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 mutations, rats with a palpable cancer were treated with R115777 for a period of 36 or 96 hours prior to sacrifice, and the proliferation and apoptosis levels in the cancers were determined. The proliferative index was significantly (>85%) decreased in all mammary cancers with HaRas mutations, whereas variable responses were observed in cancers without HaRas mutations. Apoptosis was also measured and a 5-fold increase was observed in HaRas mutant tumors, again with varying responses in the HaRas wild-type cancers. Thus, R115777 was active in the prevention and therapy of these chemically induced mammary cancers, but was strikingly more effective in cancers with HaRas mutations.
ASJC Scopus subject areas
- Cancer Research