In the past decade, the taxanes have emerged as one of the most powerful classes of anticancer drugs (1). Two unmodified taxanes, paclitaxel and docetaxel, are approved for clinical use in multiple tumors. An albumin-stabilized paclitaxel (abraxane) is also available for treatment of breast cancer (2), and a new analogue, cabazitaxel, is approved for hormone refractory prostate cancer. Despite their similar structures and a common mechanism of action (disruption of microtubule function), the taxanes differ in their pharmacological profiles, toxicity, and their patterns of clinical activity. Taxanes are predominantly employed in solid tumor chemotherapy in combination with platinum derivatives, with other cytotoxics, or with monoclonal antibodies such as Herceptin (trastuzumab). Both unmodified taxanes act synergistically with trastuzumab against HER2/neu overexpressed breast cancer cells in vitro and in vivo, and the combination of taxane and trastuzumab improves survival against HER2/neu amplified breast cancer in the adjuvant setting. The two original taxanes differ in their interaction with doxorubicin, paclitaxel potentiating the anthracycline's cardiac toxicity, while docetaxel and doxorubicin are well tolerated and highly active in combination (3). The taxanes are also primary agents for treating other malignancies, including ovarian, lung, and bladder cancer.
A closely related antimitotic agent, ixabepilone, is approved for second-line breast cancer treatment after taxanes, and differs from taxanes in its greater neurotoxicity and its lack of cross-resistance in MDR-positive tumors.
Paclitaxel was first isolated from the bark of the Pacific yew, Taxus brevifolia. Paclitaxel and its analogue, docetaxel, are now synthesized from 10-deacetylbaccatin III, a precursor found in the leaves of the European yew, Taxus baccata (4). Both molecules are composed of a 15-member taxane ring system linked to a 4-member oxetan ring at the C-4 and C-5 positions of the molecule. The structures of paclitaxel and docetaxel differ in substitutions at the C-10 ring position and in the configuration of an ester side chain attached at C-13. Docetaxel is slightly more water soluble than paclitaxel and a more potent inhibitor of tubulin in cell-free systems. The side chain substitutions at C-13 position are essential for antimicrotubule activity. The chemical structures of paclitaxel and docetaxel are shown in Figure 3-1. Abraxane is identical to paclitaxel, but is formulated within a microalbumin particle that eliminates the hypersensitivity caused for the lipid excipient used to deliver paclitaxel. Cabazitaxel retains the taxane nuclear ring system but has multiple side chain modifications to increase its solubility and decrease susceptibility to multidrug resistance.
The chemical structure of antimitotics: (A–C) taxanes, (D) ixabepilone, and (E) eribulin.
The taxanes stabilize microtubules. They bind to the interior surface of the β-microtubule chain and enhance microtubule assembly by promoting the nucleation and elongation phases of tubulin polymerization. In solution they ...