A Phase I Study of Swainsonine in Patients with Advanced Malignancies

摘要: Abstract Swainsonine, an α-mannosidase inhibitor which blocks Golgi oligosaccharide processing, represents a new class of compounds that inhibit both rate tumor growth, and metastasis, in murine experimental models. In this first phase I study, the quantitative qualitative toxicities swainsonine have been studied patients given continuous i.v. infusion over 5 days, repeated at 28-day intervals. Dose levels were escalated increments 100 µg/kg/day from 50–550 µg/kg/day. Nineteen with solid hematological malignancies total 31 courses. Hepatotoxicity, particularly liver metastases, was dose-limiting toxicity. The maximum tolerated dose (MTD) recommended starting (MTD -1 level) 550 450 µg/kg/day, respectively. Common side effects included edema, mild dysfunction, rise serum amylase, decreased retinol. Acute respiratory distress syndrome possibly precipitated by resulted treatment-related death patient significant pretreatment hepatic dysfunction. One head neck cancer showed >50% shrinkage mass for 6 weeks after treatment. Two lymphangitis carcinomatosis on chest X-ray noted improvement cough shortness breath during 1 week thereafter. Clearance half-life determined to be approximately 2 ml/h/kg, 0.5 day, putative anticancer target inhibited peripheral blood lymphocytes as evidenced marked decrease leukoagglutinin binding days Oligomannosides urine increased 5-to 10-fold treatment, indicating tissue lysosomal α-mannosidases also blocked swainsonine. Urine oligomannoside accumulation reached steady state 3 day drug state. fraction HLA-DR-positive cells following effect similar observed normal subjects cultured No changes CD3, CD4, CD8, CD16, CD25 observed. Swainsonine produces minimal toxicity when administered dosages II α-mannosidases. Detection metastases or enzyme abnormalities prior treatment predict more