Lovastatin and tumor necrosis factor-alpha exhibit potentiated antitumor effects against Ha-ras-transformed murine tumor via inhibition of tumor-induced angiogenesis

Lovastatin, a drug commonly used in the treatment of hypercholesterolemia, has previously been reported to exert potentiated antitumor activity when c ombined with either tumor necrosis factor-alpha (TNF-alpha), cisplatin or d oxorubicin in a melanoma model in mice. Since lovastatin interferes with th e function of ros oncogene-encoded (Ras) proteins, we have investigated the antitumor activity of lovastatin and TNF-alpha using a Ha-ras-transformed murine tumor model. In in vitro studies, lovastatin inhibited the growth of cells transformed with Ha-ras oncogene (Ras-3T3 and HBL100-ras cells) more effectively than control NIH-3T3 and HBL100-neo cells. In in vivo experime nts, the Ras-3T3 rumor demonstrated significantly increased sensitivity to combined treatment with both lovastatin (50 mg/kg) and TNF-alpha (I mu g/da y) compared with either agent alone. Combined treatment with both agents al so resulted in greater inhibition of blood-vessel formation, Ras-3T3 tumor cells produced increased amounts of vascular endothelial growth factor (VEG F) and lovastatin effectively suppressed VEGF production by these cells. Ou r results suggest that lovastatin increases antitumor activity of TNF-alpha against tumor cells transformed with v-Ha-ros oncogene via inhibition of t umor-induced blood-vessel formation. (C) 1999 Wiley-Liss, Inc.