cisplatin docking dinuclear platinum complex

Biomedicine & Pharmacotherapy 59 (2005) 224–229 http://france.elsevier.com/direct/BIOPHA/

Original article

Preparation of antitumor oxaliplatin/cisplatin docking dinuclear platinum complex Masahede Noji a,*, Ryoichi Kizu b, Yasutaka Takeda c, Nachio Akiyama c, Iwao Yoshizaki c, Masazumi Eriguchi c, Yoshinori Kidani d b

a Suzuka University of Medical Science, 1001-1 Kishioka-cho, Suzuka, Mie 510-0293, Japan Graduate School of Natural Science and Technology, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan c The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan d Emeritus Professor of Nagoya City University, Nagoya, Japan

Received 7 May 2004; accepted 3 June 2004 Available online 10 May 2005

Abstract A new dinuclear docking Pt(II) complex, (cis-diammine) (L-1,2-cyclohexanediamine)(µ-dichloro)-diplatinum(II) oxalate was synthesized by reacting oxaliplatin(L-OHP, [Pt(oxalato)(L-dach)]), L-dach = 1R, 2R-cyclohexanediamine), with cisplatin (CDDP). Elemental analysis of the compound indicated that it was 1:1 molar ratio complex of oxaliplatin and cisplatin. A plausible chemical structure has been proposed as Cl– bridged dinuclear complex, judged from its yellow coloration and NMR spectral analysis. This complex can be denoted as, i.e. [Pt2Cl2(NH3)2(L-dach)](COO)2 (L-OHP/CDDP). The complex showed higher cytotoxicity against L1210 than the parent complexes and low cross-resistance against L1210/CDDP and L1210/DACH. Its antitumor activity was also tested in vivo against murine leukemia L1210 cell lines. The complex showed much higher activity than the mixture(1:1 molar ratio) of oxaliplatin and cisplatin. The antitumor effect against L1210/CDDP was very high, showing collateral sensitivity, being similar to that of oxaliplatin, and against L1210/DACH it showed no cross-resistance. © 2005 Elsevier SAS. All rights reserved. Keywords: Antitumor activity; Dinuclear platinum complex; L-OHP

1. Introduction Antitumor activity of cisplatin, CDDP, was discovered by Rosenberg, et al. [24] in 1969 and it is a widely used antitumor chemotherapeutic agent. However, it shows severe emesis, nephrotoxicity [7], neuro-toxicity, myelosuppression and cross-resistance against cisplatin resistant cell lines. We synthesized [Pt(oxalato)(L-dach)] (L-OHP = oxaliplatin) to ameliorate the nephrotoxicity and reported its superior antitumor activity to cisplatin, without showing crossresistance against L1210/CDDP [17,28]. Mathé et al. [16,17] reported the high antitumor efficacy of oxaliplatin against melanoma, testicular and ovarian cancers, stomach cancer and colorectal carcinoma. Toxicity of oxaliplatin is peripheral sensory neuropathy, being the dose-limiting toxicity [4,17]. * Corresponding author. Fax: +81 0593 83 9666. E-mail address: [email protected] (M. Noji). 0753-3322/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.biopha.2004.06.006

Advantages of oxaliplatin are not showing any nephrotoxicity, cardiotoxicity, mutagenicity and cross-resistance against some cisplatin resistant tumors, showing collateral sensitivity and it shows very low myelosuppression [2,6,16,17]. Since the mechanism of oxaliplatin is not considered to be quite the same to that of cisplatin, Mathé et al. [17] carried out the combination chemotherapeutic study of two Pt complexes among three Pt agents, oxaliplatin, cisplatin and carboplatin against L1210 and found that combination of oxaliplatin and carboplatin exhibited the highest antitumor efficacy. Soulie et al. [26,27] reported on the remarkable efficacy of a formulation, “Biplatin”, being just a mixture of both oxalipaltin and cisplatin in a 1:1 molar ratio against advanced ovarian cancer and germ cell carcinoma. Combination chemotherapy of “Biplatin” in the Phase II showed superior activity against ovarian cancer and germ cell carcinoma. However, the formulation of “Biplatin” was found to be unstable and further clinical studies had not been proceeded. In order to

