Interleukin 1 alpha (IL-1) and macrophage colony-stimulating factor (M-CSF) accelerate recovery from multiple drug-induced myelosuppression.

ABSTRACT

Interleukin 1 alpha (IL-1) and macrophage colony-stimulating factor (M-CSF) interact synergistically to enhance the restoration of stem and progenitor subpopulations in murine marrow and, vis-a-vis, to accelerate hematopoietic recovery in 5FU myelosuppressed mice. Similarly, IL-1 is reported to accelerate recovery following myelosuppressive treatment with doxorubicin (AdR), cis-platinum (DDP) and cyclophosphamide (CTx). Studies were carried out in C57Bl/6 mice in order to determine whether IL-1 (+/- M-CSF) intervention was as effective against the myelosuppression experienced following 5FU-based multiple drug combinations. Maximal-tolerated doses (MTD) of AdR (10 mg/kg), DDP (8 mg/kg) or CTx (250 mg/kg) were administered either alone or in combination with 150 mg/kg 5FU. Cytokine intervention (q24 hours x 2) was initiated 24 hours later. Hematopoietic recovery was assessed by measuring the femoral content of the more primitive [IL-1 + IL-3 + M-CSF-responsive] HPP-CFC and the total granulocyte levels in the animals over a ten-day interval following treatment. MTDs of AdR, DDP and CTx, when compared with 5FU, produced only marginal levels of myelosuppression. As a result, cytokine intervention in animals treated with AdR, DDP or CTx resulted in only a modest, transient increase in the HPP-CFC and total granulocyte subpopulations when compared with their effect on 5FU--treated animals. Neither AdR, DDP nor CTx interacted with 5FU to significantly increase the cytotoxic effects of 5FU on the HPP-CFC or granulocyte subpopulations, and both IL-1 and IL-1 + M-CSF effectively stimulated hematopoietic recovery in all animals that received the 5FU--based drug combinations. However, the significant advantage (p < 0.05) achieved by combining IL-1 + M-CSF (vs. IL-1 alone) was only observed in animals that were treated with 5FU and either AdR or DDP. Furthermore, the initial stimulation of HPP-CFC recovery by IL-1 + M-CSF in animals that received DDP + 5FU, when compared with 5FU alone, was subsequently dampened. Although there were subtle, drug-related differences in the temporal response of the more primitive HPP-CFC and granulocyte populations to cytokine therapy, the data from this study demonstrated that abbreviated cytokine interaction can effectively accelerate hematopoietic recovery after combination drug therapy.