Mechanisms of Action of Cancer Chemotherapeutic Agents: DNA-Interactive Alkylating Agents and Antitumour Platinum-Based Drugs

The long-term understanding of cancer growth is that it is a net result of uncontrolled multiplication of cells that out paces the rate of natural cell death within the tumour mass. The ultimate aim of the tumour is survival by overcoming the many barriers in its path. The imperative need for continual supply of nutrients to new growth areas, for instance, is met through sustained angiogenesis. Another major factor for growth and survival is limitless replicative potential, requiring continued biosynthesis of the genetic material to provide a complementary set of chromosomes in each of the daughter cells following cell division. Inhibiting DNA replication, therefore, affords a logical approach for retarding tumour growth. For this reason, DNA has become a critical target in cancer chemotherapy. Indeed, many of the antitumour agents currently in the cancer armamentarium are DNA-interactive. Among them, the DNA alkylators or cross-linkers, which includes the platinum-based drugs, are the most active available for effective cancer management. Historically, nitrogen mustard was introduced in 1942 as the first alkylating agent to have clinical utility (Gilman and Phillips, 1946). It was an analogue of the highly toxic sulphur mustard gas, which had been used as a weapon in 1917 during the First World War and later as a therapeutic agent against squamous cell carcinoma (Adair and Bagg, 1931). The advent of nitrogen mustard was the beginning of modern cancer chemotherapy, and it spawned a series of more effective and less toxic alkylating agents that are still in use today. Five major structural classes of alkylating agents are of considerable interest: the nitrogen mustards,