Mechanism of mitotic block and inhibition of cell proliferation by the semisynthetic Vinca alkaloids vinorelbine and its newer derivative vinflunine.
The two second-generation Vinca alkaloids, vinorelbine and vinflunine, affect microtubule dynamics very differently from vinblastine, a first generation Vinca alkaloid. For example, vinblastine strongly suppresses the rate and extent of microtubule shortening in vitro, whereas vinorelbine and vinflunine suppress the rate and extent of microtubule growing events. We asked whether these differences result in differences in mitotic spindle organization that might be responsible for the superior antitumor activities of the two second-generation Vinca alkaloids. IC(50) values for inhibition of HeLa cell proliferation for vinflunine, vinorelbine, and vinblastine were 18, 1.25, and 0.45 nM, respectively, similar to the concentrations that induced mitotic block at the metaphase/anaphase transition (38, 3.8, and 1.1 nM, respectively), indicating that mitotic block is a major contributor to antiproliferative action for all three drugs. Mitotically blocked cells exhibited aberrant spindles, consistent with induction of block by suppression of microtubule dynamics. Despite differences in their actions on individual dynamic instability parameters, morphologically detectable differences in spindle effects among the three drugs were minimal, indicating that overall suppression of dynamics may be more important in blocking mitosis than specific effects on growth or shortening. We also found that the peak intracellular drug concentration at the mitotic IC(50) value was highest for vinflunine (4.2 +/- 0.2 microM), intermediate for vinorelbine (1.3 +/- 0.1 microM), and more than 10-fold lower for vinblastine (130 +/- 7 nM), suggesting that intracellular binding reservoir(s) may be partially responsible for vinflunine's high efficacy and minimal side effects.
Ngan
V K
VK
Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, California 93106, USA.
Bellman
K
K
Hill
B T
BT
Wilson
L
L
Jordan
M A
MA
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000502:physiology; D008938:Mitosis / Q000187:drug effects*; D008941:Spindle Apparatus / Q000187:drug effects* / Q000502:physiology; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014748:Vinca Alkaloids / Q000494:pharmacology; D000077235:Vinorelbine
D000972:Antineoplastic Agents, Phytogenic; D014748:Vinca Alkaloids; C111217:vinflunine; D014747:Vinblastine; D000077235:Vinorelbine