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Additive effects of tamoxifen and the farnesyl transferase inhibitor FTI-277 on inhibition of MCF-7 breast cancer cell-cycle progression


The efficacy of tamoxifen in the hormonal therapy of breast cancer is well established, but therapeutic resistance is inevitable. FTIs are a new class of anticancer drugs that are in phase III clinical evaluation. Since the mechanisms of action of these 2 classes of drugs are different, we tested the combination of tamoxifen and FTI-277 on inhibiting proliferation of hormone-dependent MCF-7 human breast cancer cells. An additive effect on cell proliferation was demonstrated, accompanied by an additive G(0)/G(1) arrest. The major effect of the combination of the 2 drugs was to maintain p21(waf/cip1) at an intermediate level, higher than that observed in the presence of tamoxifen alone. This was associated with an additive effect on inactivation of cyclin E-Cdk2 complexes and decreased phosphorylation of pRb and p130 pocket proteins. These effects were accompanied by increased association of 2 CDIs, p27(kip1) and p21(waf/cip1), with cyclin E-Cdk2 complexes. These data demonstrate that the additive effect is likely predominantly due to the recruitment of p27(kip1) and, to a lesser extent, p21(waf/cip1) into the cyclin E-Cdk2 complexes. Together, these results suggest that the combination of FTI and tamoxifen may increase the antitumor effect of either drug alone in breast cancer.

Type Journal
ISBN 0020-7136 (Print)
Authors Doisneau-Sixou, S. F.;Cestac, P.;Faye, J. C.;Favre, G.;Sutherland, R. L. :
Publisher Name INT J CANCER
Published Date 2003-01-01 00:00:00
Published Volume 106
Published Issue 5
Published Pages 789-98
Status Published In-print