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A Structure-Activity Analysis of Chemical and Biological Parameters of Chloroethylnitrosoureas in Mice¹

Division of Medical Oncology, Vincent T. Lombardi Cancer Research Center, Georgetown University School of Medicine, Washington, D. C. 20007

Linear regression analysis was performed to study the correlation of in vitro carbamoylating activities, alkylating activities, and chemical half-lives with the biological activities of six chloroethylnitrosoureas in mice. The biological parameters included the dose resulting in the death of 10% of normal mice (LD₁₀), antitumor activity for the L1210 leukemia system, and myelotoxicity as expressed by the nadir of the peripheral blood neutrophil count following an LD₁₀ dose.

There was a highly significant inverse linear relationship between alkylating activity and the chemical half-life of the chloroethylnitrosoureas. A significant linear relationship was found between the molar LD₁₀ and alkylating activity or the chemical half-life; the greater the alkylating activity or the shorter the half-life, the lower the molar LD₁₀. In contrast, carbamoylating activity did not demonstrate a significant correlation with the molar LD₁₀.

None of the three chemical parameters demonstrated a significant linear correlation with antitumor activity or myelotoxicity. Water solubility did not function as an independent variable for either of these biological activities. Two agents in this series, chlorozotocin and 1-(2-chloroethyl)-3-(ß-D-glucopyranosyl)-1-nitrosourea, produced no suppression of the peripheral blood neutrophil count at an LD₁₀ dose; both have a glucose carrier that may be responsible for their reduced myelotoxicity.

¹ This investigation was supported in part by Research Grants CH13 from the American Cancer Society and 1-RO1-CA 17583-01ET from the NIH, Bethesda, Md.

² To whom requests for reprints should be addressed.

Received 2/ 4/77. Accepted 5/13/77.