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Treatment with Farnesyl-Protein Transferase Inhibitor Induces Regression of Mammary Tumors in Transforming Growth Factor (TGF) and TGF/neu Transgenic Mice by Inhibition of Mitogenic Activity and Induction of Apoptosis¹

Vanderbilt Cancer Center [P. N., B. L., H. J., H. L. M.], Departments of Cell Biology [B. L., H. J., R. J. C., H. L. M.], Pathology [D. L. P.], Medicine [R. J. C.], Preventive Medicine [Y. S.], and Biochemistry [D. M., J. A. P.], Vanderbilt University, Nashville, Tennessee 37232; Veterans Affairs Medical Center, Nashville, Tennessee 37232 [R. J. C.]; Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486 [N. E. K., A. O.]; and Section for Radiation Biology, The Finsen Center, Rigshospitalet, Copenhagen DK-2100, Denmark [P. N., H. S. P.]

Mouse mammary tumor virus-transforming growth factor (MMTV-TGF) and MMTV-TGF/neu transgenic mice develop mammary tumors after a long latency and therefore provide useful model systems for breast cancer with its recognized activation of receptor tyrosine kinase signaling. We used these mice to study the antitumor effect of L-744,832 (FTI), a potent and selective inhibitor of farnesyl-protein transferase, and hence of Ras function. A total of 55 mice were assigned randomly to treatment with FTI or vehicle, and one-half of the mice were crossed over after initial treatment to the opposite group. L-744,832 induced reversible regression of mammary tumors that was paralleled by a decrease in serum levels of TGF secreted by the tumor cells. There was no difference in response to treatment with FTI between MMTV-TGF mice, in which tumorigenesis was accelerated by multiparity or the chemical carcinogen 7,12-dimethylbenzanthracene, and MMTV-TGF/neu mice. The tumor histological type had no impact on FTI sensitivity. For mechanistic analyses, tumor excision biopsies were obtained from 12 mice before and after treatment with L-744,832. In these samples, tumor regression was paralleled biochemically by inhibition of mitogen-activated protein kinase activity and biologically by an increase in G₁-phase and decrease in S-phase fractions, as well as induction of apoptosis. These results suggest that the potential clinical use of FTI could be expanded to include cancers harboring activated receptor tyrosine kinases as well as those containing activated Ras.

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