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3-(Tetraacetyl Glucopyranos-2-yl)-1-(2-chloroethyl)-1-nitrosourea, an Antitumor Agent with Modified Bone Marrow Toxicity

Medicine Branch, National Cancer Institute, NIH, Bethesda, Maryland 20014

3-(Tetraacetyl glucopyranose-2-yl)-1-(2-chloroethyl)-1-nitrosourea (GCNU) is an aminoglucose chloroethylnitrosourea structurally related to the nonmyelosuppressive but diabetogenic antitumor agent, streptozotocin. GCNU is active against L1210, producing a greater than 100% increase in life-span at a 10% lethal dose without an accompanying leukopenia. In contrast, treatment with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea or 1,3-bis(2-chloroethyl)-1-nitrosourea at doses of comparable overall toxicity produced a sustained 60 to 75% reduction in peripheral white blood cell counts. Twenty-four hr after administration, GCNU inhibited DNA synthesis in L1210 and gastrointestinal mucosa but spared the bone marrow. In contrast, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea nonselectively inhibited all three tissues.

Nitrosoureas and nitrosamines that have a H₁ but not a chloroethyl end group depress hepatic nicotinamide adenine dinucleotide concentrations, the proposed mechanism of diabetogenicity of streptozotocin. GCNU, a chloroethylnitrosourea, does not depress nicotinamide adenine dinucleotide and is not diabetogenic in the mouse.

These structure-activity studies suggest that the addition of an aminoglucose carrier to a cytotoxic nitrosourea moiety can selectively reduce bone marrow toxicity while retaining antitumor activity.

¹ To whom requests for reprints should be sent, at Medicine Branch, Building 10, Room 12N226, National Cancer Institute, NIH, Bethesda, Md. 20014.

Received 1/26/73. Accepted 5/ 9/73.