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-Difluoromethylornithine Alters Calcium Signaling in Platelet-derived Growth Factor-stimulated A172 Brain Tumor Cells in Culture¹

Brain Tumor Research Center of the Department of Neurological Surgery [B. G. F., H. S. B.], Division of Molecular Cytometry of the Laboratory Medicine [B. G. F., L. J. M.], and Department of Pediatrics [B. G. F.], School of Medicine, University of California, San Francisco, California 94143, and Department of Biophysics, Medical University School of Debrecen, Nagyerdei krt 98, H-4012 Debrecen, Hungary [J. S.]

² To whom requests for reprints should be addressed, at The Editorial Office, Department of Neurological Surgery, 1360 Ninth Avenue, Suite 210, San Francisco, CA 94122.

-Difluoromethylornithine (DFMO), an irreversible inhibitor of the polyamine biosynthetic enzyme ornithine decarboxylase, inhibits the growth of brain tumor cell lines and is undergoing clinical trials as a treatment for brain tumors. Platelet-derived growth factor (PDGF) is thought to regulate the growth and development of precursors of both normal and neoplastic astrocytic cells; calcium signaling is thought to play a role in the transduction of PDGF signals. Using laser fluorescence image cytometry, flow cytometry, and spectrofluorometry, we studied the effect of DFMO on the calcium signals induced by PDGF in A172 human glioblastoma cells. Four days of treatment with 5 mM DFMO substantially shortened PDGF-induced calcium signals. The effect was reversed more than 10 h but less than 24 h after putrescine treatment, even though polyamines were repleted 4 h after putrescine and spermidine were added. DFMO did not substantially affect intracellular calcium release or the timing of the opening and closing of plasma membrane calcium channels. These findings support the notion that calcium signaling may be a target for inhibitors of polyamine metabolism.

¹ Supported by Grants CA 13525, CA 37606, CA 49409, and CA 41757 from the NIH, by the National Brain Tumor Foundation, and by Grants OTKA 1492 and OKKFT 1142 from the Hungarian Academy of Science.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 4/16/92. Accepted 10/ 2/92.