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.