Platinum anticancer drugs. From serendipity to rational design

Annales Pharmaceutiques Françaises (2011) 69, 286—295

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GENERAL REVIEW

Platinum anticancer drugs. From serendipity to rational design Les dérivés du platine en cancérologie. De la sérendipité à l’innovation rationnelle C. Monneret Institut Curie, 26, rue d’Ulm, 75248 Paris cedex 05, France Received 5 September 2011; accepted 10 October 2011 Available online 8 November 2011

KEYWORDS Anticancer drugs; Cis-platin; Carboplatin; Oxaliplatin; Picoplatin; Lipoplatin; ProlindacTM

Summary The discovery of cis-platin was serendipitous. In 1965, Rosenberg was looking into the effects of an electric field on the growth of Escherichia coli bacteria. He noticed that bacteria ceased to divide when placed in an electric field but what Rosenberg also observed was a 300-fold increase in the size of the bacteria. He attributed this to the fact that somehow the platinum-conducting plates were inducing cell growth but inhibiting cell division. It was later deduced that the platinum species responsible for this was cis-platin. Rosenberg hypothesized that if cis-platin could inhibit bacterial cell division it could also stop tumor cell growth. This conjecture has proven correct and has led to the introduction of cis-platin in cancer therapy. Indeed, in 1978, six years after clinical trials conducted by the NCI and Bristol-Myers-Squibb, the U.S. Food and Drug Administration (FDA) approved cis-platin under the name of Platinol® for treating patients with metastatic testicular or ovarian cancer in combination with other drugs but also for treating bladder cancer. Bristol-Myers Squibb also licensed carboplatin, a second-generation platinum drug with fewer side effects, in 1979. Carboplatin entered the U.S. market as Paraplatin® in 1989 for initial treatment of advanced ovarian cancer in established combination with other approved chemotherapeutic agents. Numerous platin derivatives have been further developed with more or less success and the third derivative to be approved in 1994 was oxaliplatin under the name of Eloxatin® . It was the first platin-based drug to be active against metastatic colorectal cancer in combination with fluorouracil and folinic acid. The two others platin-based drugs to be approved were nedaplatin (Aqupla® ) in Japan and lobaplatin in China, respectively. More recently, a strategy to overcome resistance due to interaction with thiol-containing molecules led to the synthesis of picoplatin in which one of the amines linked to Pt was replaced by a bulky methyl substituted pyridine allowing the drug more time to reach its target, DNA. On the other hand, efforts which were made to find new orally administered

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Platinum anticancer drugs. From serendipity to rational design

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analog led to satraplatin bearing to axial acetate groups. Both drugs are still under clinical trials. An alternatively route to the discovery of new derivatives turns to the development of improved delivery strategies such as liposomes and polymers. Liposomal cis-platin or lipoplatin in under a phase III randomized clinical trial for patients suffering from small cell lung cancer whereas polymer-based drug, ProlindacTM is currently under investigation for pretreated ovarian cancers in up to eight European centers. © 2011 Elsevier Masson SAS. All rights reserved.

MOTS CLÉS Médicaments anticancéreux ; Cis-platine ; Carboplatine ; Oxaliplatine ; Picoplatine ; Lipoplatine ; ProlindacTM

Résumé La découverte du cis-platine est tout à fait liée au hasard, à la serendipity selon la terminologie anglo-saxonne. Elle est, en effet, le résultat d’une expérience simple réalisée par un biophysicien curieux du nom de Barnett Rosenberg : faire passer un courant électrique, grâce à des électrodes de platine, dans une culture d’Escherichia coli. Les bactéries ne se divisaient plus mais changeaient de morphologie. La suite des études devait montrer que cela était dû au sel de platine formé dans le milieu de culture, puis que ce même sel possédait des propriétés antitumorales. Ainsi naquis le cis-platine qui se révéla d’une extraordinaire efficacité pour le traitement de cancers testiculaires et fut approuvé en 1978 par la FDA et mis sur le marché par Bristol-Myers-Squibb sous le nom de Platinol® . Par la suite, des recherches plus rationnelles vont aboutir à la mise sur le marché de deux autres dérivés du platine, le carboplatine sous le nom de Paraplatin® et l’oxaliplatine sous le nom d’Eloxatine® , ce dernier étant le premier sel de platine actif sur le cancer colorectal métastatique en association avec le fluorouracil et l’acide folinique. Deux autres composés recevront leur AMM, l’un au Japon, le nédaplatine sous le nom d’Aqupla® , l’autre en Chine, le lobaplatine. Les récentes recherches rationnelles se proposent, d’une part, de court-circuiter les problèmes de résistance, d’autre part, trouver un dérivé actif par voie orale. C’est ainsi que pour contourner les problèmes de résistance est né le picoplatine, un composé où chimiquement l’une des amines liée au platine a fait place à une méthylpyridine beaucoup plus volumineuse de sorte que la molécule ait le temps de se lier à l’ADN avant toute interaction avec les thiols endogènes. Pour ce qui est d’un composé actif par voie orale, le satraplatine plus lipophile que les précédents composés, est actuellement le meilleur candidat. Les essais cliniques sont en cours dans les deux cas. De fac ¸on parallèle d’autres recherches en cours ont pour objet de développer des formes galéniques nouvelles, liposomes et polymères. Ainsi le platine encapsulé dans les liposomes, le lipoplatine fait actuellement l’objet d’un essai clinique randomisé de phase III chez des patients atteints de cancer du poumon à petites cellules tandis que le platine lié à des polymères comme le ProlindacTM , est à l’étude dans plus de huit centres européens pour le traitement de cancers de l’ovaire résistants. © 2011 Elsevier Masson SAS. Tous droits réservés.

