Anticancer Activity of New Nitrosoureas against Walker Carcinosarcoma 256 and DMBA-Induced Mammary Cancer of the Rat

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Abstract
Three new nitrosoureas and chlorozotocin were screened for anticancer activity against [rat] Walker carcinoma 256 cells and DMBA[7,12-dimethylbenz(a)antracene]-induced mammary cancer of the rat. High single doses (80% of LD50) of water-soluble 1-(2-chloroethyl)-1-nitroso-3-(methylencarboxamido)urea and 2-[3-(2-chloroethyl)-3-nitrosoureido]ethyl-methansulfonate effected a similar tumor weight inhibition than BCNU [1,3-bis-(2-chloroethyl)-1-nitrosourea] in treatment of s.c. implanted Walker 256. In dose-response studies low doses of the new analogs effected a higher tumor wt inhibition than BCNU in the treatment of s.c. implanted Walker 256. The therapeutic index calculated as LD50/ED50, was 2.7 and 2.4 for the new compounds in comparison to BCNU with 2.1. Chlorozotocin and 1-(methylenecarboxyethyl)-1-nitroso-3-phenylurea were not active. Against DMBA-induced mammary cancer the new BCNU analogs yielded a greater tumor weight inhibition than adriamycin and BCNU. At a dose-level of approximately LD10 the remission rates of individual tumors, which were at least 0.6 g at the beginning of treatment, were 46% (13/28) for therapy with 2-[3-(2-chloroethyl)-3-nitrosoureido]ethylmethanesulfonate, 32% (9/28) for 1-(2-chloroethyl)-1-nitroso-3-(methylenecarboxamido)urea, 26% (6/23) for chlorozotocin, 21% (7/33) for adriamycin and 17% for BCNU, respectively. As single agents 2-[3-(2-chloroethyl)-3-nitrosoureido]ethylmethanesulfonate, the water-soluble 1-(2-chloroethyl)-1-nitroso-3-(methylenecarboxamido)urea and chlorozotocin were the most effective compounds against DMBA-induced mammary cancer of the rat.