Preclinical studies identifying carboplatin as a viable cisplatin alternative

Cancer Treaeatment Reviews

Preclinical cisplatin

( 1985)

12 (Su@ment

studies alternative

A), 2 1 -33

identifying

carboplatin

as a viable

K. R. Harrap Department

of Biochemical

Pharmacology,

Institute of Cancer Research, Sutton, Surrey, U.K.

The claims ofeight cisplatin analogues as viable alternatives to the parent drug are discussed in terms of their toxicities, antitumour properties and potential biochemical selectivities. It is concluded that, of the eight, diammine( I,l-cyclobutane dicarboxylato)platinum(II) (carboplatin, CBDCA, JM8) had the features most desirable to merit its clinical evaluation.

Background Clinical

activity and toxicities of cisplatin

The powerful antitumour properties of cisplatin (cis-diamminedichloro platinum II, cis[PtCl,(NH,),], whose chemical identity was established in 1845, were first discovered by Rosenberg et al. in 1969. These and subsequent developments heralded the first clinical trials ofcisplatin under NC1 sponsorship in 1972. The background to these events has been documented elegantly by Rosenberg and further reiteration in the present setting would be inappropriate ( 1). It soon became apparent that cisplatin was to prove a powerful addition to the clinical oncologist’s armamentarium ofdrugs. Substantial successes were achieved in the treatment of testicular and ovarian cancers, both with cisplatin alone and in combination with other drugs (2-18). Notably cisplatin proved to be active against ovarian cancer which had become refractory to treatment with alkylating agents (19). Activity for cisplatin, alone and in combination, has also been shown in the treatment of bladder and head and neck cancers (20-25). Further, this drug has been an effective component in regimes used for the treatment of various childhood malignancies, endometrial cancer, neuroblastoma, osteogenic sarcoma, melanoma, breast cancer, hepatoma and thyroid cancer (reviewed in 26-28). However, the antitumour benefits ofcisplatin have been exacted in the face ofsubstantial toxic side effects. Predominantly .these include nephrotoxicity, gastrointestinal toxicity, neurotoxicity and myelosuppression. Of these there is a general consensus that kidney toxicity is dose limiting, consistent with a persistent and irreversible decrease in glomerular 0305-7372/85/12A0021+

13$03.00/O

0 21

1985 Academic

Press Inc.

(London)

Limited

K.

22

R. HARRAP

filtration rate, in treatment courses which are considered optimal to confer antitumour benefit. These events have been documented by several authors, notably Randolph et al. (29)) Gonzalez-Vitale et al. (30)) Dentin0 et al. (3 1) and Jacobs et al. (32) and reviewed by Prestayko et al. (27). Various manoeuvres, notably intravenous hydration (plus or minus furoseminole) have been adopted to lessen the incidence of cisplatin nephrotoxicity and to permit the administration of higher doses (22, 26, 27, 30, 33-35). Despite these efforts, however, nephrotoxicity has remained dose-limiting for cisplatin administration (34, 36). Nausea and vomiting, together with associated anorexia appear to be inevitable accompaniments to the administration of cisplatin. On occasion these may be sufficiently severe to restrict patient compliance with treatment. There is some evidence that antiemetics such as nabilone, metaclopromide and prochlorperazine may to some limited extent help to ameliorate these distressing side effects (27, 35, 37, 38). The neurotoxic limitations of cisplatin therapy encompass tinnitis and loss of high frequency hearing acuity, together with the appearance of peripheral neuropathies. These toxicities appear not to respond to hydration and diuresis (27, 38). A substantial incidence of cisplatin-induced myelosuppression has been reported in several phase I and phase II studies. Whilst hydration and diuresis were ofuse in restricting nephrotoxicity, the myelosuppressive consequences of cisplatin treatment were not ameliorated by this manoeuvre, as proved to be the case also with the neurological side effects of the drug (27, 35, 37, 38). Hence, by the mid to late 1970s the requirement for a more selective and primarily less nephrotoxic analogue of cisplatin had been established unequivocally (34, 36). This side effect became focal in most subsequent analogue developments, which sought to identify a derivative which retained the useful antitumour properties of the parent drug but which was, so far as possible, devoid of its major toxic limitations. Structure-activity

