Development of latent residual drug damage to the hematopoietic marrow during the subsequent growth of tumors.

Growth of the Lewis lung (LLca) tumor in BDF1 mice was found to be accompanied by a marked expansion of the multipotential stem (CFUs-8) and committed erythroid (BFUe) and myeloid (CFU-gm) progenitor cells of the marrow with a concomitant depression of more differentiated compartments. The long-term effects of adriamycin (AdR), busulfan (BU), cis-diaminedichloroplatinum II (DDP), and 5-fluorouracil (5-FU) on the LLca-induced expansion of the CFUs-8 and CFU-gm were investigated at eight weeks after drug treatment. Of the four drugs studied, only BU demonstrated a reduction of CFUs-8 at eight weeks after treatment and prior to tumor inoculation. However, all of the drugs were found to prevent the expansion of the CFUs-8 compartment after 16 days of tumor growth. BU also resulted in a depressed CFU-gm compartment at the time of tumor inoculation, while CFU-gm in ADR-, DDP-, and 5-FU-treated animals was either at control levels (AdR), or unexpectedly elevated (DDP and 5-FU). Similar to the observations made for CFUs-8, all drugs prevented the expansion of the CFU-gm associated with tumor growth. The data suggest that qualitative differences observed between the long-term effects of the drugs on the marrow compartments may be more accurately related to the temporal "fixation" of residual drug damage brought about by enhanced differentiation of a drug-limited pluripotential CFUs, than to the actual magnitude of hematopoietic damage.