Drug resistance and DNA repair in leukaemia

Most cytotoxic agents exert their action via damage of DNA. Therefore? the repair of such lesions is of major importance for the sensitivity of malign ant cells to chemotherapeutic agents. The underlying mechanisms of various DNA repair pathways have extensively been studied in yeast, bacteria and ma mmalian cells. Sensitive and drug resistant cancer cell lines have provided models for analysis of the contribution of DNA repair to chemosensitivity. However, the validity of results obtained by laboratory experiments with r egard to the clinical situation is limited. In both acute and chronic leuka emias, the emergence of drug resistant cells is a major cause for treatment failure. Recently, assays have become available to measure cellular DNA re pair capacity in clinical specimens at the single-cell level. Application o f these assays to isolated lymphocytes from patients with chronic lymphatic leukaemia (CLL) revealed large interindividual differences in DNA repair r ates. Accelerated O-6-ethylguanine elimination from DNA and faster processi ng of repair-induced single-strand breaks were found in CLL lymphocytes fro m patients nonresponsive to chemotherapy with alkylating agents compared to untreated or treated sensitive patients. Moreover, modulators of DNA repai r with different target mechanisms were identified which also influence the sensitivity of cancer cells to alkylating agents. In this article, we revi ew the current knowledge about the contribution of DNA repair to drug resis tance in human leukaemia.