 9466)

Cyctoptatam ?COCH3 H3N\

1 /Cl

(3-H2+ct

OCOCH, JM216 Fig. 4. Structures

of platinum-based

agents currently

in clinical

trial.

L.R. KeNand/Crit.

204

[166]. This complication was also encountered with divided-dose schedules [ 167- 1691. With the dl, d8 schedule, neuropathy occurred in one patient at a total dose of 280 mg/m2 [ 1671, while peripheral nerve deficits were recored in three of five patients treated at the 15 mg/m*/day x 5 dose level [168]. Clinical pharmacokinetic studies during phase 1 have found biphasic drug elimination (Tina, 10 min; T1,2fl, lo-20 h), linear plasma pharmacokinetics within the -dose-range studied, urinary elimination accounting for 40% of the dose, and ultrafiltered plasma drug levels within the cytotoxic range observed in vitro [165, 1661. To date, no clear evidence of tumor response has been reported. 3.2.2. Oxaliplatin (I-OHP) the trans-l-isomer of oxalato- 1,2Oxaliplatin, diaminocyclohexane platinum(II), was first synthesised by Kidani in 1978 [ 1701.This compound showed activity (generally similar to cisplatin) in several murine tumor models (L1210 leukemia, L40AKR leukemia, P388 leukemia, M5076 sarcoma, B16 melanoma, Lewis lung carcinoma, LGC lymphoma, mammary MA 16-C colon 26, and ascites sarcoma 180) [ 170-1721. However, as with

Table 3 Phase I studies with tetraplatin

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tetraplatin, oxaliplatin was active against cisplatinresistant L1210 murine tumours in vivo. In human tumor cell lines, oxaliplatin has greater in vitro dose potency than cisplatin [173], lack of cross-resistance in one of two in vitro sublines with induced cisplatinresistance [174], and a pattern of cytotoxicity very similar to tetraplatin [ 1751. To date, oxaliplatin has been studied mainly in France. The first phase I study (Table 3) of oxaliplatin (starting in 1986) employed an unorthodox intrapatient dosage escalation technique whereby the dose of oxaliplatin was escalated in each individual patient from a starting dose of 0.45 mg/m2, up to a predetermined target dose range [ 1761.The target dose was defined in mice as the ‘maximally efficient dose range’ or MEDR and not according to the toxicity encountered in the course of the phase I study [176]. In each of 23 patients the intravenous bolus dose of oxaliplatin was gradually increased up to the MEDR (45 to 67 mg/m*). The study design did not permit the identification of the normal phase I endpoints, i.e., the maximally tolerable dose and dose limiting toxicities. Emesis, however, was recorded for most patients at the MEDR. Other toxicities were

and oxaliplatin DLT

Other

NS

Thrombocytopenia

11651

>I23

NS

NS

i.v. 30 min dl and d8 q 4 wks

>45.6

NS

NS

i.v. 30 min daily x 5 q

>I5

NS

NS

>11.6

NS

NS

Emesis, neuropathy, 1 LFT, diarrhoea. anorexia, malaise. Emesis, neuropathy. granulocytopenia, thrombocytopenia. Emesis, anemia, neuropathy. ?SVT. hepatotoxicity, hyperglycemia. Emesis, thrombocytopenia. Leucopenia. neutropenia. neuropathy. Emesis, neuropathy, granulocytopenia

NS 200

>45 I35

NS Neurotoxicity

11761 [I771

i.v. infusion for 5 days q 21 d circadian-rhythm-modulated i.v. infusion for 5 days q 21 d

NS NS

NS 175

Anemia. emesis, t LFT. Emesis, diarrhea, myelosuppression. Emesis, paresthesiae, neutropenia. Emesis, paresthesiae, neutropenia.

i.v. bolus q 7-28

NS

Emesis, paresthesia

11791

Schedule

A. Tetraplatin i.v. 30 min q 28 d i.v. hydration antiemetics i.v. I h q 4 wk i.v. hydration

28 days i.v. hydration antiemetics i.v. 30 min daily x 5 q 28 days B. Oxaliplatin iv. bolus q 21 d i.v. 6 h q 28 d

days

MTD

RD

(mgim2)

(mdm?

90

MTD, Maximally tolerated dose; RD, recommended tests. (?SVT, possible drug-related supraventricular

NS

NS

dose for phase II; DLT, dose limiting toxicity; tachycardia.)

toxicity

NS, not stated;

