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Effect of Tamoxifen on DNA Synthesis and Proliferation of Human Malignant Glioma Lines in Vitro¹

Departments of Neurosurgery [I. F. P., M. S. R., M. P. K., R. G. S., F. T. V.] and Pathology [R. H. K., F. T. V.], University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, and the West Penn Center for Neuro-Oncology, Pittsburgh, Pennsylvania 15224

Previous studies in our laboratory have shown that proliferation of human malignant gliomas in vitro depends in part upon the activation of protein kinase C (PKC) and, conversely, can be blocked by inhibitors of PKC. Here, we examined the effect of tamoxifen, a known PKC inhibitor, on DNA synthesis and proliferation of an established human glioma line (U138) and two low passage cultures of explanted human glioblastomas. Tamoxifen produced a profound, dose-dependent inhibition of both [³H] thymidine incorporation and cell proliferation, with a 50% effective dose of 20 ng/ml under serum-free conditions and 50 to 200 ng/ml in the presence of 10% serum. These tumors were estrogen receptor negative and showed no mitogenic response to estradiol. Furthermore, concentrations of estradiol as high as 10 µg/ml had no effect on the tamoxifen-induced inhibition. This suggests that the mechanism of growth inhibition by tamoxifen in these gliomas did not involve an estrogen receptor-mediated process but may instead result from its inhibition of PKC. In view of the profound effect of tamoxifen on cultured gliomas at concentrations that can safely be achieved therapeutically, further in vitro and in vivo studies of this agent are warranted.

¹ This work was supported in part by Competitive Medical Research Fund Grant 3783 from the Presbyterian-University Hospital of Pittsburgh (I. F. P.) and American Cancer Society Institutional Research Grant IN-58-28 (F. T. V.).

² To whom requests for reprints should be addressed, at The Center for Neuroncology at Western Pennsylvania Hospital, Division of Neurosurgery, 4800 Friendship Ave., Pittsburgh, PA 15224.

Received 5/21/90. Accepted 8/20/90.

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