General review
Platinum anticancer drugs. From serendipity to rational designLes dérivés du platine en cancérologie. De la sérendipité à l’innovation rationnelle

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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 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, Prolindac™ is currently under investigation for pretreated ovarian cancers in up to eight European centers.

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 façon 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 Prolindac™, est à l’étude dans plus de huit centres européens pour le traitement de cancers de l’ovaire résistants.

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.

Section snippets

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 overall cure rate exceeds 90%, and is nearly 100% for early-stage disease. It has been also indicated for treatment of cervical, head and neck, and non-small cell lung cancer. However, its administration is

Conclusions

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

Disclosure of interest

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

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