Mechanism of Action of Paclitaxel
Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization, resulting in inhibition of the normal dynamic reorganization of the microtubule network essential for vital interphase and mitotic cellular functions. 1
Primary Mechanism: Microtubule Stabilization
Paclitaxel enhances the polymerization of tubulin to stable microtubules and interacts directly with microtubules, stabilizing them against depolymerization by cold and calcium, which readily depolymerize normal microtubules. 2
The drug has a specific binding site on the microtubule polymer, making it unique among chemotherapeutic agents, and paclitaxel can polymerize tubulin in the absence of cofactors like guanosine triphosphate (GTP) and microtubule-associated proteins (MAPs). 2
When paclitaxel and microtubule protein are irradiated with ultraviolet light, the drug preferentially binds covalently to the beta-subunit of tubulin. 2
Effects on Microtubule Dynamics
Paclitaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. 1
The microtubule cytoskeleton is reorganized in the presence of paclitaxel, with extensive parallel arrays or stable bundles of microtubules formed in cells growing in tissue culture. 2
Paclitaxel reduces the critical nucleation concentration of tubulins required to polymerize microtubules, with an 89% decrease in critical nucleation concentration when paclitaxel concentration increases from 0.1 μM to 10 μM. 3
The drug reduces the rate constant of microtubule shortening more prominently (by 100-fold) compared to the rate constant of elongation. 3
Cell Cycle Effects
Paclitaxel blocks cells in the G2/M phase of the cell cycle, and such cells are unable to form a normal mitotic apparatus. 2
The stability induced by paclitaxel results in inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. 1
Molecular Interactions
Paclitaxel binds to cells in a specific and saturable manner with a single set of high-affinity binding sites. 2
The drug enhances the interaction between alpha and beta tubulins and microtubule-associated protein 2 (MAP2) by inhibiting MAP kinase and CDC2 kinase, which regulate MAP2 phosphorylation and its affinity for tubulins. 4
Paclitaxel treatment inhibits MAP-kinase activity and p34cdc2-kinase activation at the G2/M phase, indirectly increasing the affinity between MAP2 and tubulins. 4
Metabolism
Paclitaxel is metabolized primarily to 6α-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8, and to two minor metabolites, 3'-p-hydroxypaclitaxel and 6α,3'-p-dihydroxy-paclitaxel, by CYP3A4. 1
After intravenous administration, mean values for cumulative urinary recovery of unchanged drug ranged from 1.3% to 12.6% of the dose, indicating extensive non-renal clearance. 1
A mean of 71% of radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine, with paclitaxel representing a mean of 5% of the administered radioactivity recovered in the feces. 1