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prepare a stable and highly antitumor active agent containing oxalipaltin and cisplatin together, we synthesized L-OHP/CDDP (cis-diammine)(L-cyclohexanediamine)(µdichloro)diplatinum(II) oxalate, faint yellow crystalline precipitates, which were produced by warming a mixed aqueous solution of an equimolar oxaliplatin and cisplatin under 80 °C on a water bath. Its elemental analysis showed to be a 1:1 molar ratio of the parent complex. Paper partition chromatography and HPLC analyses indicated that L-OHP/CDDP was a single compound and not a mixture of the parent complexes. Its antitumor activity in vivo exhibited high efficacy against L1210, L1210/CDDP and L1210/DACH. This paper deals with synthesis, cytotoxicity, antitumor activity in vivo and a plausible chemical structure of L-OHP/CDDP, dinuclear docking Pt(II) complex.

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2.3. Cytotoxic evaluation

2. Materials and methods

Cytotoxicity was evaluated using a cell counting Kit-8. Briefly, the sample was dissolved in water and sterilized through 0.2 µm disc filters. The drug concentration was adjusted to 10 times the final upper concentration of a dose range. Aliquots (20 µl) of this and serially diluted drug solutions and of complete media (80 µl) were pipetted in triplicate into 96-cell microtiter plates immediately before addition of cells. After diluting the L1210 (2000 per ml), L1210/CDDP (1500 per ml) and L1210/DACH (4000 per ml) cells to appropriate concentrations, 100-µl aliquots of these cell suspension were added to each of the wells. Following 5 days of incubation in a 37 °C, 5% CO2 humidified incubator, 10 µl of a cell counting Kit-8 solution (3 mg/ml) were added to each well. After a 3 h incubation, absorbances were measured at 450 nm in a multi-well-scanning spectrophotometer.

2.1. Chemicals

2.4. Evaluation of antitumor activity

Oxaliplatin and cisplatin were obtained from Tanaka Kikinzoku Kogyo (Hiratsuka, Japan) and used without further purification. 2.1.1. Synthesis of L-OHP/CDDP Oxaliplatin, L-OHP, 0.397 g (1 mmol) was dissolved in 40 ml of water by boiling and cisplatin, CDDP, 0.299 g (1 mmol) was also dissolved in 60 ml of water by boiling. Both the hot aqueous solutions were mixed and the pH of the mixture was adjusted at 3.7 with dilute nitric acid at 60 °C. The mixed solution was warmed on a water bath at 80 °C until the solution became colorless. A small amount of yellow precipitates was filtered off while hot and the filtrate was kept standing overnight at room temperature. Faint yellow precipitates deposited were collected by filtration to afford 230 mg (yield 35%) of objective compound. Elemental analysis of [Pt2Cl2(NH3)2(C6H14N2)](C2O4). Calcd. (%) C 13.78, H 2.89, N 8.03, Pt 55.95; Found (%) C 13.98, H 2.91, N 8.06, Pt 54.63. 2.2. Tumors Three different models of murine leukemia tumors, L1210, L1210/CDDP and L1210/DACH were afforded by Dr. S.G. Chaney of University of North Carolina. L1210/DACH was established in tissue cultures, being resistant to DACH-Pt complexes, by Eastman A. (Department of Pharmacology, Dartmouth Medical School, Hanouver, NH). L1210/CDDP is a subline of L1210 and 37-fold more resistant to cisplatin than L1210 in vitro [27]. L1210/DACH is a subline of L1210 about 25-fold more resistant to oxaliplatin than L1210 in vitro. Sensitive and resistant L1210 cell lines were maintained in RPMI 1640 containing 10% fetal bovine serum, 50 µg/ml penicillin, 50 µg/ml streptomycin, 100 µg/ml neomycin and 0.3 mg/ml L-glutamine and grown at 37 °C in a humidified atmosphere of 5% CO2 in air.

