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L. (1971). Mol. Pharmacol. 7, 519-529. Struck, R. , Kirk, M. C , Witt, M. , and Laster, W. , Jr. (1975). Biomed. Mass Spectrom. 2, 46. , and Yamaguchi, K. (1973). J. Am. Chem. Soc. 95, 985-986. 3 NITROSOUREAS Philip S. Schein I. II. III. IV. V. VI. Introduction Decomposition and Metabolism Mechanism of Action A. Alkylation B. Carbamolylation Clinical Use Clinical Toxicities Discussion References 37 38 39 39 40 41 44 46 47 I. INTRODUCTION In 1959, 1-methyl-l-nitro-3-nitrosoguanidine (MNNG) was reported to have limited but reproducible antitumor activity aginst the murine LI210 leukemia.
The survival at 18 months of followings for radiation therapy was 9% versus 18% for BCNU plus irradiation, a marginal improvement but achievement without appreciable additive toxicity (Walker and Gehan, 1976). The principal indication for nitrosourea therapy in lymphoproliferative disor ders is Hodgkin's disease. , 1976; Selawry and Hansen, 1972). Responses usually occur early, within 2 weeks, and with a median duration of 4 months. The Cancer and Acute Leukemia Group B (CALGB) has tested the activity of three chloroethylnitrosoureas in patients with advanced previously treated Hodgkin's disease (Selawry and Hansen, 1972).
Kohn, K. , and Gullion, A. (1974b). Cancer Res. 34, 1982-1988. Kohn, K. W. (1977). Cancer Res. 37, 1450-1454. Kovach, J. , Moertel, C. , Schutt, A. , Hahn, R. , and Reitemeier, R. J. (1974). Cancer (Philadelphia) 33, 563-567. Ludlum, D. , Kramer, B. , and Fenselau, C. (1975). Biochemistry 14, 5480-5485. Moertel, C. , Schutt, A. , Hahn, R. , and Reitemeier, R. J. (1975). J. Nati. Cancer lnst. 54, 69-71. Montgomery, J. , McCaleb, G. , Kirk, M. C , and Johnston, T. P. (1975). J. Med. Chem. 18, 568-571.