BEYOND DNA CROSS-LINKING - HISTORY AND PROSPECTS OF DNA-TARGETED CANCER-TREATMENT - 15TH BRUCE-F-CAIN-MEMORIAL-AWARD-LECTURE

The origin of cancer chemotherapy can be traced to the wartime discove ry of the lymphotoxic action of nitrogen mustards, These and other bif unctional agents were later found to produce various types of DNA cros s-links, and some of these agents continue to be mainstays of current therapy, The cellular pharmacology of these drugs was studied extensiv ely during the 1970s and 1980s by means of DNA filter elution methodol ogy. In the course of these investigations, DNA topoisomerases were di scovered to be targets of anthracyclines and several other classes of anticancer drugs, DNA cross-linkers and topoisomerase blockers have ge nerally similar cytotoxic mechanisms, which depend on DNA damage detec tion, DNA repair, cell cycle arrest, and cell death by apoptosis, The molecular control of these processes, involving oncogenes and tumor su ppressor genes, is being revealed by current research, Cancer cells of ten have defects within these control systems, and these defects may c onfer selective sensitivity to appropriately designed drug therapy. Pa nels of human tumor cell lines may serve to link the molecular defects with specific drug sensitivities, Such correlations could guide the s election of drugs for therapy based on molecular diagnosis of individu al tumors.