L1210 cells (105) were transplanted intraperitoneally into CDF1 mice on day 0, and the drug was given intraperitoneally on days 1, 5 and 9 according to the NCI protocol. From the mean survival time (days) of both treated (T) and control (C) groups (six mice per group), T/C % values were calculated. A values of T/C % exceeding 125 was taken as antitumor active. Mice alive on day 30 were considered as cured and the survival time on 30 days were used in T/C % calculation. 2.5. Measurements 1

H spectra were recorded on a 300 MHz Bruker DPX300 spectrometer in D2O at 298 K and their chemical shifts were reference to TPS (sodium 3-trimethylsilylpropionate-2,2,3,3-d(4)). 13C (solid state) NMR were measured on a 400Mz Bruker DMX400 spectrometer at 298 K and their chemical shifts were referenced to trimethylsilane (TMS), respectively. 2.6. Analyses Paper partition chromatography was carried out on Toyo filter paper #51 (20 × 200 mm), developed with either 20% EtOH or 20% MeOH aqueous solution, detected with an aqueous solution of stannous chloride. A high performance liquid chromatograph (Hitachi L-6200) was equipped with a gel permeation column (TSKgel G-2500PWxl, 1.5 × 300 mm) and a UV detector (Hitachi L-4200H). One-tenth molar Na2SO4 aqueous solution was used as an eluting solvent with a flow rate of 0.8 ml/min. 3. Results 3.1. Synthesis and chemical structure We paid attention on the antitumor efficacy of “Biplatin”, an equimolar mixture of cisplatin and oxaliplatin, which was

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Table 1 Results of PPC and HPLC of L-OHP/CDDP with its related Pt(II) complexes Complexes L-OHP/CDDP L-OHP

CDDP PtCl2 (L-dach) cis-Pt(ox)(NH3)2

PPC (Rf) 20% MeOH 20% EtOH 0.64 0.55 0.65 0.63 0.81 0.57 – 0.74 – 0.52

HPLC (tR = min) 54.5 30.2 21.3 52.1 15.2

reported to show a remarkably high antitumor activity against advanced ovarian cancer and germ cell carcinoma in the Phase II clinical trials [26,27]. Accordingly, we observed chemical reactions carefully between oxaliplatin and cisplatin, even though the leaving groups might exchange to give [Pt(ox)(NH3)2](ox = oxalate ion) and [PtCl2(L-dach)] each other, both of which are also antitumor active. When an aqueous mixed solution of oxaliplatin and cisplatin, adjusted at pH 3.7 with dilute HNO3 solution, was warmed on a water bath at 80 °C to give almost colorless solution. The small amount of yellow precipitates remained were filtered off while hot. The precipitates were identified as [PtCl2(L-dach)] by HPLC analysis. The filtrate was kept standing overnight at room temperature and faint yellow precipitates were deposited. The elemental analysis of the obtained complex indicated that it was a 1:1 molar ratio complex of the parent complexes. Paper partition chromatography was made with either 20% EtOH or 20% MeOH aqueous solution at room temperature and detected with anstannous chloride solution. The data were shown in Table 1 together with data of HPLC. L-OHP/CDDP showed one single spot at Rf = 0.55 (20% EtOH) and Rf = 0.64 (20% MeOH). These Rf values were clearly different from those of the parent complexes, whose values were 0.63 (20% EtOH) for oxaliplatin and 0.57 (20% MeOH) for cisplatin. The Rf value of cisplatin developed with 20% EtOH came near to that of L-OHP/CDDP, but discrimination between these complexes was achieved by developing with 20% MeOH, where the former gave a spot at Rf = 0.64 and the latter at Rf = 0.80. We established HPLC analytical conditions to separate various antitumor Pt(II) complexes with TSKgel G-2500PWxl using 0.1 M Na2SO4 aqueous. Na2SO4 aqueous solution as an eluent. In Table 1, retention times of Pt(II) complexes were shown together with that of L-OHP/CDDP. In this condition L-OHP/CDDP showed a new peak at tR = 54.5 min, whereas oxaliplatin and cisplatin showed peaks at tR = 30.2 and 21.3 min, respectively.

