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Ex vivo zidovudine (AZT) treatment of CD34+ bone marrow progenitors causes decreased steady state mitochondrial DNA (mtDNA) and increased lactate production

Departments of Medicine and Pharmacology and Molecular Sciences (Division of Clinical Pharmacology), The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Section of Clinical Pharmacology, Department of Medicine, Dartmouth Hitchcock Medical Center and Dartmouth Medical School, Hinman Box 7506, Lebanon, NH 03756, USA; Lionel.D.Lewis{at}Dartmouth.edu

S Amin

C I Civin

Division of Pediatric Oncology, The Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

P S Lietman

Departments of Medicine and Pharmacology and Molecular Sciences (Division of Clinical Pharmacology), The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

Haematopoietic suppression is one of the dose-limiting side effects of chronic zidovudine (AZT) therapy. We tested the hypothesis that AZT would reduce mitochondrial DNA (mtDNA) content in haematopoietic progenitors causing impaired haematopoiesis and mitochondrial dysfunction. We studied the effects of AZT 0 ^/ 50 M in vitro, on normal human CD34 / haematopoietic progenitor cells cultured ex vivo for up to 12 days. The mean AZT IC₅₀ for granulocyte (phenotype CD15 / /CD14 /) and erythroid (phenotype glycophorin / /CD45 /) cell proliferation was 2.5 M (SD9 / 0.7) and 0.023 M (SD9 / 0.005), respectively. In myeloid-rich cell cultures, the mean lactate content of the media, compared to untreated controls, increased by 86% (SD9 / 23) at 10 M AZT and in erythroid-rich cultures it increased by 134% (SD9 / 24) in the presence of 0.5 M AZT. In myeloid-rich cultures the AZT IC₅₀ for the reduction in the mitochondrial/nuclear DNA content ratio was 5.6 M, whereas in erythroid rich cultures this AZT IC₅₀ was B ^/ 0.0005 M. AZT produced concentration-dependent inhibition of CD34 / progenitor proliferation into both myeloid and erythroid lineages; erythropoiesis was more sensitive than myelopoiesis. Concurrently, AZT reduced steady state mtDNA content, while increasing lactate production. These findings support the hypothesis that mtDNA is one of the intracellular targets involved in the pathogenesis of AZT-associated bone marrow progenitor cell toxicity.

Key Words: AZT • haematopoietic toxicity • mitochondrial DNA

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