TY - JOUR
T1 - Therapeutic and chemopreventive effects of R115777, a farnesyl transferase inhibitor (FTI), on methylnitrosourea (MNU)-induced rat mammary cancer
AU - Lubet, R. A.
AU - You, M.
AU - Ruchon, Y.
AU - End, D.
AU - Wouters, W.
AU - Christov, K.
AU - Grubbs, C. J.
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
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M3 - Article
AN - SCOPUS:33749114480
SN - 0167-6806
VL - 69
SP - 216
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 3
ER -