Determinants of Cellular Sensitivity to Topoisomerase-Targeting Antitumor Drugs

Abstract

It is now clear that topoisomerase activity level is an important determinant of sensitivity to topo drugs. The regulation of topoisomerases is no doubt complex and multifaceted and is probably accomplished through redundancy at many control levels. The mechanism(s) of altered topo I expression in certain tumor types is unknown, but may be related to the central importance of topoisomerases in proliferating cell functions (transcription, replication, etc.), and the aberrant and chronic activation of these functions as a result of specific tumorigenic alterations. Small differences in sensitivity to chemotherapy can have a dramatic effect on cure rates, and therefore subtle cell type-specific differences may be important determinants of drug sensitivity. Whether abnormal topoisomerase quantity and specific activity are associated with resistance or sensitivity to topoisomerase-targeted chemotherapy in the clinic is now being studied. Determinants downstream of cleavable complex formation that affect the sensitivity of tumor versus normal cells to topo drugs in particular and DNA-damaging agents in general are little known. The goal of enhancing selective tumor cell killing relative to the normal cells that are dose limiting may be achieved either by overcoming tumor cell resistance or by protecting normal cells. Both of these strategies will become more feasible as specific molecular differences between tumor and normal cells are being rapidly identified and new combination therapies that take advantage of these differences are being designed and tested.