relationships

Complexes of the general structure PtX,A, have been widely studied, where X, = two monodentate or one bidentate anionic ligand(s) and A, = two monodentate or one bidentate amine ligand(s). Antitumour activity required neutral complexes with the A and X groups in the cis-configuration. In general the A groups contained ammine or substituted amine functions, the nitrogen-platinum bond being particularly stable. On the other hand, the X groups have included functions of varying reactivity as leaving groups (for example, halogen, NO;, -SO,, carboxylate, etc.). The broad strategy adopted in most of these structure-activity investigations was to observe the effects on antitumour activity of systematic changes in the ‘A’ and ‘X’ groups in an attempt to discover more potent and more selective analogues of cisplatin. An important early observation was the relationship between leaving group reactivity and biological activity: thus complexes containing highly reactive groups such as NO; and H,O were toxic, while complexes containing strongly bound ligands such as SCN- and NO; were inert. Antitumour activity appeared to be associated with ligands possessing intermediate stability such as Cl- or Br- (39). However this generalization appeared not to hold for a series of complexes containing the malonate ligand (40). Such compounds can exhibit activity comparable or superior to that of cisplatin, yet the malonate ligand is particularly stable. It may be that these agents require metabolic activation in order to exhibit pharmacologic activity. It would be inappropriate to dwell extensively on the general backcloth of developments in the cisplatin analogue field. Suffice it to say that many complexes have now been

PRECLINICAL

STUDIES

IDENTIFYING

23

CARBOPLATIN

discovered which possess antitumour activity comparable or superior to that of cisplatin. These developments have been reviewed elsewhere (41) and the reader is referred to this source for further detail. The purpose of this presentation is to review the preclinical studies at the Institute of Cancer Research (ICR) which highlighted diammine( I,l-cyclobutane dicarboxylato)platinum (II) (carboplatin, CBDCA, JM8*) as a promising candidate for phase I evaluation. In major substance this work has already been reported elsewhere (42,43). The reader is referred to these sources for full details of the experimentation reviewed herein.

The Background

search

for

an alternative

to cisplatin

at ICR

and basis for compound selection

Since the early 1970s more than 300 platinum complexes have been examined at ICR for their potential antitumour properties in rodent models. Approximately 40 active moieties have been identified. In view of the severe toxic limitations inherent in the clinical use of cisplatin (see above) we set out, in 1978, to explore the possibility that we might find amongst our active platinum complexes one or more examples which could be candidates for clinical study (42). Accordingly we selected 8 of the 40 active complexes for more detailed preclinical evaluation. In addition to the requirement for potent antitumour activity, several other considerations guided our selection. One of these was solubility: there had been considerable speculation that the nephrotoxic properties of cisplatin might relate to its relatively low aqueous solubility. Accordingly we selected examples which were both less (JM2, JM5, JMI 1) and more (JM8, JM9, JMIO, JM16, JM20) water soluble than cisplatin. Another important consideration was the reactivity of the leaving groups, particularly in view of the generalisations by Cleare and colleagues referred to above (39, 40). The chloride ligands in cisplatin are active leaving groups and the chemical reactivity of the drug might underlie, not only its antitumour properties, but also its nephrotoxicity. Thus we selected several compounds with substantially more stable leaving groups than cisplatin (JM5, JM8, JMlO) and others with comparable (JM2, JM11, JM16) or greater (JM20) reactivity. An additional guideline in the inclusion of JM20 was the finding of Burchenal et al. that platinum complexes containing a diaminocyclohexane ligand showed a lack ofcross-resistance to cisplatin when exposed to cisplatin-resistant tumours (44,45). We also included JM9 as an example of a platinum IV complex possessing both good antitumour properties and aqueous solubility. The list of compounds selected is shown in Table 1. Biological

evaluation

The eight putative alternatives to cisplatin were compared with the parent drug in respect of several properties. Toxicity comparisons were made in the Wistar rat following the administration of maximum tolerated doses of each complex. Measurements were made of body weight, blood urea and urinary protein levels. Kidney, ileum, liver and facial nerve were taken for

* For convenience and in acknowledgement ofits system initiated by the Johnson Matthey company

substantial contribution will be used throughout

to this programme, this presentation.

the classification

K.

