The antimicrotubule drugs include the vinca alkaloids (e.g., vincristine, vinblastine, vinorelbine and vindesine), taxanes (e.g., paclitaxel and docetaxel), and epothilones (ixabepilone).
Molecular Targets
The vinca alkaloids are naturally occurring (vincristine and vinblastine) or semisynthetic (vinorelbine) nitrogenous bases derived from the pink periwinkle plant, Catharanthus roseus. Paclitaxel was originally isolated from the bark of the Pacific yew, Taxus brevifolia. Paclitaxel can also be isolated from other members of the Taxus genus and from a fungal endophyte that grows on the Pacific yew. Docetaxel is derived semisynthetically from 10-deacetyl-baccatin III, which is obtained from the needles of the European yew, Taxus baccata.
The vinca alkaloids bind to the protein tubulin at a site distinct from that of the taxanes and, at low concentrations, inhibit microtubule dynamics. At higher concentrations, these vinca alkaloids disrupt microtubules and mitotic spindle, resulting in cell cycle mitotic arrest and apoptosis of cells (see Fig. 1). In contrast, after binding to α -tubulin, taxanes kinetically stabilize microtubule dynamics at their plus ends and shift the equilibrium toward tubulin polymerization into microtubule bundles. This also causes mitotic arrest and apoptosis of cells. The mitotic arrest caused by antimicrotubule drugs is associated with phosphorylation of the B-cell lymphoma (BCL2) protein and increased intracellular levels of the BCL2-associated X protein (Bax), which promote apoptosis.
Fig1. STRUCTURE OF COMMON ALKYLATING AGENTS.
As natural products, overexpression of the efflux pump multidrug resistance gene-1 (MDR-1) and the ABCB-1 transporter mediate resistance. Intracellular resistance to mitotic spindle and microtubule formation is mediated by numerous pathways and proliferative signals including MYC, nuclear factor kappa-B (NF κ B), and AKT.
Antimicrotubule agents, particularly the vinca alkaloids, are used in the management of lymphomas and leukemias, and continue to be used in the mainstay of clinical chemotherapeutic regimens. Because of their mechanism of action, they are best used in multiagent combi nations, in which potentiation of efficacy with other classes of agents, such as antimetabolites and DNA-damaging agents, provide better therapeutic responses and well-tolerated treatments.
