Lovastatin and tumor necrosis factor-α 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 combined with either tumor necrosis factor-α (TNF- α), cisplatin or doxorubicin in a melanoma model in mice. Since lovastatin interferes with the function of ras oncogene-encoded (Ras) proteins, we have investigated the antitumor activity of lovastatin and TNF-α 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 experiments, the Ras-3T3 tumor demonstrated significantly increased sensitivity to combined treatment with both lovastatin (50 mg/kg) and TNF-α (1 μg/day) compared with either agent alone. Combined treatment with both agents also resulted in greater inhibition of blood-vessel formation. Ras- 3T3 tumor cells produced increased amounts of vascular endothelial growth factor (VEGF) and lovastatin effectively suppressed VEGF production by these cells. Our results suggest that lovastatin increases antitumor activity of TNF-α against tumor cells transformed with v-Ha-ras oncogene via inhibition of tumor-induced blood-vessel formation.