24

Table

1. List

of platinum

complexes

chosen

R.

for

HARRAP

study Aqueous solubility

JM

No.

structure

HP

Compound

Cl

name

(mM)

cis-diamminedichloro platinum(H); cisplatin

8.9

dichlorobis(isobutylamine) platinum(I1)

0.1

diammine(2-hydroxymalonato) platinum(I1)

6.4

> HJ 2

iBuNH, \pt/C1

iBuNH 5

2’

‘Cl1

HsN

oco ‘Pt’

‘CHOH

H 3N’

9

‘OCO’

iPrNH,

OH

10

2 /ok’Cl

HsN

44.0 Iproplatin

diammine(P-ethylmalonato) platinum(I1)

’CHEt

H 3N’

160.0

‘OCO’

NH dichlorobis(cyclopropylamine) platinum(I1)

\pt/c’

D-

16

cis-dichloro-trans-dihydroxycis-bis(isopropylamine) platinum(W); CHIP,

oco ‘Pt/

11

50.0

Cl

‘P!/ iPrNH

diammine( 1, l-cyclobutanedicarboxylato)platinum(II); CBDCA, carboplatin

NH’

‘Cl

OCOCH,CI

iPrNH, ‘Pt’ iPrNH

1.6

2’

‘OCOCH

dichloroacetatobis(isopropylamine)platinum(II)

16.0

aqua( 1,2-diaminocyclohexane) sulphatoplatinum(I1)

30.0

2Cl

20 NHz\Pt~Hzo NH’ *

Et = ethyl;

‘SO

iPr = isopropyl;

4

iBu = isobutyl.

PRECLINICAL

STUDIES

IDENTIFYING

CARBOPLATIN

25

histopathological examination following treatment. Assays were also made of both peripheral blood and bone marrow haematology. Antitumour activity against the L1210 and ADJ/PCG tumours were important selection criteria, as has already been noted above. In an attempt better to rank the several alternatives for their antitumour properties we measured their activities also against a subline of the Yoshida ascites tumour which had been rendered 50-fold resistant to a spectrum of alkylating agents. In addition we measured the antitumour properties of the chosen complexes against a human epidermoid carcinoma of the bronchus (P246) grown in immune-deprived mice. We also explored the possibility that some of these compounds might exhibit greater biochemical selectivity for tumour, rather than for normal tissues of the rat. The cytotoxic properties of platinum co-ordination complexes appear to relate to DNA-binding (46648)) during which process both inter- and intrastrand cross-links are formed (49955). These reactions are closely reminiscent of those seen with the bifunctional alkylating agents. Working with the latter compounds we have shown that another major biochemical determinant of their cytotoxicity is their ability to bind to nuclear proteins with consequent enhancement of non-histone protein phosphorylation and associated changes in nuclear morphology. These effects correlate with cell kill and are seen only in cells which are sensitive to alkylating agents (56-59). Cisplatin induces similar effects on nuclear proteins (42). Thus, using the Yoshida ascites tumour growing in the rat, we compared the abilities of the chosen platinum derivatives to elevate nuclear protein phosphorylation in tumour, liver and kidney, respectively, as a possible indicator of biochemical selectivity. Results 1. Toxicity studies: (i) Body weight changes following the administration of maximum tolerated doses are shown for representative compounds in Figure 1. Cisplatin induced substantial weight loss (23:&j as did JM20 (16%). The weight loss profiles for JM2, JM5, JM9, JMl 1 were broadly similar to that elicited by JM20, though in these cases nadirs were in the range IO-12% (see Table 2). (ii) Blood urea, urinary protein and body weight changes are summarised in Table 2. It is apparent that in this experiment the maximum tolerated dose for cisplatin was exceeded: 2110 animals died (on days 7, 12) a group weight loss nadir of 23% being recorded on day 8. These events were associated with an 18-fold elevation in the blood urea level on day 5, the presence of urinary protein (day 9) and evidence of severe diarrhoea (days 4-6). In subsequent experiments a dose of 6.5 mg/kg cisplatin (i.v.) has proved to be without lethal consequences in the rat and has produced no more than a six-fold elevation in blood urea level (Z. Siddik, unpublished results). Otherwise the doses reported for the cisplatin analogues in Table 2 are, effectively, maximum tolerated. JM5 enhanced the blood urea level by 64%, while the remaining analogues produced less extensive elevations. Only minor increases were produced in response to JM2, JM8, JMIO. (iii) Huematology. Full details of bone marrow and peripheral blood data are reported by Harrap et al. (43), Peripheral blood was sampled every two days over a 14 day observation period and bone marrow aspirates taken on days 5 and 14. Lymphocyte: neutrophil ratios are plotted in Figure 2 and are for most complexes consistent with the appearance of early lymphopoenia followed by the development of neutropoenia. In some cases, for example JM8, JM 10, JM 11, the early lymphopoenia was not apparent. Anaemia became apparent

