TAXOL IN COMBINATION WITH DOXORUBICIN OR ETOPOSIDE - POSSIBLE ANTAGONISM IN-VITRO

Background. Taxol is a novel chemotherapeutic agent that promotes micr otubule assembly and stabilizes tubulin polymer formation. Clinical ev aluation of its anti-neoplastic activity as a single agent and in comb ination with other chemotherapeutic drugs is in progress. Methods. To evaluate the effect of combining taxol with other commonly used antine oplastic agents, clonogenic survival of human breast cancer MCF7 cells , human lung adenocarcinoma A549 cells, and human ovarian cancer OVG1 cells were assayed after an initial exposure to taxol for 24 hours (ap proximately LD90 for taxol), followed by a 1-hour incubation with vary ing concentrations of doxorubicin or etoposide (total taxol incubation time, 25 hours). Results. When corrected for taxol-induced cytotoxici ty, doxorubicin and etoposide caused less cell killing in the presence of taxol compared with control incubations of doxorubicin and etoposi de alone. To determine if a different schedule of drug application res ulted in a similar finding, MCF7, A549, and OVG1 cells were exposed to doxorubicin for 1 hour, followed by incubation with varying concentra tions of taxol for 24 hours. Less-than-additive cytotoxicity for the c ombination of taxol and doxorubicin was found. Flow cytometry studies in MCF7 cells showed that taxol caused a G2/M cell cycle block. Fewer cells were found to be in S-phase, which is the most doxorubicin-sensi tive phase of the cell cycle. The application of doxorubicin or etopos ide to MCF7 cells for 1 hour resulted in partial G1 and G2/M cell cycl e blocks. Fewer cells were found to be moving through the cell cycle, which is likely required for taxol cytotoxicity. Conclusion. Although direct antagonism of the cytotoxicity of doxorubicin or etoposide by t axol has not been proven. there is less-than-additive in vitro cytotox icity when taxol is combined with these chemotherapeutic agents. The c linical implications of these findings are unknown; however, these fin dings generate concern about the combination of these agents in clinic al trials and suggest that additional studies to determine optimal sch eduling are needed.