Reference

11661 11671

I1681 I1691

[I781

11781

t LFT, disturbed liver function

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mild and uncommon (grade 1 liver function disturbance (1 patient); grade l-2 anemia (3 patients); grade 1 thrombocytopenia (1 patient). The recommended starting dose for phase II studies was 45 mg/m*. Subsequent to the first phase I study, a conventionally designed phase I was initiated starting at the previously recommended phase II dose (45 mg/m*) [ 1771. Oxaliplatin was administered as a one-hour, and latterly a six-hour, intravenous infusion to 44 patients every four weeks [ 1771. The majority of patients (32 patients) had a history of prior cisplatin chemotherapy. The maximally tolerated dose was found to be 200 mg/m* and the dose-limiting toxicity was neurotoxicity; manifest by acute paresthesia of the extremities and lips, coming on during the course of the drug infusion and thereafter lasting several days. Symptoms were exacerbated when patients touched cold surfaces. Additionally, a peripheral sensory neuropathy became apparent with repeated treatment courses. Severe cases were characterised by sensory ataxia with walking difficulties, and dysesthesias of the mouth, throat, legs, forearms and extremities. The incidence and severity of the neurotoxicity was related to both dose and cumulative dose, and occurred in all patients at the MTD. At cumulative doses above 500 mg/m* six patients developed grade 3 disabling neuropathy. The symptoms slowly regressed over six months following the curtailment of therapy. Electrophysiological studies showed an axonal sensory neuropathy but no changes in motor nerve conduction velocity. With regard to other toxicities, emesis occurred in all patients and was severe (grade 3-4) in 50%. Thrombocytopenia and leucopenia were mild (grade l-2) at the MTD. No evidence of renal toxicity was apparent. Four tumor regressions were recorded in patients with oesophageal (2 cases), lung (1 case) and urothelial cancer (1 case); two of these had been pretreated with cisplatin. The recommended dose for phase II studies was 135 mg/m2 and careful monitoring of nerve function was advised. A further phase I study randomly compared constant rate and circadian-rhythm modulated rate continuous 5day intravenous infusions of oxaliplatin repeated every 21 days in 23 patients [178]. Once again, intra-patient dosage escalation was employed. The maximally tolerated dose was 175 mg/m* for the circadian-rhythm modulated schedule and the reported toxicities were emesis, paresthesias, diarrhoea and mild myelosuppression [178]. Another phase I study (30-130 mg/m* q 28 days) has recently begun in Japan; main toxicities were nausea and vomiting occurring in 80% of patients and, neurotoxicity similarly to the above studies, (paresthesia) [ 1791. The single agent activity of oxaliplatin and its utility in cisplatin-refractory disease remains unclear at present. To date only one complete phase II report of oxaliplatin has appeared [ 1801. In this study, however,

205

oxaliplatin was administered as a circadian-rhythm modulated continuous 5-day intravenous infusion (25 mg/m*/day q 3 weeks), in combination with circadianrhythm modulated i.v. infusional 5-fluorouracil and folinic acid in 93 patients with metastatic colorectal cancer. Peripheral sensory neuropathy led to discontinuation of oxaliplatin in 14 patients. An impressive objective response rate (58% (95% C.I. 48-68%)) was recorded. However, the contribution of oxaliplatin to the activity of this complex treatment protocol is difficult to ascertain. At the present time, the future clinical role of DACHcontaining platinum complexes is equivocal. From the early clinical trials of tetraplatin and oxaliplatin (Table 3) neurotoxicity is a recurring limitation to therapeutic efficacy. Thus it is possible that further chemical refinement is necessary; alternatively, the neurotoxic effects may result from the DACH carrier ligand itself. One possible means of circumventing the neurotoxic effects might be through the concomitant use of neuroprotective ACTH (4-9) peptide analogues such as ORG 2766 which has been shown to prevent or diminish cisplatin neuropathy in ovarian cancer patients without adversely affecting antitumor activity [ 1811. A second option (particularly where targetting to the liver or spleen is advantageous) might be the use of liposomal preparations of DACH-platinum complexes. A phase I study of a racemic mixture of cisBis-neodecanoato-trans-7R, R-1, 2-diaminocyclohexane platinum (II) (L-NDDP), (where the carboxylato leaving groups are isomers of branched ten carbon aliphatic chains, entrapped within liposomes comprising of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol) given as a short intravenous infusion once every four weeks was conducted at the M.D. Anderson Cancer Center (Houston, Texas) in 39 patients [182]. The dose-limiting toxicity was myelosuppression affecting all three blood cell lineages, and the maximally tolerable dose was 312.5 mg/m*. Other toxicities included mild diarrhea, malaise and emesis (which was of short duration but uncontrolled by prophylactic antiemetic therapy at high doses). Transient elevations in alanine aminotransferase activity and fever were thought to be related to the liposomal component, Importantly, although ten patients were each given at least four doses, the only evidence of neurotoxicity was the deterioration of a pre-existing peripheral neuropathy in one case. Nephrotoxicity and ototoxicity were lacking. Unfortunately, unanticipated formulation and stability problems have hindered the further study of L-NDDP.

3.3. ‘Carboplatin-like’ agents (see Fig. 4 for structures) 3.3.1. Zeniplatin and enloplatin