26

K.

R. HARRAP

701 ’ 2’ ’ 4’ ’ 6’ ’ 8’ ’ IO’ ’ 12’ I 14’ ’ Time (days) after treatment

Figure 1. Overall various platinum

body weight changes for female Wistar rats following treatment with maximum complexes. Each point represents the mean body weight of ten animals. Mean point $- + 15% (from Harrap et al. (43)).

tolerated doses of scatter about each

in response to most complexes after day 7. These haematological effects are consistent with those seen in response to alkylating agents and ionizing radiation. Thus haematological toxicity seemed to be a relatively consistent feature of the rat toxicology for all the complexes investigated. In general an examination of the bone marrow morphology provided no further help in interpreting the peripheral blood observations and these data will not be reiterated here. (iv) Histopathology. A summary of the major features observed at either of the 5 or 14 day sampling points is reproduced in Table 3. A consistent feature produced by administration of several of these derivatives was a thickening of the liver and kidney capsules which may have been an artefact deriving from the route ofadministration. A striking finding was a 50fold enhancement on day 5 of the number of mitoses seen in the liver in response to JM 10 treatment. Cisplatin treatment produced extensive necrosis of the proximal convoluted tubules of the kidney, while JMl6 induced necrosis of the distal convoluted tubules. Similar, though less pronounced, changes were also seen with JM5. Some erosion of the epithelial lining of the ileum was apparent in response to JM8, JM 10, JM 11, JM 16, JM20. None of the agents investigated produced histological changes in the facial nerve. 2. Antitumour test data: Screening results against the L1210, ADJ/PC6 and Yoshida R tumours are reproduced in Table 4. These data provided no reliable means of ranking the various derivatives. The anti-L1210 effects of all the analogues are broadly comparable to those of cisplatin. With the exception of JMl6 all the derivatives possess therapeutic indices superior to cisplatin against the ADJ/PCG turnout-. Two compounds, JM 10 and JM20, seem to be particularly active against the resistant Yoshida turnout-, though the responses to the remainder are broadly comparable to those obtained with cisplatin. In an attempt to rank more effectively

Saline

80 mg/k

20 w/k

24 mdk

12w/kg

10

11

16

20

Lalxtix”

Saline

48 w/k

9

I by ‘.4mrs

Saline

60 w/k

8

protrin

Saline

120 mg/kg

5

+ +

Saline

Arachis oil (suspn.) Saline (suspn.) Saline

80 mg/kg

2

and

Saline

NO.

Vehicle

protein

8 mg/k

urinary

cisPt

urea,

Dose (day 0, i.p.)

2. Blood

JM

Crinary

Table

+ +

weight

+ + 3 q/l:

(5)

(5) > 20 q/l:

7.Ok3.8

(6)

(“1 7.4+0.4

(1) - 16.4%

- 1.9%

(6)

(5) 8.3+0.8

+ +

+ 1 q/l:

+

+ 0.3 g/l.

1210/,

128%

143%

log:/,

(5) - 1.2% (3) - 12.4%

13496

(14) 6.3+ 1.0

- 10.0%

112%

164y0

112”/”

100% 1890%

(4) 7.8kO.6

(‘4

(1’) 6.5+ 1.2

(4) -0.8%

1.5

(6)

(5) 6.5+ 1.6

5.8kl.O 109.6+ 16.2

9.5+

+

rat

blood urea * SD. (day observed) mmol/litre “/b control

Peak

in the

(4) -9.3%

-9.8%

(8)

-23.2%

+

changes

Maximum depression of body weight (day observed)

body

(From

Harrap

(3)

(234) ++

(3, 6, 8:9:11, +++ (5) +++ (9, 14) +++ (9,1‘+) +++

(I>74

(4) +++

+ ++++ (9) +++

Peak urinary protein (day observed)

etal.

