COMPARISON OF BIOLOGICAL AND BIOCHEMICAL PROPERTIES OF 1-(4-AMINO-2-METHYLPYRIMIDIN-5-YL)METHYL-3-(2-CHLOROETHYL)-3-NITROSOUREA AND 2-[3-(2-CHLOROETHYL)-3-NITROSOUREIDO]-D-GLUCOPYRANOSE

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  • 1 January 1978
    • journal article
    • research article
    • Vol. 38  (1) , 65-68
Abstract
1-(4-Amino-2-methylpyrimidine-5-yl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) is a water-soluble nitrosourea that produced delayed hematological toxicity in man during phase 1 clinical trials. ACNU has in vitro alkylating activity 40% less than that of 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose (chlorozotocin) but shares the property of negligible carbamoylating activity with the latter compounds. ACNU is active against murine L1210 leukemia. The maximum therapeutic dose, 30 mg/kg (a dose lethal to 10% of the animals), produced a 64% reduction in peripheral WBC [white blood cells] and an 85% decrease in circulating neutrophils in normal mice. This was correlated with a 76% inhibition of normal mouse bone marrow DNA synthesis within 24 h after treatment, followed by full recovery within 48 h DNA synthesis in L1210 cells was suppressed to less than 10% of control for a minimum of 72 h. While ACNU, a pyrimidine analog, possesses many of the chemical properties of chlorozotocin, it does not share with the latter compound its reduced myelotoxicity at therapeutic doses. The glucose carrier of the chlorozotocin molecule appears to impart the selective sparing of normal bone marrow.