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Antitumor Activity and Bone Marrow Toxicity of Aminoglucose Mustard Anticancer Agents in Mice¹

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

In previous structure-activity studies, we have demonstrated that attachment of a glucose molecule to the chloroethylnitrosourea cytotoxic group produces a compound with reduced murine bone marrow toxicity and retention of full antitumor activity. To further define this protective role conferred by the glucose moiety in bone marrow cells, we have replaced the nitrosourea cytotoxic group with another class of alkylating agent, a bifunctional nitrogen mustard. In a detailed structure-activity analysis, we have now characterized four analogues, with the mustard cytotoxic group positioned at carbon 2 [1,3,4,6-tetra-O-acetyl-2-(di-2-chloroethyl)amino-2-deoxy-D-glucopyranose (TGM)], carbon 6, or carbon 1 (D- and L-isomers) of the aminoglucose molecule. On a molar basis, TGM was most toxic to normal BALB/c x DBA/2 F₁ mice, with a 10% lethal dose (LD₁₀) of 3.8 µmol/kg. The D- and L-isomers of 2,3,4,6-tetra-O-acetyl-N,N-bis(2-chloroethyl)glucopyranosylamine (C-1) were the least toxic, with an LD₁₀ of 73 µmol/kg for both. Optimal antitumor activity against the murine P388 leukemia (single i.p. administration of the LD₁₀) did not differ significantly among the four analogues, with increased life span ranging from 83–86%. P388 antitumor activity for nitrogen mustard (HN2) was significantly less, 60% increased life span (P = 0.01), while p-di(2-chloroethyl)amino-L-phenylalanine produced an increased life span of >101%. An LD₁₀ of 6-bis-(2-chloroethyl)amino-6-deoxy-D-glucose (C-6) or TGM produced significantly less depression of WBC counts than did an equitoxic dose of the C-1 isomers, HN2, or p-di(2-chloroethyl)amino-L-phenylalanine. The mean nadir WBC count for C-6 equaled 86% of control, and for TGM, 80% of control. Consistent with this sparing effect on the peripheral WBC, C-6 and TGM produced significantly less in vivo murine bone marrow DNA synthesis depression, 77 and 64% of control, respectively, as compared to the depression nadir produced by HN2 (27% of control), the D-isomer of C-1 (17%), the L-isomer of C-1 (18%), and p-di(2-chloroethyl)amino-L-phenylalanine (2%). These structure-activity studies demonstrate that conjugation of the mustard cytotoxic group to carbon 6 or carbon 2 of glucose produces an analogue that retains P388 antitumor activity significantly greater than that of HN2, with a concomitant reduction in murine bone marrow toxicity.

¹ This investigation was supported by Research Grant CH13 from the American Cancer Society and Grant 1-R01-CA17583 from NIH, Bethesda, MD. The data were presented, in part, at the 1983 meeting of the American Association for Cancer Research (1).

² To whom requests for reprints should be addressed, at Division of Medical Oncology, V. T. Lombardi Cancer Research Center, Georgetown University Medical Center, Washington, DC 20007.

Received 4/19/85. Revised 1/28/86. Accepted 1/31/86.