Clinical resistance to topoisomerase-targeted drugs

This review describes topoisomerase (topo)-mediated drug resistance and topo expression in human tissues and cancers. In some in vitro studies a relation has been observed between topo I, IIα or IIβ expression and sensitivity to topo inhibitors. Drug resistance to topo inhibitors may, however, be multifactorial. Several topo inhibitors are substrates for drug membrane transporters. As most topo inhibitors are cell cycle specific, disturbances in cell cycle regulation can also confer resistance, and downstream events following DNA damage induced by topo inhibitors may be involved in regulating cell death or survival. Several studies in patient specimens have shown a relation between topo IIα expression and the proliferative state of the tumor, higher topo IIα levels being seen in more highly proliferating tumor types. In contrast, topo IIβ appears to be expressed in both proliferating and quiescent cells. Furthermore, higher topo I levels were observed in some tumors when compared to their normal counterparts. In some studies a reduced topo IIα level was seen in samples taken after chemotherapy treatment, as compared with specimens prior to treatment. No unequivocal relation was observed, however, between expression or activity of the topo genes and response to chemotherapy; nonetheless only a few studies have properly addressed this question. This review summarizes the results of the clinical studies performed so far, and analyzes the critical issues in performing studies on patient material.