Enhancement of paclitaxel-mediated cytotoxicity in lung cancer cells by 17-allylamino geldanamycin: In vitro and in vivo analysis

Background. It has previously been demonstrated that 17-allylamino geldanam ycin (17-AAG) enhances paclitaxel-mediated cytotoxicity and downregulates v ascular endothelial factor expression in non-small cell lung cancer. This p roject was designed to evaluate the tumoricidal and antiangiogeneic effects of 17-AAG and paclitaxel in H358 non-small cell lung cancer cells grown as xenografts in nude mice. Methods. In vitro cytotoxic drug combination effects were evaluated by (4, 5-dimethylthiazo-2-yl)-2, 5-diphenyl tetrazolium bromide-based proliferatio n assays. The combinations of 17-AAG and paclitaxel were administered intra peritoneally in nude mice bearing H358 tumor xenografts. Tumor volumes were measured weekly. Tumor expression of erbB2, vascular endothelial cell grow th factor, von Willebrand factor (tumor microvasculature), and activated ca spase 3 (apoptosis) were determined by immunohistochemistry. Results. Five- to 22-fold enhancement of paclitaxel cytotoxicity was achiev ed by paclitaxel + 17-AAG combination that was paralleled with marked induc tion of apoptosis. This combination treatment profoundly sup-pressed tumor growth and significantly prolonged survival of mice bearing H358 xenografts . Immunohistochemical staining of tumor tissues indicated profound reductio n of vascular endothelial cell growth factor expression associated with red uction of microvasculature in tumors treated with 17-AAG. Apoptotic cells w ere more abundant in tumors treated with 17-AAG + paclitaxel than in those treated with 17-AAG or paclitaxel alone. Conclusions. Concurrent exposure of H358 cells to 17-AAG and paclitaxel res ulted in supraadditive growth inhibition effects in vitro and in vivo. Anal ysis of molecular markers of tumor tissues indicated that therapeutic drug levels could be achieved with this chemotherapy regimen leading to signific ant biological responses. Moreover, 17-AAG-mediated suppression of vascular endothelial cell growth factor production by tumor cells may contribute to the antitumor effects of this drug combination in vivo. (C) 2001 by The So ciety of Thoracic Surgeons.