Sustained intracellular retention of dolastatin 10 causes its potent antimitotic activity

Pascal Verdier-Pinard, John A. Kepler, George Pettit, Ernest Hamel

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Abstract

Dolastatin 10 is a highly cytotoxic antimitotic peptide in phase II clinical trials. Its cytotoxicity has been as much as 50-fold greater than that of vinblastine, despite quantitatively similar effects of the two drugs on tubulin polymerization. We compared uptake and efflux of radiolabeled dolastatin 10 and vinblastine in human Burkitt lymphoma CA46 cells to gain an understanding of the greater cytotoxicity of the peptide. In the Burkitt cells, dolastatin 10 was 20-fold more cytotoxic than vinblastine (IC50 values, 50 pM and 1.0 nM). When drug uptake at 24 h was compared at IC50 values of the two drugs, the intracellular concentrations were almost identical (50-100 nM). The accumulation factor observed for dolastatin 10 was 900 to 1800 versus 60 to 100 for vinblastine. The two drugs showed very divergent uptake kinetics, however. Vinblastine and dolastatin 10 reached maximum intracellular concentrations after 20 min and 6 h, respectively. Depletion of cellular ATP content did not alter the uptake of either drug, indicating passive uptake of both. When drug-preloaded cells were transferred to drug-free medium, there was no loss of dolastatin 10 for at least 2 h, whereas vinblastine exited the cells rapidly (approximate intracellular half- life, 10 min), with less than 10% of the initial drug remaining in the cells after the 2-h incubation. The potency of dolastatin 10 probably derives from its tenacious binding to tubulin, a property that in cells becomes translated into prolonged intracellular retention of the drug. Optimal clinical use of dolastatin 10 may require administration by infusion rather than by bolus.

Original languageEnglish (US)
Pages (from-to)180-187
Number of pages8
JournalMolecular Pharmacology
Volume57
Issue number1
StatePublished - Jan 18 2000

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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