Long-term bone marrow stromal and hemopoietic toxicity to AZT: protective role of heme and IL-1.
We studied the immediate and long-term effects of azidothymidine (AZT) and heme on murine hemopoietic and stromal progenitor cells in vivo and in vitro. Treatment of mice for 37 days with AZT produced anemia and leukopenia, whereas combined treatment with heme abrogated some of the toxic effects which were apparent even 2 weeks after cessation of treatment. Quantitation of spleen (CFU-S), erythroid (BFU-E) and myeloid (CFU-GM) colony formation from AZT-exposed animals revealed reductions in these progenitors, and this was partially reversed after heme treatment, especially when mice were allowed a 2-week recovery period. Long-term bone marrow cultures (LTBMC) of cells from treated groups revealed difficulty in establishing an adherent cell layer (ACL) by the first week in culture. Total cellularity, CFU-S, BFU-E and CFU-GM clonogenic potential of cultures remained depressed throughout 10 weeks of culture, whereas heme treatment overcame these depressions when AZT-exposed mice were allowed to recover for 14 days prior to culture of their cells in LTBMC. Interleukin-1 (IL-1) treatment to the same recovery group of AZT-exposed mice also resulted in an improvement of CFU-GM growth in LTBMC that was not seen in the nonrecovered group. Transplantation of cells from treated mice under the renal capsule of recipient mice revealed that AZT depressed the regeneration of osteogenic and hemopoietic cell growth within ectopic foci. These effects were reversed with heme treatment in vivo. In other experiments, heme was found to inhibit human immunodeficiency virus (HIV-1) reverse transcriptase and to potentiate the activity of AZT triphosphate against HIV-1 reverse transcriptase. In summary, these results demonstrate that AZT inhibits the growth and development of a variety of hemopoietic, stromal and adherent cells in vivo and in vitro. Treatment of animals with heme produced recovery to near normal levels and suggests possible therapeutic potential.
Abraham
N G
NG
Department of Medicine, New York Medical College, Valhalla 10595.
Chertkov
J L
JL
Staudinger
R
R
Jiang
S
S
Lutton
J D
JD
Argani
I
I
Levere
R D
RD
Kappas
A
A
D000740:Anemia / Q000139:chemically induced / Q000517:prevention & control; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004347:Drug Interactions; D005260:Female; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000235:genetics; D006410:Hematopoiesis / Q000187:drug effects* / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006418:Heme / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007970:Leukopenia / Q000139:chemically induced / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018894:Reverse Transcriptase Inhibitors; D013154:Spleen / Q000166:cytology; D013997:Time Factors; D015215:Zidovudine / Q000009:adverse effects / Q000494:pharmacology*
D007375:Interleukin-1; D018894:Reverse Transcriptase Inhibitors; D006418:Heme; D015215:Zidovudine; D054303:HIV Reverse Transcriptase