COMBINATIONS OF PACLITAXEL AND VINBLASTINE AND THEIR EFFECTS ON TUBULIN POLYMERIZATION AND CELLULAR CYTOTOXICITY - CHARACTERIZATION OF A SYNERGISTIC SCHEDULE

Paclitaxel (PTX) and vinblastine (VBL) represent 2 classes of drugs th at target tubulin but have separate binding properties and opposing me chanisms of action. To evaluate the potential use of these agents toge ther in a chemotherapeutic regimen, we investigated their effects on t he dynamics of tubulin polymerization and cellular cytotoxicity, when administered singly or in combination. In human epidermoid carcinoma K B cells and MCF-7 breast carcinoma cells, we observed a time-and dose dependent effect on cytoskeletal dynamics for both PTX and VBL. Tubuli n polymerization induced by PTX was stable for more than 24 hr. When P TX treatment was followed by VBL, a time-and dose-dependent reversal o f tubulin polymerization was observed. In contrast, rapid tubulin poly merization occurred when VBL was followed by PTX. When both agents wer e added simultaneously, a diminution of PTX-induced tubulin polymeriza tion was observed with increasing doses of VBL; a maximum reduction wa s achieved when equal concentrations were used. Examination of the tub ulin pattern by immunofluorescence in MCF-7 breast cancer cells confir med and extended our findings. Bundle formation followed treatment wit h PTX. Addition of increasing concentrations of VBL prevented bundling ; however, the normal cytoskeletal architecture was not restored. Cyto toxicity studies carried out using the median dose effect principles a nd the combination index analysis showed synergism when VBL and PTX we re administered sequentially and antagonism for simultaneous administr ation. Our results demonstrate changes in tubulin dynamics following d rug treatment and provide a rationale for combined PTX/VBL therapy aft er careful evaluation of the schedule of administration. (C) 1998 Wile y-Liss, Inc.