Introduction In 1963, Barnett Rosenberg (familiarly Barney), a biophysic professor at Michigan State University, initiated the research than led to the discovery of cis-platin. He decided with the help of his laboratory technician, Loretta Van Camp to examine the effects of an electric field on dividing Escherichia coli bacteria. This idea started from the fact that Barney noted a visual similarity of the pattern characteristic of the separation of chromosomes in the telophase of mammalian cell division and that of the lines of force between the poles of a magnet. He subsequently deduced that cell division might be affected by the magnetic component of an electrical field. Two platinum electrodes were used to generate the electric field. As well as the field was generated, the bacteria has undergone filamentous growth. Thus Barney observed that cell division was inhibited but not cell growth [1]. The experiments were reproduced several times while varying the electric field. Barney realized that a causative agent was produced which might be a useful anticancer agent. This was later identified as the cis-diaminodichloroplatinum or cis-platin resulting from the combination of platin with electrolytic products. Such a compound was already known

since a long time and commonly designed as sel de Peyrone, Michele Peyrone (1813—1883) being the Italian chemist who prepared it for the first time in 1845. In 1968, Barney tested the cis-platin in Sarcoma 180 solid tumor mice implanted. Instead of treating the mice on the day after the tumor was implanted, Barney waited until the tumor had grown to about 1 g in weight. Serendipity again, this produced a high percentage of complete cures [2]. The potent antitumor activity of cis-platin was next evaluated by the National Cancer Institute and cis-platin entered clinical trials in 1971 in several locations. It was approved by the FDA in 1978.

Platin derivatives Cis-platin The introduction of cis-platin into the clinical treatment of cancer has resulted in dramatic improvements with regard to several tumor types such as testicular and ovarian carcinoma. Indeed cis-platin is one of the most effective cancer agents, especially for testicular cancer, for which the

288 overall cure rate exceeds 90%, and is nearly 100% for earlystage disease. It has been also indicated for treatment of cervical, head and neck, and non-small cell lung cancer. However, its administration is hindered by its nephrotoxicity, but also by its gastrointestinal effects, neurotoxicity and myelotoxicity. Although the mechanism of action of cis-platin has been widely investigated, the mechanisms of its cellular uptake and efflux are still not fully understood. However, once inside the cell and in the nucleus, it is now well known that cis-platin in converted into species [(Pt(NH3 )2 Cl(OH2 )]+ and [(Pt(NH3 )2 (OH2 )2 ]+ which react with the DNA. Thus, the platinum atom binds covalently to the N7 position of purines (cf guanine) to form 1,2 or 1,3 strand crosslinks and interstrand crosslinks (Fig. 1). Platinum-DNA adducts activate several cellular processes that are responsible for the cytotoxicity of the drug. After removal of the chloride, platinum forms covalent bonds to the N7 of purine bases. This affords primarily 1,2 or 1,3-intrastrand crosslinks and a low number of interstrand crosslinks. DNA damage caused by cis-platin modulates several signal transduction pathways such as the p38 MAPK, c6ABL, p38MAPK, ERK, INK and p53 pathways as well cell-death pathways. This has been recently and widely reviewed [3]. Besides the side effects of cis-platin, another main problem which limits its application relies on inherent and acquired resistance. The major mechanisms of resistance are the inactivation of cis-platin by glutathione and metallothionein, increased repair of cis-platin adducts, reduced accumulation by increasing efflux and increased cisplatin adducts tolerance and failure of apoptotic pathways.

