Antimitotics

In the 1950s, the identification of antimi-crotubule agents that possess novel mechanisms of cytotoxic action and unique spectra of antitumor activity represented a major advance in cancer treatment. Based on their mechanism of action, antimitotics' primary effect is to disrupt the organization and dynamics of the mitotic spindle, preventing the M phase transit and cell division. The evident benefits of these drugs continue to promote significant interest in therapeutic agents directed against microtubule function. Most agents in use are structurally complex plant alkaloids possessing pharmacological activity. The first widely used class of microtubule directed agents were the vinca alkaloids, which have been a mainstay of chemotherapy regimens since they came into use in 1959. The development of taxanes as another subclass of antimicrotubule compounds has been important because these agents have unique mechanisms of action and unique spectra of activity. Semisynthetic strategies to produce taxanes have been important in wider use and study of these agents.

A. Vinca Compounds

1. Vinblastine, Vincristine, and Vinorelbine

Vinblastine and vincristine are alkaloids derived from the periwinkle plant Catharan-thus roseus. These compounds have cell cycle-specific activity in the M phase, which is consistent with their ability to inhibit tubulin polymerization and prevent formation of the mitotic spindle. In this manner, they induce a terminal mitotic arrest that ultimately leads to cell death. Vinblastine is indicated in the treatment of patients with Hodgkin's and non-Hodgkin's lymphomas, breast cancer, Kaposi's sarcoma, renal cell cancer, and testicular cancer. Vincristine is more widely indicated, including for the treatment of patients with myeloma, acute lymphocytic leukemia, Hodgkin's and non-Hodgkin's lymphomas, rhabdomyosarcoma, neuroblastoma, Ewing's sarcoma, Wilm's tumor, chronic leukemia, thyroid cancer, brain tumors, and trophoblastic neoplasia. Adverse reactions are broad, including typical side effects of cytotoxic chemothera-peutics, such as myelosuppression, mucosi-tis, fever, anemia, and alopecia. Vincristine also causes additional side effects, such as hypertension, neuropathy, depression, Raynaud's phenomenon, myocardial infarction, and pulmonary edema. Resistance mechanisms include gp170-mediated MDR and mutations in tubulin subunit proteins that decrease drug binding.

Vinorelbine is a semisynthetic derivative of vinblastine that also inhibits tubulin polymerization and disrupts spindle assembly in the M phase. This compound has a higher specificity for mitotic microtubules and a lower affinity for axonal microtu-bules, reducing neuropathy. Vinorelbine is indicated in the treatment of lung cancer, breast cancer, and ovarian cancer. Adverse reactions are similar to those produced by vinblastine include myelosuppression, nausea, vomiting, and constipation; altered liver function, requiring more frequent liver function tests; alopecia; neurotoxicity; hypersensitivity; and syndrome of inappropriate antidiuretic hormone secretion (SIADH).

B. Taxanes

Taxanes are complex molecules with a unique mechanism of action that is coupled to broad antitumor activity. Like vinca compounds, the primary action of taxanes is based on their ability to target microtu-bules; however, the action of taxanes is associated with microtubule stabilization rather than microtubule disruption. Since their discovery in the 1960s, taxanes have become one of the most important classes of anticancer agents available to the clinical oncologist.

1. Paclitaxel

Paclitaxel (Taxol®) is derived from extracts of the Pacific yew tree Taxus brevi-folia. This compound is cell cycle-specific acting in the M phase of the cell cycle. Paclitaxel binds to microtubules and enhances tubulin polymerization, leading to microtubule stabilization. During mitosis, paclitaxel acts to disrupt the dynamics of the mitotic spindle, preventing its ability to function normally and blocking cell division and survival as a result. Paclitaxel has a significant role in the treatment of ovarian, breast, lung, head and neck, esophageal, prostate, and bladder cancers. It is also used in treating Kaposi's sarcoma. The utility of this compound is likely to continue to expand. Adverse effects of paclitaxel include the common side effects of other cytotoxic drugs, but it can also cause transient brady-cardia, nail destruction, and mild elevation of liver enzymes. An important and notable side effect is neurotoxicity in the form of sensory neuropathy. In addition, a hyper-sensitivity reaction is observed in 20-40% of patients (attributable in part to the oil-based drug vehicle Cremophor). This reaction is commonly prevented by pre-medicating patients with steroids and antihistamine drugs. Resistance mechanisms include gp170-mediated MDR and tubulin mutations that reduce drug binding.

2. Docetaxel

Docetaxel is a semisynthetic taxane derived from extracts of the European yew tree Taxus baccata. Docetaxel is similar to paclitaxel in its mechanism of action, adverse reactions, and resistance mechanisms. However, docetaxel is more water soluble than paclitaxel, and it has a slightly higher affinity than paclitaxel for that site. In addition, hypersensitivity reactions occur in less than 5% of patients treated with docetaxel, and neuropathy is also observed less frequently. Docetaxel is effective in the treatment of breast, lung, head and neck, gastric, ovarian, and bladder cancers.

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