Fig. 1. Proposed structure for l-OHP/CDDP.

These analytical data clearly indicated that L-OHP/CDDP was not mixture of the parent complexes. 13 C-NMR spectral data in solid states and 1H-NMR data in D2O of L-OHP/CDDP and the parent complexes were shown in Table 2. The chemical shifts of 13C nuclei in L-dach moiety of the docking complex were similar to those of [PtCl2(L-dach)] rather than oxaliplatin. For example, the 13C chemical shifts due to C(a) and C(ß) in the docking complex exhibited peaks at 62.2 and 31.8 ppm, respectively, which were nearly identical to those of [PtCl2(L-dach)]. The same tendency was also observed in chemical shifts of 1H-NMR spectra. The docking complex exhibited a peak at 2.43 ppm due to H1ax and H2eq in the cyclohexane ring, which was identical to that of [PtCl2(L-dach)]. On the other hand, that of oxaliplatin was observed at 2.35 ppm. 13C nuclei of potassium oxalate and oxaliplatin showed peaks at 170.4 and 167.2 ppm, respectively, while that of the docking complex showed a peak at 169.1 ppm, which was much closer to that of potassium oxalate. All of these chemical shifts of 13C and 1H indicated that the docking complex was in chemical environments similar to those of [PtCl2(L-dach)], that is, Cl– ions bind to Pt(II) and oxalate ions act as counter ions. The proposed structure was shown in Fig. 1. 3.2. Cytotoxicity Cytotoxicity, expressed as IC50 values, was determined from dose–response curves in the leukemia L1210 cell lines and were presented in Table 3. The docking complex was more cytotoxic than the parent complexes against three L1210 cell lines. Against L1210/CDDP, which was 37-fold resistant to CDDP, the docking complex exhibited only 5.9-fold resistant and its potency was nearly comparable with oxaliplatin. Against L1210/DACH, which was 25-fold resistant to oxaliplatin, the docking complex was only 8.6-fold resistant and its potency was comparable with cisplatin.

Table 2 1 H-NMR and 13C-NMR spectral data of L-OHP/CDDP and its related complexes Complexes L-OHP/CDDP L-OHP

PtCl2 (l-dach) K2 (oxalate) 1

Hlax, H2eq 2.43 2.35 2.43 –

H3eq, H6eq 2.05 2.05 2.05 –

d (1H) (ppm) H3ax, H6ax H4eq, H5eq 1.58 1.30 1.57 1.58 1.30 –

H-NMR spectra were measured in D2O. 13C-NMR spectra were measured in solid states.

H4ax, H5ax 1.16 1.30 1.16 –

C1, C2 62.2 63.3 62.3 –

d (13C) (ppm) C3, C6 C4, C5 31.8 24.9 32.8 25.3 31.6 24.9 – –

Oxalate 169.1 167.2 – 170.4

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Table 3 Cytotoxity of L-OHP/CDDP and its related complexes against a series of L1210 Complexes L1210 0.22 0.51 0.65

L-OHP/CDDP L-OHP

CDDP

IC50 (uM) L1210/CDDP 1.3 2.1 24

3.3. Antitumor activity Antitumor activity of the docking complex was excellent against wild type L1210 in dose range from 3.12 to 12.5 mg/kg. At doses of 6.25 and 12.5 mg/kg, its T/C % values were around 340 and three mice were cured out of six mice in one group. At a dose of 3.12 mg/kg it showed the highest efficacy with T/C % values of 378 and five mice were cured. On the contrary, antitumor effects of 1:1 molar ratio mixture of oxaliplatin and cisplatin were inferior to those of the docking complex and its highest T/C % value of 286 at a dose of 3.12 mg/kg with only two cured mice. Oxaliplatin showed higher antitumor activity against L1210 than cisplatin and its T/C % value was 308 at 12.5 mg/kg with four cured mice out of six. Comparing T/C % values and number of cured mice among these Pt(II) complexes, the docking complex showed superior antitumor activity than oxaliplatin (Table 4). Against cisplatin resistant cell line, L1210/CDDP, the docking complex exhibited astonishingly high antitumor effect with T/C % value of 354 and all mice were cured at a dose of 3.12 mg/kg. It has been already reported that oxaliplatin had exhibited high antitumor activity against L1210/CDDP [28] and the fact was also confirmed in this experiment, since at doses of 6.25 and 3.12 mg/kg all the Table 4 Antitumor activity of L-OHP/CDDP and its related complexes against L1210 and its resistant cell lines Complexes 12.5 L1210 L-OHP/CDDP L-OHP + CDDP L-OHP CDDP

