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Tumor Growth Inhibition, Apoptosis, and Bcl-2 Down-Regulation of MCF-7ras Tumors by Sodium Phenylacetate and Tamoxifen Combination¹

Institut d'Oncologie Moléculaire et Cellulaire Humaine, 129 av de Stalingrad [L.A., L.I.], and S.M.B.H., 74 rue Marcel Cachin [M. C.], Bobigny 93000, France

We demonstrated previously the antitumoral and antiproliferative effects of sodium phenylacetate (NaPA) on malignant breast epithelial MCF-7ras cells and its lack of toxicity. The present in vivot protocols were as follows: (1) a control group; (2) a NaPA-receiving group (450 mg/kg) through s.c. osmotic pumps (ALZA Corp.) for 2 weeks, followed by 2 weeks with no treatment; and (3) a tamoxifen (TAM)-receiving group (20 mg/kg two times per week). The second group was further divided as follows: (a) a group receiving same doses of NaPA; (b) a TAM-receiving group; and (c) a group receiving both NaPA and TAM. Although tumors treated by TAM alone (group 3) showed progressive regrowth after 6 weeks, indicating an escape from antiestrogen inhibition, the TAM-administered group, following 2 weeks of NaPA pretreatment (group 2b), showed significant tumor regression of about 40% after 8 weeks. This effect was amplified to over 60% (P < 0.001) by simultaneous administration of the two drugs (group 2c). The last group displayed about 30% apoptotic-like nuclei, together with lower proliferation index, and less tumor vascularization, as compared to less than 5% terminal deoxytransferase-mediated dUTP-X nick end labeling-positive nuclei, highly vascularized tumors, in the TAM-treated group. Furthermore, in vitro administration of 4-OH-tamoxifen induced a Bcl-2 up-regulation in MCF-7ras cells, which was completely abolished by NaPA pretreatment. The combination of NaPA and OHT induced significant cell differentiation with cell cycle accumulation in the G₀-G₁ phase.

¹ This work was supported by a Martine Midy Foundation grant.

² To whom requests for reprints should be addressed, at M. D. Anderson Cancer Center, Cell Growth & Regulation Laboratory, University of Texas, 1515 Holcombe Boulevard, P. O. Box 36, Houston, TX 77030.

Received 11/19/96. Accepted 1/31/97.

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