Carboplatin Understanding these mechanisms provides important insight for designing more efficient platinum-based drugs. Among the 20 platinum complexes which have entered clinical trials, the second compound to be approved in 1989 under the name of Paraplatin in USA and France, was the carboplatin. It differs from cis-platin by the presence of a 5,8-dioxa-spiro[3,4]octane-6,7-dione ring instead of the

Figure 1. Mechanism of action of cis-platin. Mécanisme d‘action du cis-platine.

C. Monneret chlorine atoms. Due to the fact that this leaving group is less labile than the chloride, carboplatin exhibits lower reactivity and slower DNA binding kinetics. A reduced side effect was observed, particularly the absence of nephrotoxicity, neurotoxicity and ototoxicity. However, the main drawback to its clinical use is its myelosuppressive effect, especially neutropenia which increases risks of infection by opportunistic infections. Clinical trials of advanced ovarian cancer have documented that carboplatin is equivalent to cis-platin in activity and causes considerably less ototoxicity, neurotoxicity, and nephrotoxicity. Four systematic meta-analysis based on updated individual patient data from all available randomized controlled trial including 237 trials, 5667 patients and 4664 deaths suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cis-platin and carboplatin are equally effective. There was no evidence that carboplatin is more or less effective than cis-platin in any subgroup of patients [4] of over 2000 patients who entered into phase III clinical studies. Indeed, patients with advanced ovarian cancer had virtually identical survival durations when treated with carboplatin- versus cis-platin-containing regimens. The main indications of carboplatin are treatment of advanced ovarian carcinoma in first line therapy (approval by the FDA in 1991) or second line therapy (after other treatments have failed). The response rate of platinum-sensitive disease to carboplatin as single agent is greater than 50%, but it is only 10—20% for platinum resistant patients and less for platinum-refractory patients. These two groups of patients are therefore usually treated with other agents such as liposomal doxorubicin, gemcitabin, topotecan, etoposide and hormonal therapies [5] but targeted therapies are expected to have in a next future, a major impact on the management of this disease [6]. Other indications for carboplatin are small-cell lung cancers and epidermoid carcinoma of the head and neck. It is contraindicated in patients with severe renal impairment,

Platinum anticancer drugs. From serendipity to rational design

Figure 2. Platin derivatives on the market. * in China. ** in Japan. Dérivés du platine sur le marché. * en Chine ** au Japon.

myelosupression and, of course, those who are allergic to platinum-containing drugs. Extensive studies have also explored the potential of platinum-based combination. Thus carboplatin was combined with paclitaxel for treatment of ovarian, non-small cell lung, and other tumors types [7].

Oxaliplatin. Discovered in 1976 by Y. Kidani in Japan, oxaliplatin was in-licensed by Debiopharm in Switzerland and licensed to Sanofi-Aventis in 1994. Oxaliplatin was initially launched in France in 1996 under the name of Eloxatin and subsequently in the rest of Europe in 1999 and United States in 2002. It contains a platinum atom complexed with oxalate and diaminocyclohexane (DACH). This bulky DACH is thought not only to contribute to the greater cytotoxicity of the drug versus cis-platin and carboplatin, but also to confer a lack of cross-resistance of oxaliplatin with them (Fig. 2). It was the first platinum-based drug to demonstrate convincing activity against metastatic colorectal cancer (CRC). However, it is more active when used in combination with infused fluorouracil and leucovorin or folinic acid, a combination known as FOLFOX (Fig. 3). Oxaliplatin was also co-administered with irinotecan and bolus fluorouracil and leucovorin (IFL) or with irinotecan alone (IROX protocol). The results of a three-arm randomized trial (IFL, FOLFOX, IROX) enrolling 795 patients in 2 years as a first-line treatment for metastatic CRC [8] shows superior results with FOLFOX with median time progression of 8.7 months versus 6.9 with IFL and 6.5 with IROX. The MOSAIC trial in which a total of 2246 patients were randomly assigned to receive LV5Fu2 (fluorouracil and leucovorin) or FOLFOX4 (cf. plus oxaliplatin) showed that the addition of adjuvant oxaliplatin to LV5Fu2 in the treatment of stage II/III colon cancer improved disease-free survival (78,5% versus 76%). [9]. As capecitabine has demonstrated high efficacy as first-line treatment for metastatic CRC, a new regimen was preconized which proved to be better. This, called protocol XELOX, was based on a combination of oral capecitabine (xeloda) in a three-weekly chemotherapy with oxaliplatin. [10]. Responses rates and overall survival were similar to those observed with FOLFOX4 but XELOX provides a more convenient regimen.

