Effect of combined treatment with interleukin-3 and interleukin-6 on 4-hydroperoxycyclophosphamide-mediated reduction of glutathione levels and cytotoxicity in normal and leukemic bone marrow progenitor cells.

Abstract

4-Hydroperoxycyclophosphamide (4-HC) is widely used as an ex vivo bone marrow purging agent for acute myeloid leukemia (AML) blasts. We have determined the effect of a combined treatment with interleukin 3 (IL-3) plus IL-6 on 4-HC cytotoxicity against normal (CFU-GEMM) versus AML (L-CFU) bone marrow progenitor cells. Following an 18 h exposure to IL-3 plus IL-6, treatment with 4-HC in conjunction with IL-3 and IL-6 for one hour resulted in a significantly greater inhibition of L-CFU versus CFU-GEMM colony growth. In addition, treatment with IL-3 plus IL-6 reduced the inhibitory effects of higher concentrations of 4-HC on CFU-GEMM but not L-CFU growth. IL-3 and IL-6 did not protect the self-renewing, clonogenic, AML blast progenitor cells from the cytotoxic effects of 4-HC. While the total intracellular glutathione (GSH) levels were not significantly different between untreated normal bone marrow mononuclear cells (NBMMC) and AML blasts, greater intracellular GSH-S transferase activity was observed in the NBMMC. 4-HC produced a marked reduction in GSH levels in NBMMC as well as AML blasts. But treatment with IL-3 plus IL-6 in conjunction with 4-HC resulted in significantly higher GSH levels in NBMMC. These differences in intracellular GSH levels and GST activity may offer an explanation for the differential protective effects of IL-3 plus IL-6 treatment against the cytotoxic effects of 4-HC on CFU-GEMM colony growth.

• Authors: K Bhalla, G Bullock, J Lutzky, C Holladay, A M Ibrado, M Jasiok, S Singh
• Journal: Leukemia (Leukemia) Vol. 6 Issue 8 Pg. 814-9 (Aug 1992) ISSN: 0887-6924 [Print] England
• PMID: 1640734 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Interleukin-3
• Interleukin-6
• Cyclophosphamide
• Glutathione Transferase
• Glutathione
• perfosfamide

Topics

• Acute Disease
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Division (drug effects)
• Cells, Cultured
• Cyclophosphamide (analogs & derivatives, pharmacology)
• Drug Interactions
• Glutathione (metabolism)
• Glutathione Transferase (drug effects)
• Hematopoietic Stem Cells (cytology, drug effects, metabolism)
• Humans
• Interleukin-3 (pharmacology)
• Interleukin-6 (pharmacology)
• Leukemia, Myeloid (drug therapy)
• Tumor Cells, Cultured