Vinepidine, a new derivative of
vincristine, and three clinically used Catharanthus derivatives,
vinblastine,
vincristine, and
vindesine, were examined for their abilities to inhibit net
tubulin addition at the assembly ends of bovine brain microtubules at steady state. Although all four derivatives were generally similar in potency, their relative abilities to inhibit
tubulin addition were distinguishable.
Vinepidine and
vincristine were the most potent derivatives (Ki, 0.079 +/- 0.018 (SD) microM and 0.085 +/- 0.013 microM, respectively), followed by
vindesine (Ki, 0.110 +/- 0.007 microM) and
vinblastine (Ki, 0.178 +/- 0.025 microM). In contrast to their relative abilities to inhibit microtubule assembly in vitro,
vinblastine and its derivative,
vindesine, were generally more potent than
vincristine and
vinepidine in inhibiting cell proliferation in culture.
Vinblastine was nine times more potent than the weakest derivative,
vinepidine, in
B16 melanoma cells. In L-cells,
vinblastine completely inhibited growth at 40 nM, whereas
vincristine and
vindesine caused about 25% inhibition, and
vinepidine was inactive. When
B16 melanoma cells were treated with
drug before being injected into mice, retardation of
tumor growth was best achieved with
vindesine, one of the weaker of the four derivatives in vitro. The results demonstrate that chemical differences among the Catharanthus derivatives, which affect to small extents the abilities of the derivatives to inhibit microtubule assembly in vitro, result in significant differences in the order and the magnitude of the abilities of the drugs to inhibit cell growth.