Sensitivity of human and murine hematopoietic precursor cells to 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose and 1,3-bis(2-chloroethyl)-1-nitrosourea.

The sensitivity of mouse and human bone marrow hematopoietic precursor cells [colony-forming units committed to granulocyte-macrophage differentiatin (CFU-C)] was determined after in vitro incubation with chlorozotocin (2-[3-(2-chloroethyl)-3-nitrosoureido]-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/10(5) 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 25% reduction in CFU-C as compared to the control of 32 colonies/10(5) 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.