CELL BIOLOGICAL MARKERS OF DRUG-RESISTANCE IN OVARIAN-CARCINOMA

The aim of the study is to review the mechanisms of resistance to four classes of drugs that are widely used in ovarian carcinoma: platinum (cisplatin/carboplatin) compounds, classical alkylating agents (cyclop hosphamide/melphalan), natural drugs (doxorubicin), and ''new drugs'' (taxol and taxotere), Both platinum and classical alkylating agents me diate their cytotoxicity by the formation of drug-DNA adducts, resulti ng in DNA damage, Therefore, drug resistance mechanisms are (in part) comparable, In ovarian carcinoma cell lines increased repair of DNA da mage and increased detoxification by binding of drugs to glutathione, possibly catalyzed by glutathione S-transferases, have been identified as the most prominent resistance mechanisms to these drugs, Studies o n the role of DNA repair mechanisms and glutathione in human ovarian c arcinoma are hampered by the complexity of enzyme systems involved in DNA repair and intratumor heterogeneity for glutathione, Resistance to doxorubicin appears to be mediated by enhanced efflux from the cell b y increased expression of membrane glycoproteins acting as a drug effl ux pump, such as P-glycoprotein, Resistance to doxorubicin can also be due to quantitative and/or qualitative changes in the nuclear target of doxorubicin, topoisomerase (Topo) II, Finally, resistance to taxol may be mediated by enhanced expression of P-glycoprotein, while presum ed other mechanisms such as alterations in tubulin structure, the cell ular ''target'' of taxol, and changes in polymerization of tubulin are still largely unresolved, Several ways to modulate the reviewed resis tance mechanisms are also described. In conclusion, this review shows that many cell biological factors may be involved in drug resistance, The relevance of the identification of most of these factors in ovaria n carcinoma patients however remains to be established. (C) 1995 Acade mic Press, Inc.