TYRPHOSTIN 4-NITROBENZYLIDENE MALONONITRILE REDUCES CHEMOTHERAPY TOXICITY WITHOUT IMPAIRING EFFICACY

In mice, 4-nitrobenzylidene malononitrile (AG1714), which belongs to t he tyrphostin family, reduced toxicity induced by doxorubicin and cisp latin without impairing their antitumor efficacy. AG1714 reduced morta lity induced by doxorubicin and cisplatin, It prevented, in a dose-dep endent manner, cisplatin-induced nephrotoxicity as assessed by measure ment of serum creatinine and blood urea nitrogen levels, The protectiv e effect of AG1714 was most pronounced on its administration 2 h befor e cisplatin, AG1714 also prevented doxorubicin-induced myelosuppressio n as assessed by the scoring of bone marrow nucleated cells and colony -forming units. Cisplatin-induced small intestinal injury was also pro tected by AG1714 as assessed by histopathological analysis. In vitro, AG1714 reduced cisplatin-induced apoptosis in a murine fibroblastic ce ll line (A9) and did not affect doxorubicin-induced apoptosis of B-16 melanoma cells. In contrast to its protective effect against mortality and injury of normal tissues induced by chemotherapy, AG1714 did not impair its antitumor activity and in some tumor models enhanced it. Th is was evident by using the murine tumors B-16 melanoma, Lewis lung ca rcinoma, and methylcholanthrene-induced fibrosarcoma and the human tum ors SK-28 melanoma and human ovary carcinoma xenografts in nude mice. Experiments in which low and high doses of cisplatin and doxorubicin w ere administered to tumor-bearing mice demonstrated that AG1714 reduce d mortality of high-dose chemotherapy and increased its therapeutic in dex. AG1714 could provide a novel, useful tool to improve chemotherapy by allowing dose intensification.