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 combined with either tumor necrosis factor-alpha (TNF-alpha), 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-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 experiments, the Ras-3T3 tumor demonstrated significantly increased sensitivity to combined treatment with both lovastatin (50 mg/kg) and TNF-alpha (1 microg/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-alpha against tumor cells transformed with v-Ha-ras oncogene via inhibition of tumor-induced blood-vessel formation.
Feleszko
W
W
Department of Immunology, Institute of Biostructure, Medical University of Warsaw, Medical University Children's Hospital, Poland.
Bałkowiec
E Z
EZ
Sieberth
E
E
Marczak
M
M
Dabrowska
A
A
Giermasz
A
A
Czajka
A
A
Jakóbisiak
M
M
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D011905:Genes, ras; D008148:Lovastatin / Q000627:therapeutic use* / Q000633:toxicity*; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use* / Q000633:toxicity*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D008222:Lymphokines; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D008148:Lovastatin