Microenvironmental toxicity of azidothymidine: partial sparing with hemin. NLM AIDSLINE Important note: Information in this article was accurate in 1989. The state of the art may have changed since the publication date.

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Microenvironmental toxicity of azidothymidine: partial sparing with hemin.

Blood. 1989 Jul;74(1):139-44. Unique Identifier : AIDSLINE MED/89323327
Abraham NG; Bucher D; Niranjan U; Brown AC; Lutton JD; Distenfeld A; Ahmed T; Levere RD; Department of Medicine, New York Medical College, Valhalla, NY; 10595.

Abstract: Azidothymidine (AZT) is a useful drug in management of AIDS. Nevertheless, its hematologic toxicity such as anemia and neutropenia present further complications to an already compromised hematopoietic state in patients. We studied the effects of AZT on human and murine bone marrow (BM) colony growth as determined by assays of CFU-E, BFU-E, CFU-GM, and fibroblastoid stromal (CFU-Fb) colonies. Cultures were grown in methylcellulose with growth factors and scored after three- to 14-day incubation. In general, murine marrow cultures were more sensitive to AZT as compared with human marrow. Furthermore, interindividual variation in toxicity to AZT was observed between marrow samples; 1 mumol/L AZT inhibited murine CFU-E, BFU-E, and CFU-GM by 98% to 100%, whereas human marrow was inhibited by 52%, 87%, and 65%, respectively. Lower concentrations of AZT (0.1 mumol/L) inhibited murine erythroid colony growth by 85% to 90%, whereas human growth was inhibited by only 39% to 52%. Myeloid colony inhibition was similar for human and murine systems. CFU-Fb growth was markedly suppressed (75%) by 1 mumol/L AZT. Hemin, at a concentration of 10 mumol/L, overcame some of the inhibitory effects of 1 to 0.1 mumol/L AZT without hindering antiviral activity. Inhibition of human CFU-E growth was completely overcome with hemin, whereas CFU-GM growth was recovered to 66% to 74% of control. A similar but less pronounced effect was observed for BFU-E. Furthermore, hemin does not decrease AZT's effects of HIV antigen content in vitro. We conclude that anemia and neutropenia, occurring as a result of AZT, may not be as pronounced in the presence of hemin. Furthermore, CFU-Fb was significantly reduced in the presence of low concentrations of AZT. This may indicate a major target site for BM toxicity since the stromal microenvironment may be responsible for maintaining short- and long-term hematopoiesis.
Keywords: Animal Bone Marrow/CYTOLOGY/*DRUG EFFECTS Cell Division/DRUG EFFECTS Dose-Response Relationship, Drug Erythropoiesis/DRUG EFFECTS Hematopoiesis/*DRUG EFFECTS Hematopoietic Stem Cells/CYTOLOGY/DRUG EFFECTS Heme/*ANALOGS & DERIVATIVES Hemin/*PHARMACOLOGY Human HIV/GROWTH & DEVELOPMENT HIV Antigens/ANALYSIS Mice Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. Zidovudine/ANTAGONISTS & INHIB/*TOXICITY JOURNAL ARTICLE

KWDanimalbonemarrow/cytology/KWDdrugeffectscelldivision/drugeffectsdose-responserelationship,drugerythropoiesis/drugeffectshematopoiesis/KWDdrugeffectshematopoieticstemcells/cytology/drugeffectsheme/KWDanalogs&derivativeshemin/KWDpharmacologyhumanhiv/growth&developmenthivantigens/analysismicesupport,non-uKWDsKWDgov'tsupport,uKWDsKWDgov't,pKWDhKWDsKWDzidovudine/antagonists&inhib/KWDtoxicityjournalarticle
891130
M89B0539

Copyright © 1989 - National Library of Medicine. Reproduced under license with the National Library of Medicine, Bethesda, MD.

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