Beyond DNA cross-linking: history and prospects of DNA-targeted cancer treatment--fifteenth Bruce F. Cain Memorial Award Lecture.
The origin of cancer chemotherapy can be traced to the wartime discovery of the lymphotoxic action of nitrogen mustards. These and other bifunctional agents were later found to produce various types of DNA cross-links, and some of these agents continue to be mainstays of current therapy. The cellular pharmacology of these drugs was studied extensively during the 1970s and 1980s by means of DNA filter elution methodology. In the course of these investigations, DNA topoisomerases were discovered to be targets of anthracyclines and several other classes of anticancer drugs. DNA cross-linkers and topoisomerase blockers have generally similar cytotoxic mechanisms, which depend on DNA damage detection, DNA repair, cell cycle arrest, and cell death by apoptosis. The molecular control of these processes, involving oncogenes and tumor suppressor genes, is being revealed by current research. Cancer cells often have defects within these control systems, and these defects may confer selective sensitivity to appropriately designed drug therapy. Panels of human tumor cell lines may serve to link the molecular defects with specific drug sensitivities. Such correlations could guide the selection of drugs for therapy based on molecular diagnosis of individual tumors.
Kohn
K W
KW
Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA. kohnk@dc37a.nci.nih.gov
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000266:history* / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000266:history / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D003432:Cross-Linking Reagents / Q000266:history*; D004247:DNA / Q000187:drug effects / Q000266:history* / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D005544:Forecasting; D049673:History, 20th Century; D006801:Humans; D010151:Paintings / Q000266:history; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D059005:Topoisomerase II Inhibitors; D004247:DNA