Masterarbeit
History of platinum-based drugs from a regulatory perspective ***
PD Dr. Ganna Staal (geb. Kalayda) (2020)
Summary
Language: English
Before Barnett Rosenberg accidentally discovered cytostatic activity of cisplatin, being diagnosed with testicular cancer mostly meant a death penalty. Rosenberg had no intention to work with platinum, he aimed at studying the effect of an electric field on growth and division of bacteria. He used presumably inert platinum electrodes in his experiments. Having observed a halt in bacterial division, Rosenberg and his team pinned down the cause of the effect to the platinum complex formed upon the experimental conditions. It took some time and considerable effort to persuade the scientific community of the potential of the new drug candidate because the very idea to treat human beings with heavy metals appeared absurd. Nevertheless, cisplatin revolutionised the therapy of ovarian and testicular cancer, the latter having cure rates over 90 % nowadays. Such outstanding success but also drawbacks associated with cisplatin treatment, like severe side effects and development of resistance, stimulated search for new platinum-based drugs. Rational design and development finally led to regulatory approval of two other platinum complexes, carboplatin and oxaliplatin, all over the world. The former features clearly improved toxicity profile, whereas the latter demonstrates efficacy in colorectal cancer, which is intrinsically insensitive to cisplatin and carboplatin.
A number of other platinum drug candidates were evaluated in vitro, in animal models and some of them in clinical trials but none of them has received a worldwide approval. In this thesis, the reasons for the regulatory failure of several promising platinum compounds are analysed. These include too much focus on the exceptional cytotoxicity upon selection of drug candidates after in vitro screening, difficulties in transfer from the pre-clinical stage to the clinical benefit, flaws in clinical trial design, or wrong choice of the pursued indication. Constantly emerging new developments in the field of anticancer therapeutics also have a great impact on regulatory success. Although another platinum drug with a worldwide approval is not likely to be developed, combinations of the routinely used platinum-based drugs with novel therapies hold promise to greatly improve survival of cancer patients.
Pages: 57