Protection of 3'-azido-3'-deoxythymidine induced toxicity to murine hematopoietic progenitors (CFU-GM, BFU-E and CFU-MEG) with interleukin-1.
3'-Azido-3'-deoxythymidine (AZT) has attained wide clinical utility in the treatment of acquired immunodeficiency syndrome (AIDS). Unfortunately, associated with AZT use, is the development of severe hematopoietic toxicity as manifested by anemia, neutropenia and overall bone marrow suppression. Interleukin-1 (IL-1), a cytokine, primarily produced by activated macrophages, has been involved in the control of hematopoiesis by acting synergistically with other hematopoietic growth factors, and has been demonstrated to be an effective agent in reducing the myelosuppression associated with the therapy for malignant disease. We report here the ability of recombinant human IL-1 alpha to protect normal murine hematopoietic progenitors (CFU-GM, BFU-E, and CFU-Meg) from the toxic effects of AZT. Following the determination of the LD50 dose for each progenitor, IL-1 was added in co-culture studies (10-1000 units; 0.001-1.0 micrograms/ml protein) with adherent cell depleted marrow. Marrow progenitors expressed differences in AZT sensitivity, e.g., BFU-E, LD50 5 x 10(-9)M; CFU-Meg, LD50 10(-7) M; CFU-GM, 5 x 10(-5) M respectively. IL-1 inhibited AZT induced toxicity. The maximum IL-1 dose effect was observed for CFU-GM and CFU-Meg at 300 units, 0.3 micrograms protein; however BFU-E required a dose of 600 units, 0.6 micrograms/ml protein to reverse the effects of AZT. These results demonstrate marrow progenitors respond differently to AZT and identifies the potential efficacy of IL-1 to minimize the hematopoietic toxicity associated with AZT treatment.
Gallicchio
V S
VS
Hematology/Oncology Division, University of Kentucky Medical Center, Lexington.
Doukas
M A
MA
Hulette
B C
BC
Hughes
N K
NK
Gass
C
C
D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000494:pharmacology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D008809:Mice, Inbred C3H; D011994:Recombinant Proteins / Q000494:pharmacology; D015215:Zidovudine / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D007375:Interleukin-1; D011994:Recombinant Proteins; D004921:Erythropoietin; D015215:Zidovudine