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The Binding of Vinblastine to Tubulin and to Particulate Fractions of Mammalian Brain¹

Oncology Center, The Johns Hopkins University, School of Medicine, Baltimore, Maryland 21224 [R. J. O., D. W. D., C. A. H., R. M. D.], and Department of Pharmacology and Experimental Therapeutics, The Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205 [M. J. K.]

The binding of tritium-labeled vinblastine (VLB) to tubulin derived from mammalian brain was measured by Sephadex gel column chromatography and by adsorption onto diethylaminoethyl-cellulose filter paper. Tubulin purified by the reassembly method gave results consistent with prior data, obtained from ammonium sulfate-diethylaminoethyl-cellulose-purified tubulin, with a K_a for VLB of 5.2 x 10⁶ liters/mole, and for colchicine of 2.0 x 10⁶ liters/mole. The ratio of VLB to colchicine binding was 1:2, indicating that 1 mole of VLB binds to 240,000 daltons. Crude tubulin solutions had essentially the same binding properties as the purified protein. Binding of VLB to the microsomal-synaptosomal fraction of homogenized brain was found to be significant, and quantitatively greater than binding to the soluble tubulin fraction. The ratio of bound VLB to colchicine in the microsomal-synaptosomal fraction was 2:1. It is felt that binding of the Vinca alkaloids to tubulin and tubulin-like proteins is the primary mode of action of these drugs, and a scheme relating the observed interactions of VLB with tubulin is presented.

¹ This work was supported by NIH Grant CA 06973 and by the Eli Lilly Company.

² To whom requests for reprints should be addressed, at The Oncology Center, The Johns Hopkins University, School of Medicine, B2-South, Baltimore City Hospitals, 4940 Eastern Avenue, Baltimore, Md. 21224.

Received 4/22/74. Accepted 7/30/74.