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Sodium Phenylacetate Induces Growth Inhibition and Bcl-2 Down-Regulation and Apoptosis in MCF7ras Cells in Vitro and in Nude Mice¹

Institut d'Oncologie Moléculaire et Cellulaire Humaine, 129 av. de Stalingrad, 93000 Bobigny [L. A.]; Université Paris Nord, 74 rue Marcel Cachin, 93012 Bobigny [M. C.]; Service d'Anatomie Pathologique [C. S.]; and Clinique Universitaire de Cancérologie, 125 av. de Stalingrad, 93000 Bobigny [L. I.], France

Using a highly tumorigenic human breast cancer model (Ha-ras-transfected MCF7 cell line) we analyzed the efficacy of the differentiation-inducing agent sodium phenylacetate (NaPA), both in vitro and in vivo. NaPA-treated MCF7ras cells showed dose-dependent growth inhibition from 2.5 to 15 mM without apparent toxicity. Western blot analysis showed a Bcl-2 down-regulation after 48 h treatment with 5 mM NaPA, together with apparition of apoptotic nuclei by DAPI staining. Mice bearing MCF7ras xenografts (n = 40) were treated for 2 weeks through s.c.-delivering osmotic pumps, followed by 6 weeks of daily i.p. NaPA administration. After 3 weeks, the treated tumors showed growth arrest without regression for the whole observation time, e.g., 12 weeks. Immunohistochemical analysis showed Bcl-2 down-regulation and differentiation patterns: decrease of Ki-67 and increase of steroid receptors (estrogen and progesterone receptors) compared to controls. Cells cultured from treated tumors (II.b) displayed pseudotrabecular disposition as MCF7ras cells treated in vitro. They also showed a higher NaPA sensitivity, together with 70% Bcl-2 down-regulation as compared to the derived cells of untreated tumors (II.a). When reinjected into nude mice, II.b cells induced only one poorly vascularized, noninvasive tumor (8%) with lower proliferation index, 100% progesterone receptor positive cells, and 35% terminal deoxynucleotidyltransferase-mediated dUTP-X nick end labeling (+) nuclei, as compared to 100% induction of highly vascularized and invasive tumors with 3% terminal deoxynucleotidyltransferase-mediated dUTP-X nick end labeling (+) nuclei induced by II.a cells.

¹ Supported by a grant from the Association pour la Recherche sur le Cancer and the Association pour le Développment de l'Enseignement et la Recherche Médicale.

² To whom requests for reprints should be addressed.

Received 8/ 4/95. Accepted 9/27/95.

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