14)

(43)).

(12)

l/lo (6)

o/10

l/l0

o/10

Oil0

o/10 o/10

l/l0 (7) 119 (12)

Deaths (day observed)

(W

severe

9/10

(4-h)

moderate

(5)

5/10 mild

(44)

8/ 10 mild

lo/l0

Diarrhoea (day observed)

28

K.

R. HARRAP

40 30 20

IO ; ;; t 1

3 2

I 8:; 0.5 04 I

I 2

I I I 5 7 9 Tbme after treatment

I 12 (days)

I 14

Figure 2. Mean lymphocyte/neutrophil ratios in female Wistar rats following one single (i.p.) injection of various platinum complexes. Doses were according to the schedule summarized in Table 2. Horizontal lines marked ‘untreated control’ represent the upper and lower limits for the L/N ratio in untreated animals (from Harrap et al. (43)).

the putative utilities of these agents in man, we compared their effects against the P246 human lung tumour in immune-deprived mice. These results are outlined in Table 5. JM8 elicited dose-dependent antitumour activity without associated toxicity. None of the other analogues exhibited selective activity comparable to that of JM8.

3. Nuclear protein phosphorylation: Cisplatin can induce nuclear protein phosphorylation enhancements reminiscent of those seen in response to bifunctional alkylating agents. These events appear to correlate with cell kill (42, 56, 59). Table 6 summarizes the maximum increases observed during a 72-hour period in the phosphorylation of nuclear proteins isolated from tumour, kidney

Table

3. Summary

of histopathology

JM No. cisPt 2 5 8 9 10 11 16 20

Liver capsular capsular

thickening thickening

capsular mitotic capsular capsular capsular

thickening rate O.5o/o thickening thickening thickening

‘pet = proximal convoluted tubule. bdct = distal convoluted tubule. (From Harrap et al. (43)).

in the

rat

Kidney

Ileum

necrosis pcta capsular thickening necrosis dctb capsular thickening

-

necrosis

dctb

erosion erosion erosion erosion erosion

PRECLINICAL Table

4. Antitumour

STUDIES effects

against

Ll2lob*c’d Max y0 T/C Day 1 Days

JM No. cisPt 2 5 8 9 10 11 16 20

164229 171 150 150 171 171 157 179 200-Z 17

IDENTIFYING transplantable

l-9

5. Comparative antitumour dermoid carcinoma (P246)

157-285 193 200 157 207 186 164 207 279300

effects grown

rodent

8.1 13.4 30.6 12.4 12.9 13.6 24.6 1.4 37.1

of platinum in immune

29

tumours

Yoshida R” o/o surviving cells at 72 hr (range)

ADJ/PCSe TI

a 50-fold resistant to a spectrum of alkylating ‘Data of Bristol-Myers and Johnson Matthey ’ Prestayko et al. (1979). d Cleare et al. (1978). e Wilkinson etal. (1978). (From Harrap et al. (43)).

Table

CARBOPLATIN

53.0% 85.4% 40.0% 60.0% 30.0% 6.0% 85.0% 87.0% 5.8%

(4465) (79-91) (3G-50) (4870) (28-31) (4-8) (70.-100) (5&120) (4.5-6.0)

analogues tested deprived mice

against

agents. (1978).

a human

epi-

Toxicity Body

JM No. cisPt 2

11

Dose level h&z)

Total

6 2 24

2 4 2

8 90 30 48 16 48 16 75

1 4 4

25 24

4 1

Duration of test (weeks)

T/C

x 100”

Deaths (week observed)

1.0 12.0 46.0

216 l/6 l/6 l/5

-13 +3 -8

(3) (3) (3) (7)

51.0 104.0 1.0 34.0

weight change in survivors (% Day 0 Body weight)

+2 Severe loss + 10 -1 +3

3;5 O/5 0 416’( 1)

59.0 2.0 7 7

59.0 2.0

-7 +1

l/6’(5) l/5 (7)

+7 -2

W”!l! ‘I5 (2) l/4 (3)

16 20

8 24 8 9 3

74.0 18.0 87.0 2.0 3

6

27.0

*Mean tumour volume as y0 untreated controls at termination days, and the test was completed at the end of the sixth or seventh (From Harrap et al. (43)).