In 1989, the synthesis and biological properties of a

206

series of highly water soluble platinum (II) malonate derivatives incorporating cyclic ether or diol amine ligands were reported from the American Cyanamid Company [ 1831. Enloplatin, [ 1,l cyclo-butanedicarboxyalato(2-)-0,0][tetrahydro-4H-pyran-4,4-dimethanamine-N,ZVlplatinum(II) (CL287,l lo), was the most active of three tetrahydropyran derivatives in the cisplatin-resistant L1210CPR murine leukemia in vivo, while zeniplatin, [2,2-bis(aminomethyl)-1,3-propanediol-N,N’J[ 1,2-cyclobutane dicarboxylato(2-)O,O’]platinum(I1) (CL286,558), was more active than either cisplatin or carboplatin against the B16 melanoma and M5076 sarcoma murine solid tumors in vivo. Crossresistance studies in two cisplatin-resistant human tumor cell lines (GLC,-small cell lung cancer, and Teracrossembryonal carcinoma) showed complete resistance for zeniplatin and partial lack of crossresistance for enloplatin [82]. Both compounds showed similar activity to cisplatin and carboplatin in the breast MX-1 and ovarian H207 human tumor xenografts. In preclinical studies, neither enloplatin nor zeniplatin caused elevations in blood urea nitrogen in rats [ 1831, however, enloplatin was nephrotoxic in dogs (1841. The phase I clinical evaluation of zeniplatin was undertaken at the Institut Jules Bordet, (Brussels, Belgium) using 60-90 min intravenous infusions repeated every three weeks without pre-hydration or prophylactic antiemetic therapy in 46 patients with refractory cancers [ 1851. Accrual at high doses was limited to patients with good bone marrow reserve. The starting dose was 8 mg/m* and dosages were escalated to the maximally tolerable dose of 145 mg/m*. A total of 14 patients recieved three or more courses. The dose limiting toxicities were leucopenia and neutropenia, which were dose-related and dependent upon previous Thromexposure therapy. to myelosuppressive bocytopenia was mild and uncommon (5 patients). Emesis was ubiquitous at doses > 50 mg/m* and was severe in 50% of patients. Low dose oral metoclopramide therapy was ineffective. A substantial fall (40%) in creatinine clearance was recorded at the MTD after 2 cycles of therapy. Other toxicities included phlebitis (5 patients), alopecia (1 patient), mucositis (1 patient), grade l-3 diarrhea (5 patients), fever (1 patient), and grade l-2 liver function abnormalities (4 patients). Two objective tumor regressions were noted (in patients presenting with malignant melanoma and renal cell cancer). Recommended doses for phase II trials were 145 mg/m* for previously untreated patients and 120 mg/m* for those with a history of prior chemotherapy. Phase II reports of zeniplatin have, to date, mainly been in the form of preliminary reports of ongoing studies published only in abstract form. The exception is a study performed at the Royal Marsden Hospital (London, UK) [186]. In previously untreated patients presenting with non-small cell lung cancer, a modest partial

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response rate (22%) was observed. Significantly, this represents a response rate similar to the single agent activities of cisplatin or carboplatin in this disease. Additional trials of zeniplatin in advanced malignant melanoma by the EORTC Early Clinical Trials Group and at the Peter MacCallum Institute (Melbourne, Australia) have, to date, produced a combined response rate of 19% (95% C.I.; 6-32) [187,188], while the preliminary results of ongoing studies in relapsed or refractory ovarian [189] and metastatic breast carcinoma [ 190) have reported encouraging responses. In these phase II trials, the most frequently recorded toxicities have been neutropenia and emesis, in keeping with phase I results. Emesis was moderate or severe in 25-50% of patients despite prophylactic antiemetic therapy. Perhaps surprisingly, in view of the leaving groups being identical to the non-nephrotoxic carboplatin, nephrotoxicity has been reported in all studies using the 145 mgim* dose level. This was regardless of the initiation of intravenous pre-hydration. The Royal Marsden trial recorded a fatal case of acute renal failure in a 71year-old man with previously normal renal function [186]. This appeared to be clearly related to the zeniplatin treatment since no other nephrotoxins were given and the presentation was 24 h following the second dose. Post mortem findings were those of gross proximal tubular damage, granular cyst formation, and mild interstitial inflammation. Falls in creatinine clearance occurred in an additional live patients necessitating treatment delay, although these were reversible. Most patients receiving zeniplatin sustained renal tubular damage, evident by rises in urinary N-acetyl-@glucosaminidase (3.2-fold) and leucine aminopeptidase (2. l-fold) activities 24 h after zeniplatin treatment [ 1861. Reversible renal toxicity was also reported at this dose level in other studies (in three patients in one study [ 1871 and in one patient in another study [ 1881). Enloplatin also entered phase I clinical trial in Belgium. The drug was given intravenously over 60-90 min every 21 days without pre-hydration or prophylactic antiemetics to 47 patients with refractory malignancies [ 1911. The starting dose was 83 mg/m*, and grade 2-3 neutropenia and leucopenia was encountered at 1023 mg/m*. As with zeniplatin, nephrotoxicity (evident from a reduction in creatinine clearance), was recorded at 1227 and 1500 mg/m*. Emesis was also noted. The recommended phase II dosage was 1023 mg/m*. To date, no reports of phase II studies have appeared. 3.3.2. D WA2114R DWA2 ll4R [(-)-(R)-2-aminomethyl-pyrrolidine( l,lcyclobutane-dicarboxylato) platinum(I1) monohydrate represents another more water soluble analogue of cisplatin. Preclinically, the drug exhibited similar antitumor efficacy to cisplatin and carboplatin against a variety of murine tumors (except the Lewis lung where

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it was less active) [192, for a review]. In common with carboplatin, DWA2114R was less nephrotoxic than cisplatin in rodents. Interestingly, the enantiomeric isomer of DWA2114R (DWA2114S) was nephrotoxic in mice [193]. In vitro data, using K562 human leukemia cells, showed that the cytotoxic effects of DWA2114R were more dependent on exposure time than for cisplatin [194]. Clinical trials of DWA2114R have been performed in Japan. The MTD for single i.v. dose of DWA2114R (q 3-4 weeks) in patients with solid tumors was 800 and myelosuppression (predominantly mg/m*, leucopenia) was dose-limiting 1192, for a review]. In contrast, the MTD for DWA2114R given as a 4-5-day continuous iv. infusion in patients with hematological malignancies was 1200 mg/m*/day. Interestingly, gastrointestinal toxicity is dose-limiting with this schedule 11951. Phase II studies have revealed a 44% response rate (complete plus partial) in ovarian cancer (34 patients) and around a 15-20% response rate in breast, prostate and lung cancers [ 1921.A phase III study versus cisplatin has been initiated in ovarian cancer [196]. 3.3.3. 254-S (NSC 3751010) The Shionogi Pharmaceutical Company (in Japan) have developed a highly water soluble platinum complex with very close structural similarities to carboplatin [diammine(glycolato-o,o’)platinum(II) (254-S)]. Although one might predict that, following intracellular aquation, 254-S forms DNA adducts identical to those produced by cisplatin and carboplatin, 254-S has been reported as possessing superior activity to cisplatin in murine tumor models (P388, L1210, B16 melanoma, colon 26) [ 192, for a review]. In common with carboplatin, 254-S was less nephrotoxic than cisplatin in experimental systems. In phase I trials of 254-S, the drug has been administered either as a single bolus or using a 5-day continuous i.v. infusion [ 192,197]. Dose-limiting toxicities were thrombocytopenia for the single bolus schedule (recommended phase II dose of 100 mg/m* q 4 weeks). With the continuous infusion schedule, thrombocytopenia and leucopenia were dose limiting with nadir counts delayed to between 4-5 weeks after the initiation of drug infusion (recommended phase II dose was interestingly lower than that for bolus administration: 75 mg/m*i120 h q 6 wk)[197]. Non-hematological toxicity was insignificant. To date, the only phase II studies to have been reported in full (both 100 mg/m* q 4 weeks single dose schedule) are in non-small cell lung cancer when the objective response rate was 14% (95% C.I., 7-25%) (a response rate comparable to that obtained for single agent cisplatin in this disease) [198] and in patients with genitourinary cancers where objective response rates were 28.6% (95% C.I., 14.6-46.3%) for transitional-cell

