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Inhibition of Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF) Activity by Suramin and Suramin Analogues Is Correlated to Interaction with the GM-CSF Nucleotide-binding Site¹

Veterans Affairs Medical Center, Lexington, Kentucky 40536-0093 [M. D.]; Colleges of Medicine and Pharmacy, Lucille P. Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0093 [M. D., A. C., C. G., B. H.]; AMGEN, Inc., AMGEN Center, Thousand Oaks, California 91320 [T. B.]; and University of Bonn, D-53115, Bonn 1, Germany [P. N.]

Suramin and suramin analogues strongly inhibit both nucleotide interaction with the nucleotide-binding site of granulocyte-macrophage colony-stimulating factor (GM-CSF) and bioactivity of the molecule as assessed by competition photoaffinity labeling and cell proliferation assay, respectively. The half-maximal inhibition of cell proliferation by suramin occurs at 68 ± 2.5 µM; three suramin analogues achieved comparable activity. The degree of competitive inhibition of nucleotide-binding by these compounds and the inhibition of GM-CSF bioactivity are correlated such that the compounds show similar rank-order by both of these methods. The strong interaction of suramin and related compounds with the nucleotide-binding site may mimic nucleotide-mediated inhibition of GM-CSF bioactivity and may be an important mechanism by which suramin acts as a pharmacological anti-growth factor agent.

¹ This work is supported by a Merit Review grant of the Department of Veteran Affairs (M. D.) and NIH Grant GM35766 (B. H.).

² To whom requests for reprints should be addressed, at Hematology/Oncology Section (111-E/CDD), Veterans Affairs Medical Center, 2250 Leestown Road, Lexington, KY 40511-1093. Phone: (606) 281-4956; Fax: (606) 281-4939.

Received 8/11/95. Accepted 9/27/95.