Vinca Alkaloids

NATURAL PRODUCT CANCER CHEMOTHERAPY DRUGS

VINCA ALKALOIDS

Vinblastine

Vinblastine is an alkaloid derived from the periwinkle plant Vincarosea. Its mechanism of action involves inhibition of tubulin polym-erization, which disrupts assembly of microtubules, an important part of the cytoskeleton and the mitotic spindle. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death. Vinblastine and other vinca alkaloids are metabolized by the liver P450 system, and the majority of the drug is excreted in feces via the hepatobiliary system. As such, dose modification is required in the setting of liver dysfunction. The main adverse effects are outlined in Table 54–4, and they include nausea and vomiting, bone marrow suppression, and alopecia. This agent is also a potent vesicant, and care must be taken in its admin-istration. It has clinical activity in the treatment of Hodgkin’s and non-Hodgkin’s lymphomas, breast cancer, and germ cell cancer.

Vincristine

Vincristine is another alkaloid derivative of V rosea and is closely related in structure to vinblastine. Its mechanism of action, mechanism of resistance, and clinical pharmacology are identical to those of vinblastine. Despite these similarities to vinblastine, vincristine has a strikingly different spectrum of clinical activity and safety profile.

Vincristine has been effectively combined with prednisone for remission induction in acute lymphoblastic leukemia in children. It is also active in various hematologic malignancies such as Hodgkin’s and non-Hodgkin’s lymphomas, and multiple myeloma, and in several pediatric tumors including rhabdomyosarcoma, neuroblastoma, Ewing’s sarcoma, and Wilms’ tumor. The main dose-limiting toxicity is neurotoxicity, usually expressed as a peripheral sensory neuropathy, although autonomic nervous system dysfunction with orthostatic hypotension, urinary retention, and paralytic ileus or constipation, cranial nerve palsies, ataxia, seizures, and coma have been observed. While myelosuppression occurs, it is generally milder and much less significant than with vinblastine.

The other adverse effect that may develop is the syndrome of inap-propriate secretion of antidiuretic hormone (SIADH).

Vinorelbine

Vinorelbine is a semisynthetic derivative of vinblastine whose mechanism of action is identical to that of vinblastine and vincris-tine, ie, inhibition of mitosis of cells in the M phase through inhibition of tubulin polymerization. This agent has activity in non-small cell lung cancer, breast cancer, and ovarian cancer. Myelosuppression with neutropenia is the dose-limiting toxicity, but other adverse effects include nausea and vomiting, transient elevations in liver function tests, neurotoxicity, and SIADH.