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Human CD34+ hematopoietic progenitors have low, cytokine-unresponsive
O6-alkylguanine-DNA alkyltransferase and are sensitive to O6- benzylguanine
plus BCNU
SL Gerson, W Phillips, M Kastan, LL Dumenco and C Donovan
Department of Pharmacology, Case Western Reserve University School of
Medicine, Cleveland, OH 44106, USA.
Human bone marrow (BM) cells contain low levels of the DNA repair protein,
O6-alkylguanine-DNA alkyltransferase, which may explain their
susceptibility to nitrosourea-induced cytotoxicity and the development of
secondary leukemia after nitrosourea treatment. Isolated CD34+ myeloid
progenitors were also found to have low levels of alkyltransferase
activity. The level of alkyltransferase in CD34+ cells or in mononuclear BM
cells did not increase after incubation with granulocyte-macrophage
colony-stimulating factor, interleukin-3, stem cell factor, the
combination, or 5637 conditioned medium. BCNU sensitivity remained
unchanged as well. In addition, O6-benzylguanine depleted alkyltransferase
activity in BM cells at concentrations as low as 1.5 mumol/L after a 1-hour
exposure. O6-benzylguanine pretreatment markedly sensitized hematopoietic
progenitor colony-forming cells to BCNU, resulting in a reduction in the
dose of drug (termed the dose- modification factor) required to inhibit 50%
of the colony formation (IC50) of threefold to fivefold. Since, unlike many
other cell types, proliferating early (CD34+) hematopoietic precursors do
not induce alkyltransferase, myelosuppression may be the dose-limiting
toxicity of the combination of O6-benzylguanine plus BCNU in clinical
trials.
Volume 88,
Issue 5,
pp. 1649-1655,
09/01/1996
Copyright © 1996 by The American Society of Hematology
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