LONG LASTING PROLIFERATIVE DEFECT IN THE HEMATOPOIETIC STEM-CELL COMPARTMENT FOLLOWING CYTO-TOXIC AGENTS

We have reported a significant proliferative defect caused by busulfan and L-phenylalanine mustard (L-PAM) while cyclophosphamide and 5-fluorouracil (5-FU) did not cause such a defect as measured by serial transplantation of bone marrow up to 110 weeks after drug administration. If the proliferative capacity of the initial colony-forming units (CFU-S) as expressed by the ratio (Rs) of the number of CFUs recovered (after 14 days) compared to the number seeding the hind limb prior to transplantation is determined, one finds that the RS correlates with the defect in serial transplantation. Thus, damage to the proliferative capacity of the hematopoietic stem cell caused by chemotherapeutic agents can be expressed in terms of RS, a measure of the self-renewal potential of the stem cell compartment. If RS is assessed after a single drug injection, the pattern of the rise and decline of RS with time following injection offers an efficient method of classifying drug injury to the CFU-S compartment. Busulfan was found to be the most damaging since it killed the most primitive stem cells preferentially. 5-FU was found to be the least damaging to the proliferative capacity of the stem cell compartment while BCNU and cyclophosphamide damaged it in an intermediate way. Therefore, busulfan would be expected to be most damaging to the normal hematopoietic tissue, followed by BCNU, cyclophosphamide and 5-FU in descending order of risk. © 1979.