Biochemical and Molecular Mechanisms of Cisplatin Resistance

Abstract

According to the DISCOVERY Anticancer Drug Screen of the National Cancer Institute in the USA, the inorganic antitumor agent cisplatin(cisdiammine-dichloro-platinum(II); Figure 1) and its analogs fall into at least 13 clustered regions, each reflecting a distinct mechanism of action1. Many of these analogs have not been investigated in depth to unravel their fundamental mechanism of action. Indeed, almost 30 years after its clinical acceptance as a potent antitumor drug, which has dramatically changed the course of treatment of ovarian, testicular and head and neck cancerscancers2 we are still searching for answers to explain how cisplatin works. There is no doubt, however, that DNA is the primary target of cisplatincancers3 but understanding how signals emanating from the damaged DNA are relayed to the apoptotic or cell death machinery is still a subject of much debate. An understanding of this process can be an important step toward defining mechanisms of resistance, which continues to impede the curative use of cisplatin in the clinic. This impediment can be gleaned from the knowledge that in ovarian cancer, for instance, the initial response rate of up to 70% leads to a 5-year survival rate of only 15-20%cancers4. Indeed, the majority (80-85%) of patients relapse and fail to further treatment with cisplatin as a result of acquired drug resistance. Similarly, in patients with small cell lung cancer,the relapse rate can be as high as 95%5.