Interleukin 1 alpha (IL-1) and macrophage colony-stimulating factor (M-CSF) accelerate recovery from multiple drug-induced myelosuppression.
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.
Department of Radiation Oncology, Leo Jenkins Cancer Center, East Carolina University School of Medicine, Greenville, North Carolina 27858, USA.
C J
CJ
Kovacs
J A
JA
Kerr
B M
BM
Daly
M J
MJ
Evans
R M
RM
Johnke
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D003520:Cyclophosphamide / Q000633:toxicity*; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D006098:Granulocytes / Q000166:cytology* / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL
D007375:Interleukin-1; D004317:Doxorubicin; D016173:Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; D002945:Cisplatin