Alkylating Agents and Platinum Antitumor Compounds

Abstract

Overview Alkylating agents and platinum‐based compounds constitute two important classes of antitumor drugs in the war against cancer. These drugs transform spontaneously or metabolically to induce DNA monofunctional adducts and interstrand and intrastrand crosslinks. As a result, the DNA unwinds and/or bends, which are then recognized by specialized DNA damage recognition proteins to induce cell cycle arrest that allows cells time to repair the DNA and survive. If DNA damage is extensive and repair cannot be completed, then cells undergo programmed cell death to result in a positive antitumor response. Since active species in the two drug classes are not tumor‐selective, they will also interact with DNA in normal cells to induce several side effects, some of which can be irreversible and cumulative and, thereby, become life threatening. Another limitation is that tumor cells can become resistance to alkylating and platinating drugs through mechanisms that are either intrinsic or acquired. Such resistance mechanisms are manifested as reduced drug accumulation, increased drug inactivation, increased DNA repair, failure of DNA damage recognition system to recognize the damage, and aberrant apoptotic signal transduction pathways. Therefore, identifications of rational personalized combination therapeutic strategies involving these two potent classes of DNA‐reactive drugs are desperately needed to combat resistance mechanisms and enhance curative responses.