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Growth Inhibitory Effects of Sodium Phenylacetate (NSC 3039) on Ovarian Carcinoma Cells in Vitro¹

Departments of Gynecologic Oncology [G. F., B. M., A. L., C. L. E., R. S. F.], Gynecologic Medical Oncology [C. F. V., A. P. K., J. J. K.], and Gastrointestinal Oncology and Digestive Diseases [J. L. A.], The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030; and Department of Gynecology and Obstetrics, Catholic University, Rome 00168, Italy [G. F., G. S.]

The aim of this study was to determine the antiproliferative activity of sodium phenylacetate (NaPa) against ovarian carcinoma cell lines. NaPa induced a dose-dependent inhibition (IC₅₀ from 12 mM to >20 mM) of all ovarian carcinoma cell lines, although the sensitivity of individual lines to NaPa varied. Both cisplatin-sensitive and -resistant cell lines responded to NaPa, and growth-inhibitory activity was also detected against cells freshly isolated from malignant ascites of previously treated patients. The growth inhibitory effects that were produced by NaPa were time dependent, showing a maximum effect at 72 h, and were not associated with cytotoxic action. Growth inhibitory effects of NaPa were also reversible. After 48- and 72-h exposures to NaPa, a reduction in the percentage of cells in the S-phase was detected, with a concomitant recruitment of cells in the G₀–G₁ phase. Treatment with NaPa after different exposure times did not significantly increase the proportion of cells undergoing apoptosis. NaPa also produced a significant reduction in the percentage of cyclin-D1- and p21/ras-positive cells and in the percentage of cells positive for bcl-2, whereas the percentages of bax/p21-positive cells increased. NaPa produced minimal, if any, alterations of expression of HLA class I and transforming growth factor ß1 antigens. In contrast, the percentage of transforming growth factor ß2-positive cells decreased after exposure to NaPa. The combination of NaPa with cisplatin resulted in an additive inhibitory effect. Our results show, for the first time, that NaPa inhibits the growth of ovarian carcinoma cell lines and the cells from malignant ascites of chemotherapy-treated patients with ovarian carcinoma. The growth-inhibitory properties of NaPa suggest that this molecule could represent a prototype of a new class of compounds with possible therapeutic potential in patients with ovarian carcinoma.

¹ This work was supported in part by National Cancer Institute Grants UO1 CA97-001 and RO1 CA64943.

² To whom requests for reprints should be addressed, at Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 67, Houston, TX 77030.

Received 4/ 7/97. Accepted 8/ 2/97.

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