carcinoma of the urinary bladder, 18.8% (95% C.I., 4-45.6%) in prostatic cancer and 80% (95% C.I., 51.9-95.7%) in testicular cancer [199]. In the lung cancer study, three partial responses occurred in patients previously treated with cisplatin whereas, in the genitourinary cancer trial, only one responder was observed among patients who had received prior cisplatin-based chemotherapy [ 1981. In common with the phase I data, myelosuppression was the doselimiting toxicity. One patient, however, showed severe irreversible renal toxicity after the first treatment resulting in fatality. 254-S is currently undergoing extensive phase II evaluation in Japan (in head and neck, breast, cervix and small cell lung cancers) as well as being randomised with vindesine against cisplatin plus vindesine in non-small cell lung cancer. To date, no studies have been conducted outside Japan. 3.3.4. CI-973 (NKl2f) cis- 1,l -Cyclobutanedicarboxylato(2R)-2-methyl1,4butanediamine platinum(I1) (NK-121, CI-973) is a cisplatin analogue in development both in Japan and the United States of America. As for lobaplatin (see below) CI-973 may, in some respects, be regarded as a carboplatin-DACH hybrid platinum complex. Preclinically, as with DACH-platinum complexes, CI-973 exhibited comparable potency to cisplatin and retained activity against cisplatin-resistant murine leukemia (L1210 and P388) cells [200]. Three phase I studies have been reported (one in Japan [201] and two more recently in the United States [202,203]). In Japan, NK121 (CI-973) was administered as a brief (30 min) i.v. infusion once every 3-4 weeks. Leucopenia was the dose-limiting toxicity at the MTD of 360 mg/m* q 3-4 weeks [201]. The white cell count nadir occurred approximately two weeks following treatment with recovery to normal limits by 3 weeks. Interestingly, thrombocytopenia was only slight and emesis was the only notable non-hematological toxicity. A study from the M.D. Anderson Cancer Center (Houston) using this schedule reported similar findings [202]. Again, (and contrasting with carboplatin) the absence of thrombocytopenia at doses that reliably caused granulocytopenia was noted. The recommended phase II dose was somewhat lower than that proposed in the Japanese study at 230 mg/m2. Investigators from the Fox Chase Cancer Centre (Philadelphia) using a daily x 5 i.v schedule again found the dose-limiting toxicity to be neutropenia, while thrombocytopenia and nonhematological toxicities were mild [203]. The MTD was 40-50 mg/m*/dx5 and the recommended phase II dose was 30 mg/m2/dx5 repeated every 28 days. No tumor responses were noted in any of these phase I trials. 3.3.5. Lobaplatin (019466) In some regards, lobaplatin

(1,2-diaminomethyl-

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cyclobutane-platinum(II)-lactate, 019466) like CI-973 represents a carboplatin-DACH-like hybrid complex. Little preclinical data on lobaplatin has been published. However, in one study, using two human tumor cell lines with acquired resistance to cisplatin, lobaplatin behaved similarly to tetraplatin, exhibiting crossresistance in GLCdCDDP (small cell lung) but no cross-resistance in Tera-CP (embryonal carcinoma) [82]. Again, as with tetraplatin, lobaplatin retained activity against a murine P388 leukemia cell line with acquired resistance to cisplatin [204]. In vivo, using human tumor xenograft models, lobaplatin was more active than cisplatin in 3 tumors and equally active in 3 others [204]. Three phase I trials of lobaplatin have been initiated. In Germany, lobaplatin was administered intravenously according to a single dose schedule every 4 weeks to 24 patients. Thrombocytopenia was the dose-limiting toxicity; the MTD was 60 mg/m2 [204]. A partial remission was noted in a patient with an adenocarcinoma of the lung. In the Netherlands, lobaplatin was administered either as an intravenous bolus daily for 5 days from total weekly doses of 20-100 mg/m2 (to a total of 27 patients) [205] or by a 72-h continuous infusion from total 72-h doses of 30 to 60 mg/m2 (to a total of 11 patients) [206]. Thrombocytopenia was dose-limiting; as with carboplatin, its degree appeared to be related to both dose and renal function (creatinine clearance). No nephrotoxicity was noted, nausea and vomiting was observed but was generally WHO grade II. Notably three responses (two partial and one complete) were obtained, all in patients presenting with ovarian cancer. Recommended phase II doses were dependant upon renal function; from 30 mg/m2-70 mg/m2 for the daily x 5 schedule and 45 mg/m2 for the 72 h continuous infusion schedule. In view of the promising attributes of lobaplatin observed in phase I studies, the results of phase II trials are awaited with interest. 3.3.6. Cycloplatam Cycloplatam S(-)malatoamine(cyclopentylamine) platinum(I1) has been developed in Russia. Little of the preclinical findings have been published; the drug appears to be more effective than cisplatin or carboplatin in at least some animal tumor models [207]. Cycloplatam is currently undergoing phase I clinical evaluation in Moscow. Our own studies with cycloplatam (conducted under the auspices of the European Organisation for the Research and Treatment of Cancer (EORTC) new drug development office) have shown it to confer similar in vitro cytotoxicity to cisplatin. Using six paired human tumor cell lines (parent and subline with derived resistance to cisplatin) cycloplatam showed non cross-resistance in one and partial to full crossresistance in the remainder. In vivo, using the CHl and CHlcisR pair of ovarian xenografts, cycloplatam was less active than cisplatin against the parent line and

