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Lovastatin and tumor necrosis factor‐α exhibit potentiated antitumor effects against Ha‐ ras ‐transformed murine tumor Via inhibition of tumor‐induced angiogenesis
Author(s) -
Feleszko Wojciech,
Bałkowiec Ewa Z.,
Sieberth Elisabeth,
Marczak Maria,
Dabrowska Anna,
Giermasz Adam,
Czajka Anna,
Jakóbisiak Marek
Publication year - 1999
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19990517)81:4<560::aid-ijc10>3.0.co;2-7
Subject(s) - lovastatin , angiogenesis , cancer research , tumor necrosis factor alpha , pharmacology , tumor necrosis factor α , tumor cells , medicine , cholesterol
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. Int. J. Cancer 81:560–567, 1999. © 1999 Wiley‐Liss, Inc.