BIOLOGICAL AND BIOCHEMICAL PROPERTIES OF 1-(2-CHLOROETHYL)-3-(BETA-D-GLUCOPYRANOSYL)-1-NITROSOUREA (NSC D 254157), A NITROSOUREA WITH REDUCED BONE-MARROW TOXICITY

Abstract

1-(2-Chloroethyl)-3-(.beta.-D-glucopyranosyl)-1-nitrosourea (GANU), a water soluble nitrosourea, differs from 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose (chlorozotocin) by the placement of the cytotoxic group on C-1 of glucose. Its biological and biochemical properties are compared with those of chlorozotocin. At a 10% LD (10 mg/kg i.p.), GANU demonstrates minimal myelosuppression. This dose failed to depress normal bone marrow DNA synthesis, in contrast to a 96% inhibition in L1210 [lekemia] DNA synthesis. In L1210 cell suspension, equimolar doses of GANU and chlorozotocin produced equivalent degrees of inhibition in DNA synthesis. GANU has significant L1210 activity in BALB/c .times. DBA/2 F1 mice treated on day 2 of tumor growth. A 117% increased lifespan and 15% 45-day survivors are attained with 15 mg/kg i.p., a 50% LD. In concurrent studies using randomly selected littermate groups of mice, GANU proved less active than chlorozotocin which produced a 306% increased lifespan (15 mg/kg i.p.). GANU and chlorozotocin have similar in vitro alkylating activity but the in vitro carbamoylating activity of GANU is 7-fold that of chlorozotocin. On a molar basis, the lethal toxicity of GANU is twice that of chlorozotocin. The significant carbamoylating activity of GANU may contribute to its greater toxicity and limit the .mu.mol of alkylating agent that can be administered to the tumor. These structure-activity studies further confirm that the addition of a glucose carrier to a cytotoxic nitrosourea moiety can selectively reduce bone marrow toxicity while retaining antitumor activity.