[Combination cancer chemotherapy using a DNA topoisomerase inhibitor CPT-11, as a core agent--the in vitro evaluation]

Abstract

CPT-11, a derivative of camptothecin, has drawn attention to cancer chemotherapy because of the specific mode of action, and the clinical study is now under progress. Liu et al. proved that camptothecin was a DNA topoisomerase I inhibitor, and some kinds of antitumor agents have been recognized as DNA topoisomerase II inhibitors. Based on these findings, DNA topoisomerases have emerged as target enzymes of antitumor agents in cancer chemotherapy. This paper dealt with investigation on the cytotoxic effects induced by combined use of DNA topoisomerase targeting antitumor agents, especially using CPT-11 as a core antitumor agent. Synchronous administration of CPT-11 with other antitumor agents induced cytotoxic effects less than metachronous administration of CPT-11 with other antitumor agents, especially preceding use of CPT-11. Dose of antitumor agents was not necessarily correlated to the cytotoxic effects. In some instances, small doses of the agents showed better therapeutic effects than large doses. The cytotoxic effects of vincristine, vindesine, and hydroxyurea were reduced by combination with CPT-11. On the other hand, non-cytotoxic agents such as aphidicolin, novobiocin, propentofylline, pentoxifylline, norfloxacin, and tosufloxacin enhanced the cytotoxic effects of CPT-11. Hypothetical consideration of cell killing and acquisition of drug resistance was proposed.