Therapeutic and chemopreventive effects of R115777, a farnesyl transferase inhibitor (FTI), on methylnitrosourea (MNU)-induced rat mammary cancer

FTIs block the farnesyiation and processing of proteins including the Ras oncogenes. Sprague-Dawley rats given a single dose of MNU at 50 days of age develop hormonally responsive mammary cancers roughly 50% of which have HaRas mutations. To determine the role of HaRas mutations in the therapeutic efficacy of FTIs, rats bearing small palpable tumors were treated daily with FTI [Janssen R155777] (50 or 100 mg/KgBW) for 28 days. Although cancers of vehicle-treated rats grew variably, >60% of these tumors grew at least 2.5X and 56% (14/25) had HaRas mutations determined by DNA sequencing. In contrast >50% of palpable cancers in rats treated with FTI profoundly regressed (>80%), while 0/13 tumors which failed to regress had HaRAS mutations. In a second study palpable cancers were surgically biopsied and, beginning 3 days after the biopsy, rats were treated with FTI (50 mg/KgBW) for 28 days. All 9 of the tumors with HaRas mutations underwent complete regression while 7/13 without Ha Ras mutations underwent significant regression (>50%). When small palpable tumors were treated with R155777 for 3 days more striking effects (↓ proliferations; ↑ apoptosis) were found in tumors with Ha Ras mutations. To examine the ability of FTI to prevent mammary cancer FTI was administered daily beginning 3 weeks after MNU. Doses of 16 and 50 mg/ KgBw/Day of FTI decreased tumor multiplicity 40 and 75% respectively. Thus this FTI can be both an effective preventive and therapeutic agent in this specific model of mammary tumorigenesis and is more effective in tumors with Ha Ras mutations.