289

Figure 3. Structures of irinotecan, leucovorin, capecitabine or Xeloda® , and 5-fluorouracil. Structures de l’irinotecan, des leucovorine, capecitabine ou Xeloda® , et du 5-fluorouracile.

More recently, oxaliplatin has been studied in combination with bevacizumab as first-line therapy for advanced non-small-cell lung cancer. Clinical activity resulting from this combination seemed to be similar to that seen with other platinum regimens but due to the lower toxicity of oxaliplatin, makes it an alternative treatment, especially in patients unable to tolerate cis-platin. [11]. Oxaliplatin is also widely used in combination with fluoromyrimidines in stage II and III colon cancer. A MRC COIN trial was reported as a phase III randomized controlled trial of first-line therapy in advanced CRC with special attention to the toxicity. This weekly associated the monoclonal antibody cetuximab to the oxaliplatinfluoropyrimidine combination and a total of 804 patients was enrolled in this trial. The key finding of this report was the synergistic effect on diarrhoeal toxicity of the oxaliplatin, capecitabine and cetuximab combination. There is an increased incidence of grade 3 and 4 toxicities overall [12]. Later on, the same group reported that this regimen did not improve overall survival or progression free survival in KRAS wild-type patients [13]. Similarly, no improvement was observed by combination of oxaliplatin with cetuximab or bevacizumab, as reported by a French Oncology Research Group [14].

Nedaplatin Nedaplatin or Aqupla® is a cis-diammine-glycolato platinum which was approved in Japan since 1995. Experiments have shown that nedaplatin is less nephrotoxic than cis-platin in rat models and was more potent than cis-platin in several tumor cell lines as ovarian, cervical and endometrial cell lines. Following these results, a phase II trial in lung cancer was conducted at the National Cancer Center Hospital in Tokyo by Fukuda et al. [15]. Objective responses were observed in 10 patients (14.7%) with a median duration of response of 15 weeks [16], followed by a subsequent trail on urological tumors. Objectives responses were also observed on urological tumors (bladder, prostate and testicular cancer). Later nedaplatin was combined with various agents including paclitaxel, 5-FU, gemcitabin and irinotecan. As a randomized trial comparing vindesine with either nedaplatin

290

Figure 4. Recent platinum derivatives reaching clinical development. Récents dérivés du platine ayant atteint le développement clinique.

or cis-platin in patients with advanced non-small cell lung cancer did not show any superior effect of nedaplatin versus cis-platin [15], it was not developed outside of Japan (Fig. 4).

C. Monneret The starting dose of lobaplatin was 50 mg/m2 i.v. every three weeks. No objective responses were recorded whereas thrombocytopenia was the most frequent since grade 4 toxicity was observed in 15 patients in the first two cycles of treatment. No pharmacokinetic differences were observed between patient with normal organ function and those with an impaired liver function. However, an increase of final half-live was detected in patients with impaired renal function which indicates that the urinary platinum excretion is the major route of elimination [22]. According to all these results, Asta Medica discontinued development of lobaplatin which became the responsibility of Zentaris AG (AEterna Laboratories). Finally, lobaplatin was approved in China for treatment of chronic myelogenous leukaemia and inoperable metastatic breast and small cell lung cancer. Very recently, a China group reported that lobaplatin arrest cell cycle progression in G1 phase, in human hepatocellular carcinoma cells which is still a big burden in their country. Simultaneously these authors reported that lobaplatin down-regulated a number of kinases as cyclin B, CDK1, CDC25C, pCDK1 and pCDK4. Lobaplatin also downregulated genes Rb, E2F and pRb whereas up-regulating the tumor suppressor protein p53, the cyclin-dependent kinase inhibitors p21 (with a 7-fold increase) and p27 [23].