+4

l/k

0 + 10 -6

li& l/5 (6) 0 of test. Animals week.

+3 received

the agents

every

14

30

K.

Table

6. Maximum phorylation liver nuclei”

R.

HARRAP

changes observed in nuclear protein phosin Yoshida tumour, and in rat kidney and

Maximum enhancement of nuclear protein phosphorylation in 72-h (Oh control) JM

No.

cisPt 2 5 8 9 10 11 16 20

15 180 240 160 80 180 60 60 15

Tumour

Kidney

Liver

150 189 71 176 209 157 144 121 400

190 180 93 75 117 104 101 520 233

156 143 175 104 98 370 430 103 121

“Data are the means of duplicate observations experiments. Overall scatter at each point $ f lo”/,. “The complexes were administered S.C. in DMSO. (From Harrap et al. (43)).

and liver following JM5, all exception either in increase

in three

separate

of rats carrying the Yoshida R tumour (50-fold resistant to alkylating agents) treatment with the several analogues under study here. With the exception of the analogues stimulated nuclear protein phosphorylation in the tumour. With the ofJM8 all the platinum complexes enhanced nuclear protein phosphorylation the kidney or in the liver or in both tissues. JM8 was unique in initiating an in tumour phosphorylation without associated increases in either liver or kidney.

Discussion Several of the agents studied in these investigations were shown not to be prohibitively nephrotoxic at therapeutically effective doses. All showed activity comparable or, in some cases, superior, to cisplatin in the treatment of several transplantable rodent tumours. However, when tested against the P246 human bronchogenic carcinoma xenografted into immune-deprived mice, JM8 was clearly more selective than the other analogues. Studies of nuclear protein phosphorylation, an event possibly underlying one of the cytotoxic reactions of alkylating drugs, revealed that JM8 and possibly JM9 may be more biochemically selective than the other analogues tested. In view of these findings JM8 was identified as the ‘lead’ candidate meriting detailed toxicological evaluation and clinical study.

Acknowledgements It is a pleasure to acknowledge the pioneering contributions of Prof. Sir Alexander Haddow and Dr T. A. Connors, who initiated work on the platinum complexes at ICR soon after the discovery of cisplatin. This also provides a timely opportunity to acknowledge a long-

PRECLINICAL

STUDIES

IDENTIFYING

31

CARBOPLATIN

standing collaboration with the Johnson Matthey company who supplied all the complexes investigated herein: in particular, thanks are due to Dr Cleare and Mr Hydes for their constructive advice and help throughout the course of these investigations. This work was supported by grants from the Medical Research Council/Cancer Research Campaign, the Johnson Matthey Research Centre and the Bristol-Myers Company.

References 1. Rosenberg, B. (1978) Platinum complexes for the treatment of cancer. Znterdirc$din. Sci. Reu. 3: 134147. 2. Higby, D. J., Wallace, H. J, Jr., Albert, D. & Holland, J. F. (1974) Diamminodichloroplatinum in the chemotherapy of testicular tumors, 3. (id. 112: 100 -104. 3. Merrin, C. E. (1979) Treatment of genitourinary turnout-s with cis-dichlorodiammineplatinum(II): Experience in 250 patients. 4. Carter, S. K. & Wasserman, 5. Rozencweig,

M.,

Von

Cancer Treat. Rep. 63: 15791584. T. H. (1975) The chemotherapy

Hoff,

D. D.,

Catane,

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of urologic

& Muggia,

F. M.

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Cancer 36: 729747.

Platinum

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chemotherapy. In Schabel, F. M. ed. Antibiotics and Chemotherapy, Volume 23. Basel: 6. Williams, C. (1977) Current dilemmas in the management of non-seminomatous testis. Cancer Treat. Rev. 4: 275 297.

Karger, pp. 999112. germ cell tumors of the

7. Einhorn,

testicular

L. H. & Donahue,

J. P. (1977)

Improved

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3.