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showed shared cross-resistance with cisplatin against the CHlcisR tumor. 3.3.7. Summary In addition to the two DACH platinum complexes, the remaining seven platinum complexes currently in clinical trial are essentially carboplatin-like; indeed four possess identical leaving groups while 254-S, lobaplatin and cycloplatam possess similar leaving group chemistry. Surprisingly (in view of the extensive clinical data with carboplatin) nephrotoxicity has been observed with at least two of these complexes (zeniplatin and enloplatin). In addition, one case of severe renal toxicity has been observed with 254-S. This increase in nephrotoxicity over carboplatin suggests a limited future role for these complexes. Some indications of tumor response have been observed in the phase I trials with lobaplatin; further trials in patients refractory to treatment with cisplatin/carboplatin will determine the true utility of this compound. Presently, over 20 years since the introduction of cisplatin and over 10 years since the introduction of carboplatin, there is some doubt as to whether any of the 9 platinum complexes described above will confer a significant contribution to either circumventing clinical resistance to cisplatin or improving upon the advantages in terms of reduced patient morbidity currently offered by carboplatin. Clearly, there is an unquestionable need to continue the search for novel platinum-based platinum drugs capable of circumventing clinical resistance to cisplatin and carboplatin. 4. Future approaches 4.1. Ammine/amine platinum (IV)

dicarboxylates

The evaluation cascade established as part of a collaborative programme between the Johnson Matthey Technology Centre, Bristol Myers Squibb and the Section of Drug Development at the Institute of Cancer Research to discover novel platinum-based drugs possessing activity in cisplatin-resistant disease was described in section 2.1. To date, the most exciting class of compounds to emerge from this venture are the ammine/amine platinum (IV) dicarboxylates [general formula c,t,c- ( PtC12(0CORi)2NH3 (RNH2) I] which demonstrate promising in vitro cytotoxic effects against human tumor cells exhibiting resistance to cisplatin [208-2091 and are active in vivo by the oral route of administration [210,211]. Both cisplatin and carboplatin (see Fig. 1) possess symmetrical diammine ligands. Moreover, the two drugs have been shown to ultimately form the same spectrum of adducts on DNA [34]. Our synthetic chemistry program has centered on novel asymmetric ammine/amine (or ‘mixed amine’) platinum complexes which may bind to alternative regions of DNA or in a different spatial

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orientation than cisplatin/carboplatin. Consequently, the adducts induced by such complexes, may be recognised to differing extents by damage recognition proteins or by alternative proteins. Furthermore, the mixed amines often provide optimal physicochemical properties (primarily improved aqueous solubility) compared to corresponding bis-substituted complexes. Our initial in vitro cytotoxicity studies showed that a number of platinum(I1) and platinum(IV) mixed amine complexes (particularly those containing an alicyclic amine ligand) exhibited promising cytotoxicity profiles against our panel of human ovarian carcinoma cell lines [212] and showed non-cross resistance to L1210 leukemia sublines with acquired resistance to both cisplatin and tetraplatin [213]. Our concurrent objective to develop a platinum complex capable of oral administration led to the synthesis of a novel class of complex possessing lipophilic axial ligands; the ammine/amine platinum (IV) dicarboxylates [208-21 I]. Indeed, we have subsequently shown that this class of platinum complex does circumvent the poor oral absorption properties of cisplatin and carboplatin [210,211]. One such complex, bis-acetate-amminedichloro(cyclohexylamine) platinum(IV) (JM216) (see below) has been selected for phase I clinical trial as an orally administrable platinum drug. Investigations of structure-activity relationships with these complexes revealed that the nature of the amine (R ligand) and particularly the axial (Rl substituent) markedly influenced cytotoxicity [209]. The effect of increasing the alkyl chain length of the Rl group on cytotoxicity to two human ovarian carcinoma cell lines; the relatively cisplatin-resistant HX/62 and the intrinsically cisplatin sensitive 41M line revealed two important points. Firstly, as the number of axial carbons is increased above 4 (diacetate) there is a dramatic stepwise increase in cytotoxicity. Secondly, when compared to cisplatin the increase in cytotoxicity is selectively greater for the intrinsically resistant HX/62 line. For example, JM274 (10 axial carbons) is 105 times more potent (in terms of ICsO values) than cisplatin to the HX/62 line but only 16 times more potent to 41M. As platinum analogues to date have been hard pressed to match the potency of cisplatin itself, these highly cytotoxic dicarboxylates signify the enormous sensitivity tumor cells have to platinum if it can be delivered to critical cellular targets. The effect of varying the amine (R) ligand for a series of dibutyrato complexes revealed a similar pattern of response across six human ovarian carcinoma cell lines [209]. Although changes in cytotoxicity were not as pronounced as altering the length of the axial (Rl) groups, complexes possessing an alicyclic group (particularly cyclohexyl or cycloheptyl) were most cytotoxic. For example, JM271 (R = cycloheptyl) is 57 times more potent (in terms of IC,, values) than the corresponding diammine complex (JM323).

