The effect of recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) on 3'-azido-3'-deoxythymidine (AZT)-mediated biochemical and cytotoxic effects on normal human myeloid progenitor cells.
Administration of 3'-azido-3'-deoxythymidine (AZT) to patients with acquired immunodeficiency syndrome (AIDS) causes significant anemia and neutropenia. The bone marrow cytotoxicity of AZT has been attributed to deoxyribonucleotide pool perturbations that might result in impaired DNA synthesis in normal bone marrow elements. We examined the effect of human recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) on AZT-mediated biochemical perturbations and in vitro growth inhibition of normal bone marrow myeloid progenitor cells. Exposure of nonadherent, bone marrow mononuclear cells (BMMC) to 100 ng/ml of rGM-CSF for 6 h resulted in approximately twofold increments in the mean intracellular deoxycytidine triphosphate (dCTP) and thymidine triphosphate (dTTP) levels. Administration of 10 microM AZT alone to BMMC for 6 h markedly reduced dCTP and dTTP levels and generated significant levels of AZT triphosphate (AZT-TP). Coadministration of rGM-CSF (100 ng/ml) along with AZT (10 microM) partly restored dCTP and dTTP levels and significantly reduced AZT-TP levels. Furthermore, simultaneous exposure of BMMC for 4 h to 100 ng/ml of rGM-CSF reduced the mean DNA incorporation of [3H]AZT (10 microM) from 27.2 to 19.1 pmol/micrograms of DNA. Additionally, the inhibitory effects of AZT (10 microM) on granulocyte-macrophage colony-forming unit (CFU-GM) colony growth were significantly reduced in the presence of 100 ng/ml of rGM-CSF. These in vitro studies suggest that rGM-CSF partly corrects AZT-mediated biochemical perturbations as well as reduces the cytotoxicity of AZT in normal human bone marrow myeloid progenitor cells.
Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York.
K
K
Bhalla
M
M
Birkhofer
S
S
Grant
G
G
Graham
D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D004347:Drug Interactions; D006098:Granulocytes; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D008264:Macrophages; D009711:Nucleotides / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology*
D003115:Colony-Stimulating Factors; D009711:Nucleotides; D011994:Recombinant Proteins; D015215:Zidovudine