ENHANCED SENSITIVITY TO TOPOISOMERASE INHIBITORS IN SYNCHRONOUS CHO CELLS PRETREATED WITH 5-AZACYTIDINE

Multidrug combination has been shown to be very useful to improve anti tumor activity as well as to reduce the toxicity of different anti-can cer drugs. We have evaluated the interaction between the hypomethylati ng agent 5-azacytidine and the topoisomerase I and topoisomerase II in hibitors Camptothecin (CPT) and 4'-(9-acridinylamino) methanesulfon-m- anisidide (m-AMSA) respectively, based on the hypothesis that through the alteration of chromosome replication timing following DNA hypometh ylation, the number of replication forks in early S phase might increa se, so enhancing the probability of a collision between a blocked clea vable complex (DNA-topo I-CPT or DNA-topo II-m-AMSA) and a replication fork. We have tested the capacity of CPT and m-AMSA to induce chromos omal aberrations as well as reproductive cell death in synchronous cul tured Chinese hamster ovary cells after a pretreatment with 5-azacytid ine with positive results. (C) 1998 Elsevier Science B.V. All rights r eserved.