ta-077 and Leukopenia

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

TA-077, 1-(2-chloroethyl)-3-isobutyl-3-(beta-maltosyl)-1-nitrosourea, is a new water-soluble nitrosourea derivative which is disubstituted at the N-3 position of the structure, and is activated by a unique mechanism whereby organic isocyanates can never be produced. In order to clarify the biological functions of the organic isocyanates which common nitrosourea derivatives generate, TA-077 was tested in BDF1 mice for lethality, weight loss and hematological toxicity. TA-077 showed qualitatively and quantitatively similar toxicity to other nitrosourea derivatives which generate organic isocyanates, such as 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosour ea (ACNU), methyl 6-[3-(2-chloroethyl)-3-nitrosoureido ]-6-deoxy-alpha-D-glucopyranoside (MCNU), and 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea (GANU), indicating that the organic isocyanates do not play an important role in the biological activity of the nitrosourea derivatives. Furthermore, the toxicity of TA-077 did not increase significantly (except for weight loss) when the drug was administered daily for five days, and TA-077 given according to this schedule showed far more effective antitumor activity than when given as a single treatment. These results suggested that TA-077 is an analog suitable for consecutive administration in cancer treatment.

Topics: Animals; Body Weight; Drug Administration Schedule; Female; Leukopenia; Mice; Mice, Inbred Strains; Nitrosourea Compounds; Time Factors