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Sensitivity of Human and Murine Hematopoietic Precursor Cells to 2-[3-(2-Chloroethyl)-3-nitrosoureido]-D-glucopyranose and 1,3-Bis(2-chloroethyl)-1-nitrosourea¹

Division of Medical Oncology, Vincent T. Lombardi Cancer Research Center, Georgetown University School of Medicine, Washington, D. C. 20007 [P. S., D. D., D. H.], and Medicine Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20014 [J. B.]

The sensitivity of mouse and human bone marrow hematopoietic precursor cells [colony-forming units committed to granulocyte-macrophage differentiation (CFU-C)] was determined after in vitro incubation with chlorozotocin (2-[3-(2-chloroethyl)-3-nitrosoureldo]-D-glucopyranose), or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with the use of drug concentrations achieved during clinical administration. Chlorozotocin, at a concentration of 1 x 10^-4 M, did not decrease mouse CFU-C below the control of 44 colonies/10⁵ nucleated cells; 5 x 10^-4 M produced a 70% reduction in CFU-C, and 1 x 10^-3 M chlorozotocin eliminated all colony formation. In contrast, BCNU at 1 x 10^-4 M resulted in a 55% reduction in CFU-C, and at 5 x 10^-4 M it eliminated all colony formation. For human marrow the threshold concentration for chlorozotocin toxicity was 1 x 10^-4 M, which resulted in a 25% reduction in CFU-C as compared to the control of 32 colonies/10⁵ nucleated cells. In contrast, BCNU at 5 x 10^-5 M decreased human CFU-C to 47% of control, and at 1 x 10^-4 M it eliminated all colony formation. Twenty-four hr after in vitro exposure to 1 x 10^-4 M chlorozotocin, there was no reduction in human bone marrow DNA synthesis in contrast to a 42% reduction with 1 x 10^-4 M BCNU. The plasma concentration of drugs following a therapeutic dose in patients was measured and was found to correspond to the concentration range used in the in vitro studies of marrow toxicity.

¹ Supported by Research Grants CH-13 from the American Cancer Society and 1-R01-CA-17583-01ET from NIH, Bethesda, Md.

² To whom requests for reprints should be addressed, at Division of Medical Oncology, Georgetown University Hospital, 3800 Reservoir Road, N.W., Washington, D.C. 20007.

Received 6/23/77. Accepted 10/24/77.