347 (3/6)

T/C (%) at doses (mg/kg) 6.25 3.12

308 (4/6) 78

343 (3/6) 169 253 (1/6) 249

378 (5/6) 284 (2/6) 211 (1/6) 226

207 (2/6) 105 278 (6/6) 107

308 (5/6) 113 275 (6/6) 107

354 (6/6) 103

235 (2/6) 185 123 196 (1/6)

205 125 112 178 (1/6)

167 105

1.56 118 167 124

L1210/CDDP L-OHP/CDDP L-OHP

+ CDDP

L-OHP

CDDP L1210/DACH L-OHP/CDDP L-OHP L-OHP

CDDP

+ CDDP

118

Drugs were i.p. injected on days 1, 5 and 9 after i.p. inoculation of 105 L1210 cells. Numbers in parentheses indicate cured mice in one group of six mice on 30-day observation.

L1210/DACH 1.9 13 3.4

L1210/CDDP L1210 5.9 4.1 37

L1210/DACH L1210 8.6 25 5.2

mice treated with oxaliplatin were cured. However, a 1:1 mixture of the parent complexes was inactive against L1210/CDDP, showing cross-resistance. The docking complex also exhibited relatively high antitumor effect against L1210/DACH comparable with cisplatin, while oxaliplatin was inactive. The mixture of the parent complexes was marginally active without any cured mice. Cisplatin was active at doses of 12.5 and 6.25 mg/kg with one cured mouse, showing no cross-resistance to L1210/DACH. These results showed that the docking complex was more efficacious against both L1210/CDDP and L1210/DACH cell lines. Therefore, the docking complex was not a simple mixture of oxaliplatin and cisplatin, but it is a new class of novel dinuclear Pt(II) complex, which contains L-dach and diammine as carrier ligands. This unique character will show a clinical merit in the cancer chemotherapy. The docking complex exhibited the highest efficacy at a dose of 1.56 mg/kg with a T/C values of 354, and all mice were cured. From the data it was nearly equal antitumor efficacy to oxalipaltin.

4. Discussion Cisplatin is a highly antitumor active Pt(II) complex and one of the most widely used antitumor agents in cancer chemotherapy. However, its clinical usage is limited by the severe nephrotoxicity and appearance of resistant cells. In order to overcome these side effects we have synthesized numerous Pt complexes and screened [11–15,19–23]. Among these Pt complexes, oxaliplatin was proved experimentally and clinically to be one of the most promising anticancer agents. Clinical trials revealed that oxaliplatin was superior to cisplatin against melanoma and breast cancer without nephrotoxicity [2,4], although it has side effect on nerve endings [4,17]. Oxaliplatin was approved in the clinical usage for patients with colorectal cancer in France in March 1996. FDA also approved oxaliplatin for colorectal cancer in August 2002. While developing oxaliplatin as an anticancer drug, we noticed its excellent antitumor activity against cisplatin resistant L1210 in vivo [17,28]. This fact prompted us to investigate reactions between oxaliplatin and cisplatin. As a result we succeeded in synthesizing the docking complex containing components of the parent complexes. In the synthesis, two possibilities are conceivable as shown in Fig. 2. Initially, it may form both dinuclear Pt(II) complexes simultaneously. The Cl– bridged complex with Rf = 0.55 (20% EtOH), faint yellow, is more stable than oxalate-bridged complex, which may be so unstable to decompose into two com-

