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Reversal of Basic Fibroblast Growth Factor-mediated Autocrine Cell Transformation by Aromatic Anionic Compounds¹

Department of Oncology, Hadassah University Hospital, Jerusalem, Israel [M. B., I. V., R. B-S.]; Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel [A. Y.]; Department of Medicinal Chemistry, Rhone-Poulenc Rorer Central Research, King of Prussia, Pennsylvania [J. R., M. C.]; and The Hubert H. Humphrey Center for Experimental Medicine and Cancer Research, the Hebrew University-Hadassah Medical School, Jerusalem, Israel [S. B-S.]

NIH-3T3 cells transfected with basic fibroblast growth factor (bFGF) fused to a signal peptide sequence (spbFGF cells) are transformed in vitro and tumorigenic in vivo. Treatment of spbFGF cells with low and nontoxic concentrations (0.5–2.5 µg/ml) of negatively charged, nonsulfated aromatic compounds (e.g., aurin tricarboxylic acid, 4-hydroxyphenoxyacetic acid) resulted in restoration of their normal proliferative rate, morphological appearance, and adhesion properties. Binding and cross-linking experiments using ¹²⁵I-labeled bFGF revealed that these alterations were associated with an up-regulation of high affinity receptors for bFGF on the cell surface. A similar up-regulation of cross-linkable bFGF receptors was induced by these compounds in spbFGF cells that were seeded on fibronectin to enforce a firm cell attachment and flattening. Thus, induction of spbFGF cell adhesion and spreading may not be related to restoration of normal bFGF-receptor interactions. Although the negatively charged aromatic compounds mimic many of the effects of heparin in other systems (e.g., release of heparin- and heparan sulfate-bound proteins, inhibition of heparanase), heparin, heparan sulfate, and dextran sulfate were not effective at the low concentrations of the anionic compounds used in the present study. Likewise, suramin, a sulfated aromatic molecule, was effective at toxic concentrations, 400–600-fold higher than the nonsulfated aromatic compounds. The development of defined, nontoxic anionic compounds may provide a new strategy to interfere with the autonomous and anchorage independent mode of cell growth involved in autocrine cell transformation and cancer.

¹ This work was supported by USPHS Grant CA-30289 awarded to I. V. by the National Cancer Institute, Department of Health and Human Services, and by a grant from Rhone-Poulenc Rorer Pharmaceuticals, Inc.

² To whom requests for reprints should be addressed, at Department of Oncology, Hadassah Hospital, P.O. Box 12000, Jerusalem 91120, Israel.

Received 4/ 8/92. Accepted 8/ 3/92.

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