Picoplatin Lobaplatin or D-19466 Lobaplatin or D-19466 is a 1,2-diammino-l-methylcyclobutane-platinum(II)-lactate which consist of nearly a 1:1 mixture of two diastereoisomers with SSS configuration (LP-D1) and RRS configuration (LP-D2). The compound developed by Asta Pharma has shown antitumor activity in human lung, gastric, testicular and ovarian cancer xenografts while demonstrating incomplete crossresistance to cis-platin, both in vitro and in vivo [17]. Such a non-cross resistance with cis-platin was next reported in human testicular, ovarian, and gastric carcinoma [18]. Then, a phase I trial was undertaken which involved 11 patients. Each patient received by continuous infusion a total of 230 courses of lobaplatin ranged from 30 to 60 mg/m2 /72 h, every four weeks. Thrombocytopenia was the dose-limiting toxicity but no signs of renal, neuro or ototoxicity were reported. The recommended phase II dose for this regimen was 45 mg/m2 /72 h every four weeks [19]. Following these results, a clinical screening cooperative group phase II was developed which included 49 patients with advanced head and neck cancer, receiving by i.v. bolus 50 mg/m2 of lobaplatin. One complete and two partial responses were observed in 43 eligible patients. As previously, the dose limiting toxicity was thrombocytopenia (26%) but also granulocytopenia (12%) and anemia (121%). These authors concluded that lobaplatin is well tolerated but its efficacy in squamous cell carcinoma of the head and neck was marginal [20]. Same lack of relevant activity was reported in platinum-resistant ovarian cancer [21]. As lobaplatin suffered from low urinary excretion but also from short half-life, pharmacokinetics and pharmacodynamics were also evaluated in patients having advanced solid tumors but also impaired renal or liver function. A total of 25 patients entered the study.

Picoplatin (formerly ZD0473, JMD473 or AMD473) which is a 2-methylpyridine analog of cis-platin resulted, as carboplatin and satraplatin, from a collaboration between the Institute of Cancer Research (London) and Johnson Matthey Plc. Picoplatin is currently developed by Poniard Pharmaceuticals (Fig. 5). Preclinical studies [24] having shown its promising antitumor activity, even in resistant cell lines to cis-platin [25] and oxaliplatin [26], picoplatin entered in clinical trials. Several phase I were conducted with picoplatin administered as single agent [27] or in combination with paclitaxel for the treatment of solid tumors [28] or with gemcitabine [29]. On the other hand, comparison of in vitro effects of combinations of picoplatin with a large range of cytotoxic drugs (docetaxel, paclitaxel, vinorelbine, irinotecan, gemcitabine, pemetrexed) suggest that the best combination is that of picoplatin with gemcitabine. In conclusion of this study, authors recommended for phase II, doses of 90 and 750 mg/m2 for picoplatin and gemcitabine, respectively [30]. Several phase II studies have been conducted in patients with either metastatic breast cancer [31—33] or platinum pretreated ovarian cancer [34] or as second line therapy in mesothelioma [35]. Interestingly, a recent in vitro study demonstrates that picoplatin is able to overcome carboplatin and cis-platin resistance in small cell lung cancer (SCLC) cells. This provided a rationale to develop picoplatin for the treatment of recurrent SCLC [36]. In contrast, a randomized phase II study (SPEAR) of picoplatin in patients with SCLC refractory or progressive within 6 months after first-line platinum-based chemotherapy was slightly disappointing. Indeed, analysis of survival (321 patients among the 401 involved

Platinum anticancer drugs. From serendipity to rational design in the study) did not achieve statistical significance (P = 0.09). This means that the study did not meet the primary endpoint of overall survival. Nevertheless, refractory patients who never responded or relapsed with 45 days had a significant improvement in survival with picoplatin [37]. With reference to these results, on March 2010, Poniard Pharmaceutical decided to stop pursuing FDA approval for picoplatin as SCLC treatment. Similarly, in a randomized phase II trial of picoplatin which was conducted with 101 metastatic CRC patients, iv. combination of picoplatin with 5-fluorouracil and leucovorine (FOLPI regimen) did not show any improvement versus FOLFOX regimen except a significant reduction in neurotoxicities.

