Abstract
OverviewAlkylating agents and platinum‐based compounds are highly potent antitumor drugs used in the treatment of a variety of cancers. These drugs target DNA (deoxyribonucleic acid) but require activation by spontaneous or metabolic transformation to induce formation of DNA monofunctional adducts and interstrand and intrastrand crosslinks. As a result of this damage, the DNA unwinds and/or bends, and such distortions are then recognized by specialized DNA damage recognition proteins to activate checkpoints, which arrest the cell cycle to allow cells time to repair the damage and survive. If the DNA damage is extensive and repair cannot be completed, then cells activate p53‐dependent or independent apoptosis (programmed cell death) to affect antitumor drug response. As activated species from alkylating agents and platinum compounds are not tumor‐selective, they will also interact with DNA and other endogenous macromolecules in normal cells to induce severe side effects; at times the toxicity can be irreversible and cumulative and, thereby, presents a dose‐limiting barrier. Another limitation is that genetic changes in tumors that are either intrinsic or acquired can inhibit apoptosis and induce resistance to alkylating and platinating drugs. Resistance mechanisms may be observed in the form of 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. Rational strategies to circumvent resistance mechanisms are, therefore, needed desperately to enhance patient care.