ta-077 and Neoplasms

A new nitrosourea antitumor agent TA-077, 1-(2-chloroethyl)-3-isobutyl-3-(beta-maltosyl)-1-nitrosourea, was intravenously administered to 15 cancer patients at doses ranging from 7 to 100 N (1 N = 30 mg/m2) in a phase I clinical trial. Time courses of blood concentrations of TA-077 and its active metabolite TA-G, 3-beta-D-glucopyranosyl analog of TA-077, were followed. The TA-G concentration reached a maximum at 7.0 +/- 2.3 min, and decreased thereafter with a half-life of 12.9 +/- 2.8 min. The time-course patterns and various pharmacokinetic parameters of TA-077 and TA-G were similar to those in the guinea pig, which, like humans, lacks plasma maltase activity. The 2 h-urinary excretion rate of TA-G in the above patients ranged from 0.15 to 7.7% of the dose. The areas under the concentration-time curve and maximal concentration values were both linearly correlated to the dose with correlation coefficients of 0.78 and 0.82, respectively. Repeated administration of TA-077 (29 to 40 N) for 5 or 6 consecutive days did not affect the pharmacokinetic parameters of TA-077 and TA-G in 7 cancer patients except for slight increases in the half-life and area under the curve of blood TA-G.

Topics: Adult; Aged; Antineoplastic Agents; Drug Evaluation; Female; Half-Life; Humans; Injections, Intravenous; Male; Middle Aged; Neoplasms; Nitrosourea Compounds

Topics: Antineoplastic Agents; Cell Division; HeLa Cells; Humans; Lymphocytes; Monocytes; Neoplasms; Nitrosourea Compounds

A phase I study on TA-077, a water-soluble nitrosourea, was performed by a 9-institution clinical group using 89 patients with various malignant tumors. The study consisted of single-dose i.v. administration and daily i.v. administration for 3-6 consecutive days. The dose-limiting factor was delayed leukopenia and thrombocytopenia which reached nadirs about 5 weeks and about 4 weeks after the initiation of administration and recovered in 2 to 3 weeks, respectively. Gastrointestinal toxicity, such as nausea, vomiting and anorexia, appeared in the early stage of treatment, although most of these symptoms were mild or moderate. Other side effects, including transient liver and renal dysfunctions observed in a few cases, were mild and appeared not to be dose-dependent. M.T.D. in single administration was considered to be more than 3,000 mg/m2 and M.T.D. in 5-day consecutive administration was considered to be 1,000 mg/m2/day. The recommended dose schedule for initiation of the phase II study was assumed to be 700 to 900 mg/m2/day for 5 consecutive days.

Topics: Antineoplastic Agents; Drug Administration Schedule; Drug Evaluation; Humans; Leukopenia; Neoplasms; Nitrosourea Compounds; Thrombocytopenia