Triplatin, BBR 3464 Multinuclear platinum complex, BBR 3464 was synthesized by Boehringer Mannheim, Italian, now Novuspharma Italia, and a first paper dealing with its preclinical profile was reported in 2000 [38]. According to this paper, BBR 3464 was extremely potent against a panel of seven human tumour cell lines naturally resistant to cis-platin, with IC50 values at least 20-fold lower than cis-platin. This was confirmed against eight human tumor xenografts including tumors refractory to cis-platin. Moreover, BBR 3464 was claimed to cause more prolonged effect than cis-platin and as its profile of sensitivity differed from those of established drugs, authors hypothesized that BBR 3464 may have a distinct mechanism of cytotoxicity. In phase I testing [39,40], the dose-limiting toxicities were myelosuppression and diarrhea. Among different schedule, intermittent schedule (day 1, every 21—28 days with administration of 0.9 mg/m2 i.v.) was chosen for further development. Thirty-seven patients with small cell lung cancer were enrolled onto a multicenter study. Hematological toxicities included neutropenia (62%), febrile neutropenia (16%), anemia (10%), fatigue (5%) and hypokalemia (5%). Whereas no objective responses were seen in 34 evaluable patients, 11 patients had disease stabilization with 23 patients experiencing continued disease progression. Nevertheless, the lack of activity in either patient subgroup led the authors to do not support further evaluation of BBR 3464, at least as a single agent in small cell lung cancer disease [41] (Fig. 4).

Cl Cl

OCOCH3

NH3 Pt

N

Cl Cl

Pt

NH3 N H2

OCOCH3 Picoplatin

Satraplatin

Figure 5. Platin derivatives under clinical trials. Dérivés du platine en phase d’essais cliniques.

291

Satraplatin All the above three platinum drugs are administered intravenously. Subsequently, efforts were made to find new orally administered analogs and among them, satraplatin was the first to enter in clinical trials. Satraplatin, initially developed under the name of JM 216 is a [bis-aminodichloro-(cyclohexyl)amine)platinum(IV). Developing a p.o. platinum drug formulation may provide different pharmacological and pharmakinetics properties and thereby may exhibit a different spectrum of antitumor activity. As carboplatin given p.o. resulted in severe gastrointestinal side effects and poor absorption, Kelland et al. focused upon complexes designed to be neutral and more lipophilic than cis-platin/carboplatin [42] (Fig. 5). The two axial acetate groups increase the lipophilicity of the drug and thereby its oral bioavailability. Satraplatin is rapidly metabolized into the corresponding cyclohexylcis-platin analog, by removal of the two axial acetate groups. This metabolite called JM 118, binds to DNA to form intrastrand and interstrand crosslinks between adjacent purine bases [43]. The schedule dependency of JM216 antitumor action against a murine (ADJ/PC6plascytoma) and a human tumor model (ovarian carcinoma xenograft) was studied in vivo. Optimal antitumor activity, tolerance, and pharmacokinetics occurred with daily X5 dosing [44]. The DNA damage occurring after satraplatin administration is repaired by a mammalian nucleotide excision repair pathway, with similar kinetics to the repair of damage by cis-platin and oxaliplatin. [45]. In contrast, mismatch repair proteins does not recognized satraplatin-induced adducts comparatively to the other platin derivatives adducts. Moreover, reports suggest that this induced adducts do not bind to high mobility group 1 protein, which recognizes DNA damage caused by cis-platin and inhibits trans-lesions replication by certain DNA polymerases. This could explain why some resistances may be overcome by satraplatin [46]. Toxicity of satraplatin was evaluated in vitro against a panel of seven human ovarian carcinoma cell lines as the relative cis-platin resistant SKOV-3 and the cis-platinsensitive 41 M cell line, respectively. While satraplatin was less potent than cis-platin in the SKOV-3 cell line (3.8-fold), it was dramatically more potent in the PXN/94 cell line (10-fold). This last result may be attributable to a better intracellular accumulation of satraplatin versus cis-platin. Nevertheless, cross-resistance was observed between cisplatin and satraplatin in six cell lines. Cytoxicity of satraplatin was also evaluated in a panel of 10 cis-platin-sensitive small cell lung cancer cell lines. It was 2- and 7-fold more potent than cis-platin [47]. In vivo, satraplatin exhibited markedly superior antitumor efficacy to cis-platin and carboplatin. Across four human ovarian carcinoma xenografts of varying sensitivity to cis-platin and carboplatin, satraplatin displayed p.o. activity broadly comparable to i.v. administered cis-platin and carboplatin. Satraplatin was also tested in combination with several cytotoxic agents as docetaxel, paclitaxel, 5-fluorouracil, capecitabine, oral etoposide, with the anti-EGFR monoclonal antibody, trastuzumab, and with radiations. On the contrary of cis-platin and of JM118, the major metabolite of satraplatin, satraplatin was found to be a