Ural.

117: 65-69. 8. Samson, M. K., Baker, L. H., Devos, J. M., Buroker, T. R., Izbicki, R. M. & Vaitkevicius, V. K. (1976) Phase I clinical trial of combined therapy with vinblastine (NSC 49842), bleomycin (NSC 125066), and cisdichlorodiammineplatinum(II) (NSC 119875), Cancer Treat. Rep. 60: 91-97. 9. Einhorn, L. H. (1979) Combination chemotherapy with cis-dichlorodiammineplatinum(II) testicular 10. Samson,

cancer. Cancer Treat. Rep. 63: 1659-1662. M. K., Stephens, R. L., Rivkin, S., Opipari,

Vinblastine, Preliminary 11. Williams, Crooke,

M.,

Maloney,

bleomycin and cis-dichIorodiammineplatinum(II) report of a Southwest Oncology Group study.

in disseminated

T., Groppe, C. W. & Fisher, in disseminated testicular

R. (1979) cancer:

Cancer 7’reat. Rep. 63: 1663-1667.

S. D. & Einhorn, L. H. (1980) Cisplatin chemotherapy of testicular cancer, In Prestayko, A. W., S. T. & Carter, S. K. eds. Cisplatin. Current status and new developments. New York: Academic Press. pp.

323-328. 12. Seeber,

S., Scheulen,

M. E., Schilcher,

R. B., Higi,

M.,

Niederle,

Schmidt, C. G. (1980) In Prestayko, A. W., Crooke, S. T. & Carter, developments. New York: Academic Press. pp. 329-344. 13. Wiltshaw, advanced 14. Bruckner,

E. & Kroner, adenocarcinoma H. W., Cohen,

N., Mouratidou,

D., Bierbaum,

S. K. eds. Cisplatin.

T. (1976) Phase II study of cis-dichlorodiammineplatinum(II) of the ovary. Cancer Treat. Rep. 60: 55-60. C. J., Wallach, R. C., K a b a k ow, B., Deppe, G., Greenspan,

Current (NSC

W. C. &

status and new 119875)

E. M., Gusberg,

in

S. B. &

Holland, J. F. (1978) Treatment ofadvanced ovarian cancer with cis-dichlorodiammineplatinum(II): Poorrisk patients with intensive prior therapy. Cancer Treat. Rep. 62: 555-558. 15. Young, R. C., Von Hoff, D. D., Got-n&y, P., Makuch, R., Cassidy, J., Hawser, D. & Bull, J. M. (1979) Cisdichlorodiammineplatinum(II) for the treatment of advanced ovarian cancer. Cancer Treat. Rep. 63: 1539-1544. 16. Ehrlich, C. E., Einhorn, L. H. & Morgan, with cis-diamminedichloroplatinum(CDDP), Res. 19: 379. 17. Bruckner, H. W., Ratner,

L. H., Cohen,

J. L. (1978) Combination chemotherapy a d rtam y tin (ADR) and cytoxan (CTX). C. J., Wallach,

R., Kabakow,

B., Greenspan,

of ovarian carcinoma Proc. Am. Assoc. Cancer E. M. & Holland,

J. F.

(1978) Combination chemotherapy for ovarian carcinoma with cyclophosphamide, adriamycin and cisdichlorodiamminepIatinum(II) after failure of initial chemotherapy. Cancer Treat. Rep. 62: 1021l1023. 18. Holland, J. F., Bruckner, H. W., Cohen, C. J., WaIIach, R. C., Gusberg, S. B., Greenspan, E. M. & Goldberg, J. (1980) Cisplatin therapy ofovarian cancer. In Prestayko, A. W., Crooke, S. T. & Carter, S. K. eds. Cisplatin. Current status and new deuelopments. New York: Academic Press. pp. 383-392. 19. Wiltshaw, E. & Carr, T. (1974) Cis-platinum(II)d iamminedichloride: Clinical experience of the Royal Marsden Hospital and Institute of Cancer Research. Rec. Res. Cancer Res. 46: 178 182.

32

K.

R. HARRAP

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PRECLINICAL

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The

IDENTIFYING

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CARBOPLATIN

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33

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of Yoshida

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