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Fig. 2. Reaction process between oxaliplatin and cisplatin.

plexes, i.e. [Pt(ox)(NH3)2], and [PtCl2(L-dach)], by boiling in an aqueous solution. Just like cisplatin, oxaliplatin acts on the DNA, forming platinated intrastrand cross-links with two adjacent guanines or two adjacent guanine and adenine. The major effect of the formation of these platinated DNA adducts is the inhibition of DNA replication, resulting in cell cycle arrest and apoptosis. The difference between cisplatin and oxaliplatin is thought to be the results of their varying effects on the mechanism of resistance rather than a fundamental difference in their modes of action. It has been suggested that the mismatch repair (MMR) proteins serve as a detection system for the cisplatin-DNA adducts to induce apoptotic signal transduction [3,5,8,18]. Aebi et al. [1] reported that defects of MMR system due to the lack of hMLH1 or hMSH2 allows cell survival with resultant resistance cisplatin. Since it has been shown that hMutSa can not recognize oxaliplatin-DNA adducts, oxaliplatin exhibits antitumor effects against cisplatin resistant cells [25]. It was reported nearly two decades ago that oxaliplatin shows much higher antitumor effects against cisplatin resistant L1210, first by Tashiro et al. [28] and their results were confirmed by Mathé et al. [17]. This experimental fact has activated the research concerning resistance mechanism of Pt antitumor agents. From the cytotoxicity experiments moderate level resistances are observed for oxaliplatin (4.1-fold resistance) and the docking complex (5.9-fold), both complexes exhibit excellent antitumor activity exceeding against sensitive L1210 (Table 3). The facts conflict with the findings by Fink et al. [9] whose data indicate that low level of resistances (2.1-fold) are sufficient for a tumor to lose antitumor effects in vivo. However, Sergent et al. [25] pointed out that among six human colon cancer cell lines high level of resistance against cisplatin does not seem to be related to acquired defects in the MMR proteins except HCT116 colon

cell line. So it is uncertain whether MMR system works in L1210 cells. Gourdier et al. [10] found an interesting fact that a defect in the mitochondrial apoptotic path-way due to a loss of Bax expression is associated with oxaliplatin resistant HCT116 colon cell line. The docking complex exhibited the highest cytotoxicity against mouse leukemia L1210 among the three Pt complexes examined (Table 3). Its corresponding antitumor effects in vivo is also excellent exceeding that of oxaliplatin, especially in lower administration range of 6.25 and 3.12 mg/kg. Based on the facts found by Fink et al. and Gourdier et al. [9,10] this tendency can be explained by taking account for the docking complex to biotransform into cisplatin and oxaliplatin derivatives inside the cells. The former derivatives are recognized by MMR system and the latter by mitochondria with resultant activation of both apoptotic pathways, which cause the more enhanced cytotoxicity and antitumor effects. Against oxaliplatin resistant L1210, which is 25-fold resistant to oxaliplatin, the docking complex shows 8.6-fold resistance and its antitumor effects are nearly equal to that of cisplatin. This experimental result is rather contradictory, since the docking complex contains cisplatin counter part less than cisplatin itself and its antitumor effects should be less than that of cisplatin. At present time precise mechanism of mode of action and resistant mechanism are only partially resolved and more study is needed.

5. Conclusion We determined the structure of the docking complex of oxaliplatin and cisplatin from the analytical data of paper partition chromatography, HPLC and NMR spectra to be (cisdiammine)(L-1,2-cyclohexanediamine)(µ-dichloro)-diplatinum(II) oxalate. Against three L1210 cell lines a mixture of

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oxaliplatin and cisplatin in 1:1 molar ratio exhibited quite different antitumor activity from the docking complex and this biological data also indicated that docking complex is not mixture of the parent complexes but a dinulear Pt complex, L-OHP/CDDP. The docking complex exhibited superior cycotoxicity and antitumor effects against the three examined L1210 cell lines compared to those of cisplatin and oxaliplatin. Acknowledgements This study was supported in part by Grant-in-Aid by Kidani Memorial Trust. References [1]

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