Vincristine Oncovin Vincasar PFS

4.2.2.1 Medical Uses. Vincristine (35) is a common component of antitumor cocktails used in treating acute lymphoblastic leukemia and solid tumors of youngsters and in adult lymphoma. It is commonly used with corticosteroids. Study of its use in the form of liposomes has also been carried out (344).Its use produces limited myelosuppression, so it is an attractive component in cocktails. The reduced myelotoxicity may be attributable to oxidative degradation of the drug by myeloperoxidase, a heme-centered peroxidase enzyme present in acute myeloblasts leukemia but not in acute lymphoblastic leukemia (345,346).

4.2.2.2 Pharmacokinetic Features. Vincristine is extensively metabolized in the liver and the metabolites are excreted as conjugates in the bile. About 15% of the drug is found unchanged in the urine.

4.2.2.3 Side Effects and Contraindications. Vincristine causes severe tissue necrosis upon extravasation (123).Neurotoxicity is a significant potential problem with vincristine and is often treated in part by reducing the dose of the drug (347). Myelosuppression also occurs but to a lesser extent and this effect should be monitored to prevent significant toxicity to the patient. Gout can occur with vincristine administration and can be controlled by use of allopuri-nol. The other side effects of vinblastine are common to antitumor agents (alopecia, ulceration, nausea, diarrhea, etc.).

4.2.2.4 Resistance. Resistance to vincris-tine is mediated in part by export resulting from the multidrug resistance protein and, interestingly, is characterized by cotransport with reduced glutathione (348).

4.2.3 Vinorelbine (Navelbine) 4.2.3.1 Medicinal Uses. Vinorelbine (37) is used against non-small-cell lung cancer and

against breast cancer (349-353). It appears to be intermediate in its neurotoxicity and my-elosuppression compared to that of the other vinca antitumor agents (354).

4.2.3.2 Pharmacokinetic Features. Vinorelbine is extensively metabolized in the liver and the metabolites are excreted as conjugates in the bile. About 15% of the drug is found unchanged in the urine.

4.2.3.3 Side Effects and Contraindications. Vinorelbine causes severe tissue necrosis upon extravasation as well as phlebitis (355). Prior i.v. administration of cimetidine partially avoids this. Mild neurotoxicity and myelosuppression occur and these effects should be monitored to prevent significant toxicity to the patient. Its most notable toxic side effect appears to be granulocytopenia. The other side effects cf vinorelbine are common to antitumor agents (alopecia, ulceration, nausea, etc.).

4.2.3.4 Things to Come. Vindisine (36) is an analog prepared from vinblastine (34).Its antitumor spectrum, however, is more closely similar to that of vincristine. Clinical studies show activity against acute leukemia; lung cancer; breast carcinoma; squamous cell carcinoma cf the esophagous, head, and neck; Hodgkin's disease; and non-Hodgkin's lymphomas. Its toxicities include myelosuppression and neurotoxicity. Despite these promising findings, it has yet to be introduced into the clinic (356).

Vinflunine (38) is a dimeric alkaloid, containing two gem-fluorine atoms, prepared by a mechanistically interesting process using super acidic reactants on vinorelbine. This com-

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