209

These cytotoxicity data indicate that the mixed amine platinum (IV) dicarboxylates are of exceptional interest as leads to the discovery of improved platinum-based anticancer drugs. Two of the most studied complexes have been JM221; ammine dibutyratodichloro (cyclohexylamine) platinum(IV) and JM244; ammine dibenzoatodichloro(propylamine) platinum(IV). In vitro studies using the intrinsically cisplatin-resistant SKOV-3 human ovarian carcinoma cell line and the sensitive 41M ovarian carcinoma cell line (9-fold difference in ICsO values to cisplatin but only 2.7-fold difference to JM221) indicate that the mechanism of circumvention of intrinsic cisplatin resistance by JM221 involves enhanced drug accumulation and DNA platination as well as impaired removal of DNA-bound platinum [214]. Using two pairs of human ovarian carcinoma cell lines with acquired resistance to cisplatin (4 1McisR and CHlcisR), JM221 and JM244 have been shown to completely circumvent resistance in 41McisR (where resistance is primarily due to reduced platinum influx) but not in CHlcisR (where resistance is mediated at the level of DNA) [21,72]. Therefore, we believe that both the dramatic potency of these agents and their circumvention of acquired cisplatin resistance (in 41McisR) are largely attributable to enhanced intracellular uptake compared to cisplatin. This hypothesis is supported by the platinum accumulation curves for the 41M pair of lines after exposure to cisplatin or JM221 or JM244 [21,72]. These results are the first to imply that the reduced platinum influx observed in many cell lines with acquired cisplatin resistance (see Table 1) may not be common to all platinum complexes per se but, importantly, signify the existence of platinum drug structureactivity requirements for the circumvention of acquired cisplatin resistance due to reduced uptake.

4.1.1. Bis-acetate-ammine-dichloro-cyclohexylamine platinum (IV) JA4216; an orally active platinum drug While the majority of current platinum drug discovery initiatives are rightly focusing on the circumvention of cisplatin/carboplatin resistance, the success of carboplatin is testimony to the importance of considering patient morbidity in the treatment of cancer. A further means by which compliance might be improved is through the availability of an orally active platinum drug. This could represent a clinical advantage with regard to ease of administration, allow the possibility of treatment on an outpatient basis (with a concomitant reduction in hospitalization costs) and more easily permit detailed studies of the effect of drug scheduling to be performed. Bis-acetate-ammine-dichloro-cyclohexylamine platinum(IV) (JM216) (see Fig. 4) has recently entered clinical trial at the Royal Marsden Hospital (Sutton) as an orally administrable platinum drug.

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4.1.2. Preclinical toxicology

Studies in rodents have shown that JM216 possesses toxicological properties in rodents which are similar to carboplatin rather than cisplatin [215,216]. JM216 administered orally at its maximum tolerated dose of 200 mg/kg exhibited no damage to the kidneys as measured by 14C insulin clearance [215]. In rodents, the dose limiting toxicity is myelosuppression; gastrointestinal effects were less than those observed in comparative experiments with cisplatin and carboplatin and no hepatotoxicity was evident [216]. The evaluation of emetic potential using ferrets revealed that JM216 (given by oral gavage) produced emesis of similar severity to carboplatin and was substantially less emetic than cisplatin (administered intravenously) (S. Morgan, pers. commun.). Parenthetically, platinum(IV) dicarboxylates possessing longer axial ligands (including JM221 and JM244) were generally more emetic than JM216 and carboplatin [2 lo]. 4.1.3. In vivo antitumor activity Studies using the murine ADJ/PC6 plasmacytoma (a model used previously in our studies to identify the antitumor properties of carboplatin 171)showed that cisplatin, carboplatin and tetraplatin were less toxic but also showed markedly less antitumor efficacy after oral compared to intraperitoneal administration [217]. With JM216, however, while toxicity was reduced ten-fold upon oral administration, EDg0 values (the dose required to reduce tumor mass by 90%) were similar for both routes of administration. Hence, upon oral gavage, the therapeutic index (toxic dose/ED% dose) for JM216 is substantially higher than that obtained following intraperitoneal administration, whereas, for cisplatin, carboplatin and tetraplatin the converse occurs. Across four human ovarian carcinoma xenografts of widely differing sensitivity to cisplatin (SKOV-3, PXN/l09T/C, OVCAR-3 and HX/llO) JM216 exhibited oral activity, broadly comparable to intravenouslyadministered cisplatin or carboplatin but markedly superior to intraperitoneally-administered tetraplatin [217]. For example, with the PXN/l09T/C tumor, growth delays (the difference in time required for control and treated tumors to double in volume) for maximum tolerated doses, q7dx4 schedule, were as follows: cisplatin 35.6 days, carboplatin 42 days, tetraplatin 5 days and JM216 44.7 days [217]. 4.1.4. Circumvention of transport-determined resistance to cisplatin by Jh4216

