Drugs Targeting DNA Repair, Cell Cycle, and Apoptosis

A wide variety of established and investigational anticancer drugs target topoisomerases, enzymes that adjust the torsional strain in DNA during normal physiologic processes, or components of the DNA damage response, a series of biochemical reactions that recognize DNA alterations and help cells respond to them. If not properly repaired, damage induced by topoisomerases or perpetuated by inhibitors of DNA repair can lead to apoptosis. Thus, the processes of DNA metabolism, DNA repair, and apoptosis play critical roles in current anticancer therapies. This chapter highlights the physiologic roles of topoisomerases, components of the DNA damage response, antiapoptotic proteins, and cyclin-dependent kinases. Agents that target these proteins impact critical cellular processes and induce cytotoxic effects either by themselves (as with the topoisomerase inhibitors and cyclin-dependent kinase inhibitors) or by overcoming cellular mechanisms of resistance (inhibitors of DNA damage response/repair and inhibitors of antiapoptotic molecules).