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 (IC(50) values, 50 pM and 1.0 nM). When drug uptake at 24 h was compared at IC(50) 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.