Preclinically, JM216 shows similar in vitro cytotoxicity to cisplatin; mean ICsOacross seven human ovarian carcinoma cell lines of 3.5 PM for cisplatin and 1.7 FM for JM216 [217]. Moreover, as alluded to above, studies indicate that JM216 provides a structural lead to platinum complexes which may circumvent transport-

m

cisplatin

q carboplatin 0

tetraplatin

q JM216

0

4tM

CHl

A2780

CELL

OV

GCT

HX

CAR-3

27

I155

LINE

L1210

PAIR

Fig. 5. Cross-resistance profiles to cisplatin, carboplatin, tetraplatin or JM216 for various human and murine cell lines with acquired resistance to cisplatin: 41M/41McisR, CHlKHlcisR, A2780/A2780cisR, OVCAR-YOVCAR-3cisR all human ovarian carcinoma; GCT27/ GCT27cisR testicular teratoma; HXlSYHX155cisR cervical carcinoma and L12lO/L1210cisR murine leukemia. Redrawn from refs 217,218.

determined resistance to cisplatin [72,95,2 171. The ability of JM216 (compared to carboplatin and tetraplatin) to circumvent acquired cisplatin resistance in a series of murine (L1210) and human tumor lines is shown in Fig. 5 (from references 217 and 218). Interestingly, JM216 shows non cross-resistance (i.e., resistance factor of less than 1.5) in four lines (41McisR, OVCAR-3cisR, HX/lSScisR and L12lOcisR) whereas tetraplatin (which entered clinical trial on the basis of exhibiting non crossresistance to L1210 lines with acquired resistance to cisplatin) showed non cross-resistance in the murine L12 10 pair but partial to full cross resistance in all six human pairs. In addition, studies using L1210 lines with derived resistance to carboplatin and tetraplatin indicate that JM216 is unique among cisplatin, carboplatin, tetraplatin and JM216, in retaining activity against all three L1210 sublines with acquired platinum resistance [218]. The most notable difference between JM216 and tetraplatin occurred with the cervical carcinoma HX/l55 and HX/155cisR lines. We have investigated whether the respective levels of intracellular platinum uptake following exposure of HX/155 and HX/155cisR to tetraplatin and JM216 are responsible for the circumvention of resistance by JM216 and the complete cross resistance to tetraplatin. Fig. 6 (summarized from references 72 and 95) shows the result from such an experiment where the two cell lines were exposed to 25 micromolar of cisplatin, tetraplatin or JM216 for 2 h. Two major conclusions may be drawn. Firstly, there is significantly (P < 0.01) less platinum uptake in the resistant versus parent line

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r q HX155cisR

1.25

JM216

CISPLATIN

PLATINUM + P = < 0.01

cf parent

TETRAPLATIN

DRUG

line

Fig. 6. intracellular accumulation of pladnum in the 41M, 41McisR. HX/155 and HX/lSScisR human tumor cell lines immediately following a 2-h exposure to 25 pM of either cisplatin, JM216 or tetraplatin. Redrawn from refs 72 and 95.

following exposure to cisplatin and tetraplatin. Secondly, the intracellular platinum levels obtained after exposure to JM216 are considerably higher than those obtained for cisplatin or tetraplatin for both cell lines. Moreover, with JM216, there is no significant difference in levels between the two lines. Thus, the circumvention of resistance in HX/155cisR does appear to correlate with enhanced platinum uptake. Moreover, reduced transport has been shown to be the major cause of resistance in the murine L12lOcisR line [159-1601 and in 41 McisR [21,72], two other lines where non-cross resistance to JM216 was observed. Notably, in two of the other cell line pairs (GCT27/GCT27cisR and CHl/CHlcisR) where JM216 was unable to completely circumvent acquired cisplatin resistance, mechanistic studies have shown that enhanced DNA repair and not reduced transport is the major cause of resistance [2 1,96,103]. JM216 entered clinical trial in August 1992 given as single oral doses ranging from 60-200 mg/m’ repeated every 21 days [219]. Platinum levels in plasma and plasma ultrafiltrate indicate that the drug is well absorbed; 24 h urinary platinum accounted for 8.4% of the dose at 60 mg/m2. Vomiting (of variable severity) and grade 1 thrombocytopenia have been observed to date, 4.2. Bis-platinum complexes and trans platinum complexes

The strategy of designing platinum drugs to produce a differing spectrum of adducts on DNA from cispla-

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tinicarboplatin has also been exploited by Farrell and co-workers who have synthesized a series of novel neutral bis(platinum) complexes where two cis-diammine (Pt) groups are linked by an alkyldiamine of variable length [220-2231 and, of great interest, compounds where the activation of the trans geometry has been achieved through the presence of bulky planar ligands (e.g., pyridine or thiazole) [224-2251. Studies of DNA interactions with bis(platinum) complexes (of general formula ( [cis-PtC12(NH3)2] 2H2N(CH2)nNH2 1, which are potentially tetrafunctional, show that, under some conditions, interstrand crosslinks are 250-fold more frequent among bis(platinum) adducts than among cisplatin-derived adducts and that their base sequence specificity for binding is not identical to that of cisplatin [222]. Preclinical antitumor studies have shown that these bis(platinum) complexes (particularly where n = 4) retained at least partial activity against murie L 1210 leukemia lines with derived resistance to either cisplatin or tetraplatin and a different spectrum of activity compared to cisplatin against human tumor cell lines [223]. The trans platinum complexes evaluated to date (e.g. trans-[PtC12(pyridine)2]) exhibit in vitro cytotoxicities comparable to cisplatin and dramatically more so than trans-[PtC12(NH3),] against our human ovarian carcinoma cell line panel (see above). Moreover, they exhibit non-cross-resistance to the 41M and CHl (and murine L1210) cell lines with acquired resistance to cisplatin and give a different pattern of cytotoxicity compared to cisplatin [225]. Mechanistic studies have shown that cellular uptake is enhanced for pyridine relative to ammine complexes and that the trans pyridine complexes inhibit DNA synthesis [225]. Further structureactivity refinement of this exciting novel series of platinum complex (which by definition must act by a different molecular mechanism to that of cisplatin) is required however, as the above ‘parent’ complexes show a disappointing level of activity in vivo [224]. More recently, another series of trans platinum complexes possessing imino ether substituents (general formula [PtC12(imino ether)d) have been shown to confer higher in vitro activity than corresponding cis isomers and, notably, significant activity in vivo in mice bearing the murine P388 leukemia [226]. 4.3. Additional synthetic approaches Other novel platinum chemistry approaches include the synthesis of a series of cationic trisubstituted platinum(II) complexes containing three nitrogen donors (e.g.cis-[Pt(NH&(4-Br-pyridine) Cl]+) whose cytotoxicity most probably arises from the formation of monofunctional adducts on DNA [227]. Although the 4-bromopyridine complex conferred some activity in vivo against the S 180a sarcoma ascites and L 1210 leukemia [228] it was markedly less cytotoxic than cisplatin

