Effects of the farnesyl transferase inhibitor R115777 (Zarnestra) on mammary carcinogenesis: prevention, therapy, and role of HaRas mutations

Molecular Cancer Therapeutics
Ronald A LubetClinton J Grubbs

Abstract

The ability of the farnesyl transferase inhibitor R115777 to act as a cancer therapeutic/preventive agent and to modulate proliferation/apoptosis markers was determined in the methylnitrosourea-induced model of mammary carcinogenesis. Female Sprague-Dawley rats were given methylnitrosourea at 50 days of age. In the prevention study, R115777 (5, 16, or 50 mg/kg body weight/d), beginning 5 days after methylnitrosourea treatment, decreased the formation of mammary cancers by 6%, 42%, and 75%, respectively. Approximately 50% of the mammary cancers that developed had HaRas mutations. Only 1 of 15 tumors that grew out in the presence of R115777 (16 or 50 mg/kg body weight/d) had a HaRas mutation. In the therapeutic study, a surgical biopsy of a mammary cancer was done to determine HaRas status, and growth of the cancer was then followed during treatment of the rat with R115777. Virtually every cancer with a HaRas mutation underwent complete regression within 3 weeks, whereas tumors without a HaRas mutation had variable responses to the inhibitor. Both of these studies implied a high sensitivity of tumors with HaRas mutations to the effects of R115777. In order to understand the preferential susceptibility of tumors with HaRas mutatio...Continue Reading

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Citations

Jul 16, 2014·Expert Review of Hematology·Muneera Al-Hussaini, John F DiPersio
Sep 8, 2010·Seminars in Oncology·Vernon E Steele, Ronald A Lubet
Mar 28, 2013·Cancer Prevention Research·Ronald A LubetClinton J Grubbs
Sep 19, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Konstantin ChristovRonald A Lubet

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