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

R. A. Lubet, M. You, Y. Ruchon, D. End, W. Wouters, K. Christov, C. J. Grubbs

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)216
Number of pages1
JournalBreast Cancer Research and Treatment
Volume69
Issue number3
StatePublished - 2001

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Therapeutic and chemopreventive effects of R115777, a farnesyl transferase inhibitor (FTI), on methylnitrosourea (MNU)-induced rat mammary cancer'. Together they form a unique fingerprint.

Cite this