292 poor substrate of cation transporters as it also reacts with glutathione with a rate markedly lower than the former derivatives [48]. Satraplatin was no nephrotoxic, no hepatotoxic but, in rodents, myelosuppression was the doselimiting toxicity. All these data suggested that satraplatin represents a suitable candidate as a p.o. administrable platinum drug of phase I clinical trial. In a first phase I, satraplatin was administered at doses ranging from 60 to 700 mg/m2 as a single oral dose [49]. As the maximum tolerated dose was never reached in this study, a subsequent phase I pharmacokinetic study was conducted [50] in which satraplatin was given at doses from 30 to 140 mg/m2 /d for 5 days. Additional trials investigated daily oral administration of satraplatin for 5 days or 145 days. In all cases, the serum ultrafiltrate platinum AUC was linearly proportional to the daily oral administration dose [51 and references cited therein]. More recently, a phase I study of satraplatin was conducted in sequential combination with capecitabine in 27 patients with advanced solid tumors such as ovarian and prostate cancer [52]. It appears that the combination of satraplatin at 70 mg/kg and capecitabine at 2000 mg/kg, was well tolerated with only few toxicities. Recommended doses for phase II/III were 100 to 120 mg/m2 /d for 5 days or 45 to 50 mg/m2 /d for14 days. The dose limiting toxicities were thrombocytopenia and neutropenia, which were reversible and non cumulative. A notable absence of nephrotoxoxicity was reported. Phase II and III trials have been conducted with satraplatin alone or in combination with other cytotoxics for the treatment of prostate, non-small cell lung and small cell lung cancers as well as recurrent ovarian or cervical cancer. A phase III study was conducted by the European Organization Research and Treatment of Cancer (EORTC) with 50 patients suffering from hormone refractory prostate cancer (HRPC) in which satraplatin was administered at doses of 100 mg/m2 :d for 5 days every five week with prednisone, 10 mg twice daily. This trial showed that the satraplatin/prednisone combination increased PSA response and overall survival [53]. The oral route of administration and the intermittent schedule makes satraplatin, very convenient for clinical use [54].

Lipoplatin An alternative strategy to the discovery of new platinum derivatives turns to the development of improved delivery strategies. Among the number of strategies for tumor targeting of cytotoxic agents, liposomes and polymers have been investigated in the case of platinum. Liposomal cis-platin or lipoplatin was reported as a combination of dipalmytoyl phosphatidyl glycerol, soyphosphatidyl choline cholesterol and methoxypolyethylene glycol distreatoyl phosphatidyl ethanolamine. It is composed of 8.9% of cis-platin and of 91.1% of lipids. This formulation seems to be light resistant, presumably because liposomes shield the drug. A phase I study including 27 patients was performed [55] for dosage escalation. A maximal plasma level of lipoplatin was reached after 6 to 8 h (half-life) and the duration of release from the blood was 60—117 h depending on the dose.

C. Monneret No nephrotoxicity was observed when lipoplatin was administered once every 14 days at the dose of 125 mg/m2 . A second phase I trial was performed using a combination of lipoplatin and gemcitabin in non-small cell lung cancer being refractory to a previous cis-platin-based chemotherapy. A third phase I trial included lipoplatin dose-escalation and a combination of lipoplatin and paclitaxel. From this study, the DLT of lipoplatin was found to be 250 mg/m2 and that of paclitaxel to be 175 mg/m2 . On the other hand, the MTD of lipoplatin was evaluated as 200 mg/m2 and that of paclitaxel as 175 mg/m2 . A phase II study with 35 patients was undertaken using a combination of lipoplatin with vinorelbine in a first-line treatment of HER2/neu-negative metastatic breast cancer. The choice of the aforementioned combination was based upon the interesting results which were previously observed by the use of combination of cis-platin with vinorelbine. A second phase II randomized study including 88 patients compared the combination of lipoplatin (120 mg/m2 ) or cisplatin, with gemcitabine (1000 mg/m2 ). Response rate and disease control rate were superior for the group lipolatingemcitabine. Morever there was a significant reduction in nephrotoxicity for the group of patients receiving lipoplatingemcitabine versus those receiving cis-platin-gemcitabine [56]. A phase III trial was performed to compare the toxicity between liposomal cis-platin and cis-platin, both combined with 5-fluorouracil. It was carried out in 43 patients with advanced head and neck cancer. The liposomal formulation resulted in greater body clearance and shorter half-life than conventional cis-platin with decreased toxicity such as renal deterioration [57]. A second phase III randomized clinical trial was conducted with 229 patients, with small cell lung cancer, who were divided in two groups [58]. Group A received lipoplatin and paclitaxel and group B, cis-platin and paclitaxel. Nephrotoxicity was significantly reduced (P < 0.001) as well as leucopenia in group A. With regard to other side effects, such as neurotoxicity, thrombocytopenia, diarrhea and alopecia, no statistically difference was determined. This was also the case for median survival, overall survival and time tumor progression. However, the response rate was higher with the administration of liposomal-paclitaxel (58.8%) versus cis-platin-paclitaxel (47%). Lipoplatin has also been investigated in other cancers such as pancreatic, head, neck, and breast cancer but the main researches concern non-small cell lung cancer. It is still under investigation.

