vintriptol and Neoplasms

The vinca alkaloids remain among the most useful classes of anticancer agents used in the clinic today. However, previous analogs of these agents have not realized either increased safety or an enhanced antitumor spectrum. Currently, three derivatives are in clinical trial: vinorelbine, vintripol, and vinxaltine. Vinorelbine has shown consistent antitumor activity in patients with breast carcinoma and is in phase III trials in the United States, Europe, and Japan. Vintripol and vinxaltine, vinca alkaloids conjugated to amino acids, are in early clinical trials in Europe. The dose-limiting toxicity of these agents is leukopenia. A similar agent with a different chemical structure, rhizoxin, is in early phase II clinical trials with initial activity noted in breast carcinoma. The ultimate role of these agents in treatment of human malignancy awaits the results of ongoing studies.

Topics: Animals; Antineoplastic Agents; Chemistry, Pharmaceutical; Clinical Trials as Topic; Drugs, Investigational; Humans; Lactones; Macrolides; Neoplasms; Vinblastine; Vinca Alkaloids; Vinorelbine

Vintriptol, a tryptophan ester of vinblastine, is a new vinca alkaloid derivative. Preclinical studies have demonstrated its antitumour activity in a large variety of animal models. In this phase I study, 47 patients with advanced cancer were exposed to escalating doses of vintriptol, starting at 6 mg/m2 and following a modified Fibonacci schedule. The drug was administered as an intravenous push on a weekly schedule. Myelosuppression was the dose-limiting toxicity and the maximum tolerated dose was 45 mg/m2. Other toxicities consisted of mild nausea and vomiting and the occurrence of fever and dryness of the mouth immediately after drug administration. Neurotoxicity, a major side-effect of other vinca alkaloids, was insignificant. 1 partial remission in a patient suffering from colorectal cancer and 1 minor response in a patient with a metastatic tumour of the cutaneous appendagous glands were documented. Pharmacokinetics of vintriptol were evaluated at the highest dose levels. A dose schedule of 40 mg/m2 vintriptol per week is recommended for phase II studies.

Topics: Adult; Aged; Antineoplastic Agents; Drug Evaluation; Female; Fever; Humans; Leukopenia; Male; Middle Aged; Neoplasms; Thrombocytopenia; Vinblastine

Vinblastine tryptophan ester (VTrpE) is a new vinca alkaloid derivative that achieves antitumor activity in a large variety of animal models. In this phase I study the drug was given as an i.v. injection over 5 min, once a week or once every 2 weeks. Twenty patients with advanced cancer were entered in this trial. The doses ranged from 2.5 mg/m2 to 35 mg/m2. Myelosuppression is the dose-limiting toxicity, with the risk of leukopenia being more serious than that of thrombocytopenia, but the myelosuppression is always reversible. Neurotoxicity, well documented when other vinca alkaloid derivatives are used, is insignificant. Two cases of disease stabilization have been observed in patients with non-small cell lung cancer. For VTrpE, a dose schedule of 30 mg/m2 per week may be recommended for phase II studies in non-small cell lung cancer.

Topics: Adult; Child; Drug Evaluation; Female; Humans; Leukopenia; Male; Neoplasms; Thrombocytopenia; Vinblastine