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to our human ovarian carcinoma cell line panel and was inactive in vivo against the cisplatin-sensitive ADJ/PC6 murine plasmacytoma. Platinum (II) complexes with the potential to target breast cancers (which generally respond poorly to cisplatin) have been prepared with a binding affinity for the estrogen receptor (using 5-hydroxy-2-[4hydroxyphenyllindole as a receptor binding fragment) [229-2301. Two platinum-linked phosphonic acids have recently been shown to confer promising antitumor activity against rat osteosarcoma and autochthonous rat colorectal cancer in vivo [231]. There have been recent attempts to link cis-PtC& complexes to anthraquinone intercalators [232]; some complexes within these series show comparable in vitro cytotoxicity and in vivo activity to cisplatin against murine P388 leukemia. Antitumor activity against P388 leukemia in mice has also been demonstrated for some ‘non-traditional’ platinum(I1) organoamides (general formula [Pt (NRCH&L2] where R = polyfluorophenyl; L = pyridine or substituted pyridine) which do not have an hydrogen substituent on any nitrogen donor atom [233]. All of these novel approaches are at an early stage of development. Future synthetic initiatives to discover additional platinum-based agents which bind to differing regions of DNA compared to cisplatin or carboplatin are progressing. This strategy may be assisted by recently developed methodologies based on Taq DNA polymerase which allow the measurement of sequence specificity of covalent DNA modification by anticancer drugs, including platinum-based [234-2351.

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strategies aimed at the circumvention of intrinsic and acquired tumor resistance to cisplatin. Approaches to circumvent resistance will probably involve not only the rational development of a new generation of platinumbased drugs (e.g., compounds designed to overcome reduced cisplatin accumulation or enhanced removal of cisplatin-induced DNA adducts) but also non-platinum drugs which are capable of modulating resistance (e.g., modulators of signal transduction pathways, ras and myc oncogene expression and glutathione biosynthesis). One may look forward with a great deal of optimism that these promising new approaches will result in clinical benefit by the end of the century. Nevertheless, cisplatin and carboplatin remain the standard anticancer drugs to which novel platinum-based complexes must be compared. 6. Acknowledgements Studies described from the Drug Development Section of the Institute of Cancer Research were supported by grants from the UK Cancer Research Campaign, the Medical Research Council, the Johnson Matthey Technology Centre (JMTC) and Bristol Myers Squibb Oncology. Thanks are due to my colleagues Professor Ken Harrap, Drs Mark McKeage, Prakash Mistry, Sarah Morgan and Rosanne Orr, and Mervyn Jones, Phyllis Goddard, George Abel, Melanie Valenti, Frances Boxall, Swee Loh, Ciaran O’Neill, Kirste Mellish and Dr Barry Murrer (JMTC). 7. Biography

5. Summary Over the past two decades, platinum-based drugs (cisplatin and, latterly, the less toxic analogue carboplatin) have conferred significant therapeutic benefit to a large number of cancer sufferers. However, there remains scope for substantial improvement in the clinical utility of metal coordination complexes through the discovery of additional platinum-based complexes (or possibly alternative metals). Future drug discovery strategies should focus on tumor resistance and its circumvention. To date, only one series of compounds, those containing a 1,2-diaminocyclohexane carrier ligand (e.g., oxaliplatin, tetraplatin), has entered clinical trial based on their circumvention of acquired cisplatin resistance in some (mainly murine) preclinical tumor models. At present these agents are in early clinical trial and thus their true clinical utility in cisplatin/carboplatin refractory disease is not yet determinable (and may not be due to dose-limiting neurotoxicity). Over the past few years, our understanding of mechanisms of resistance to cisplatin and its interaction with DNA has vastly increased. This new information will undoubtedly guide the development of new

Lloyd R. Kelland obtained a B.Pharm. at the University of Bath, UK in 1979, completed pharmaceutical hospital training (M.R.PharmS) in 1980 and obtained his Ph.D in 1984 at the University of Bath in Pharmaceutical Microbiology. Dr Kelland had a Postdoctoral Fellowship at the Radiotherapy Research Unit, The Institute of Cancer Research, Sutton, Surrey, U.K. From 1988 up to present he is the Team Leader of Drug Evaluation, Section of Drug Development, The Institute of Cancer Research, Sutton, Surrey, UK

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