Prolindac Macromolecules have been used to target drugs by virtue of the enhanced permeability and retention effect. The first attempt in the field of platinum derivatives was made by scientist at Access Pharmaceutical and focused on an HMPA copolymer in which the platinum moiety was linked to the polymer via one of its nitrogen atom. Under the effect of lysosomal enzymes, the platinum was release, a peptide sequence being prone to cleavage. However, due to the inconsistency of the conjugate, such a compound was discontinued. Next, a second generation of polymer-containing

Platinum anticancer drugs. From serendipity to rational design

Figure 6. Structure of ProlindacTM . Structure du ProlindacTM .

platinum was developed and among them, AP5280 entered in clinical trials [59]. Despite promising results, Access Pharmaceutical opted to focus on a third generation polymer named AP5346. This, which was named ProlindacTM , was based on an improved biocompatible polymer carrier and used to deliver the active moiety of oxaliplatin, diamino cyclohexyl platinum (or DACH). The polymeric structure of ProlindacTM which is depicted on figure includes a linear polymer chain of 25 kDa, a copolymer of hydroxypropylmethacrylamide (HMPA) with a linker chelator monomer in a 10:1 ratio. This pH-sensitive linker that binds cyclohexylamine platinum to the copolymer releases platinum more rapidly at low pH as found in the relatively acidic environment of hypoxic tumors [59] (Fig. 6). The antitumor activity of ProlindacTM was first evaluated in eleven mouse tumor models, including both syngenic murine and human tumor xenograft models. ProlindacTM was as potent as oxaliplatin in any model. It demonstrated a superior therapeutic index in multiple preclinical tumor models. In the B16F10 melanoma model, it provided more than 12-fold greater delivery of platinum to the DNA of the tumor than the DACH-platinum agent oxaliplatin when both drugs were given at equitoxic dose. In a phase I clinical trial intended to determine the MTD, safety and pharmacokinetics, 26 patients suffering from advanced solid tumor were enrolled and received the drug weekly for 3 weeks [60]. ProlindacTM was tolerated up to a dose of 640 mg Pt/m2 on the first cycle when given with antiemetic prophylaxis. The pharmacokinetics of AP5346 indicates a prolonged half-life, and evidence of antitumor activity was observed at this dose level. Both preclinical and clinical studies indicate that ProLindacTM is at least as potent as oxaliplatin, sometimes more. Thus a phase 2 monotherapy clinical study of Prolindac in combination with paclitaxel involving patients suffering from heavily pretreated ovarian cancers, is currently conducted in up to eight European centers.

Conclusions In attempts to overcome the drawbacks of cis-platin — severe toxicity, drug resistance and poor oral bioavailability

293 — the development of platinum-based drugs has progressed from carboplatin and oxaliplatin to the newest generation of drugs, such as satraplatin, picoplatin and the multinuclear platinum complex BBR3464 (triplatin) along with new formulation as lipoplatin and platin-containing polymer. Despite incontestable progress in the treatment of testicular cancers, platin derivatives suffer from a lack of efficacy in other cancers such as SCLC. This is also true in the case of ovarian cancers since 15% of all patients are resistant to such a treatment and moreover, some of them developed resistance. As suggested by recent studies, a better knowledge of the mechanism of resistance to platin derivatives may hope a better efficacy of these drugs in the future. Indeed recent work implied that the cellular copper machinery may be involved in cis-platin cell export and drug resistance [61]. By binding to Atox1, the Cu chaperone, in the cytoplasm, cis-platin transport to DNA may be blocked. As recently reported [62], outcomes of clinical trials of these coordination complexes remained below expectations. The nature of the active species generated in vivo, uptake, efflux, intracellular trafficking and detailed mechanisms involved in chemoresistance of platinum drugs in vivo need further investigation to provide clues for the rational formulation of new drugs. Better preclinical assays with improved predictive power for the clinical outcome of the compounds are also needed.

Disclosure of interest The author declares that he has no conflicts of interest concerning this article.

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