Cellular uptake and tubulin binding properties of four vinca alkaloids

doi:10.1016/0006-2952(92)90577-6

Biochemical Pharmacology

Volume 43, Issue 3, 4 February 1992, Pages 545-551

https://doi.org/10.1016/0006-2952(92)90577-6 Get rights and content

Abstract

The in vitro effects of four Vinca alkaloids, vinblastine (VLB), vincristine (VCR), vindesine (VDS) and vinepidine (VPD), on B16 melanoma proliferation, binding to bovine brain tubulin and B16 melanoma cell extracts, and uptake by the B16 cells were compared. The relative binding affinities to bovine brain tubulin were VPD > VCR ⋍ VDS > VLB with the K_a for VPD being about 4-fold higher than that for VLB. On the other hand, the relative effects on B16 cell proliferation were exactly the opposite. Differences were found in the degree of concentration of the four alkaloids by the cells: 100-fold for VLB, 50-fold for VCR and VDS, and 20-fold for VPD. At the extracellular concentrations of drugs which inhibit proliferation by 50%, the intracellular concentration would still be far less than the tubulin concentration. Thus, it is likely that all of the Vinca alkaloids would be bound to tubulin and difference in uptake rather than K_a values is the major factor in determining the relative effectiveness of the drugs. L cells showed 50% the sensitivity of B16 melanoma cells toward VLB and 30% the sensitivity toward VPD. The L cells also concentrated these drugs to a lesser extent than did the B16 cells.

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Cellular uptake and tubulin binding properties of four vinca alkaloids

Abstract

J Mol Biol

Biochim Biophys Acta

Anal Biochem

J Biol Chem

Biochem Pharmacol

J Biol Chem

J Mol Biol

J Biol Chem

Biochem Pharmacol

Biochemical and pharmacological properties of microtubules

Adv Cell Mol Biol

Interaction of drugs with microtubule proteins

Biochemistry of the dimeric Catharanthus alkaloids

Nonstoichiometric poisoning of microtubule polymerization: A model for the mechanism of action of the Vinca alkaloids, phodophyllotoxin and colchicine

Mechanism of inhibition of cell proliferation by Vinca alkaloids

Cancer Res

Aggregation of microtubule subunit protein. Effects of divalent cations, colchicine and vinblastine

Biochemistry

Inhibition of tubulin-microtubule polymerization by drugs of the Vinca alkaloid class

Cancer Res

Binding of vinblastine to stabilized microtubules

Mol Pharmacol