Deoxycytidine stimulates the in vitro growth of normal CFU-GM and reverses the negative regulatory effects of acidic isoferritin and prostaglandin E1.
We have examined the effect of supraphysiologic concentrations of the naturally occurring nucleoside deoxycytidine (dCyd) on the in vitro growth of normal (CFU-GM) and leukemic (L-CFU) myeloid progenitor cells. Bone marrow samples obtained from 34 consecutive patients undergoing routine diagnostic bone marrow aspirations for nonmalignant hematologic disorders exhibited nearly a twofold increment in CFU-GM when continuously cultured in the presence of 10(-4) mol/L dCyd. Higher dCyd concentrations were associated with a smaller degree of enhancement of colony formation. In contrast, the growth of leukemic blast progenitors obtained from patients with acute nonlymphocytic leukemia were not enhanced by any of the dCyd concentrations tested. Coadministration of 10(-3) mol/L tetrahydrouridine (THU), a cytidine deaminase inhibitor, failed to alter the relative inability of dCyd to enhance L-CFU colony growth. The stimulatory effect of dCyd on normal CFU-GM was not mediated by the adherent mononuclear cell population of the marrow, nor was it restricted to the subpopulation of CFU-GM in S phase at the time of initial exposure. Moreover, treatment of normal bone marrow cells with dCyd at concentrations ranging from 10(-6) to 5 X 10(-3) mol/L for 24 hours had only a minor effect on the fraction of CFU-GM in S phase. Coadministration of 10(-4) mol/L dCyd was able to reverse the inhibitory effects of several putative regulators of normal myelopoiesis, including leukemia inhibitory activity (LIA), acidic isoferritins (AIF), and prostaglandin E1 (PGE1). Leukemic myeloblasts exposed to 10(-4) mol/L dCyd exhibited substantial expansion of intracellular pools of dCyd triphosphate (dCTP), demonstrating that inability to metabolize dCyd could not be solely responsible for the absence of growth potentiation in these cells. These studies suggest that supraphysiologic concentrations of dCyd may confer a selective in vitro growth advantage upon normal v leukemic myeloid progenitor cells, and may free the former from the inhibitory effects of several potential negative regulators of myelopoiesis.
Bhalla
K
K
Cole
J
J
MacLaughlin
W
W
Baker
M
M
Arlin
Z
Z
Graham
G
G
Grant
S
S
D000527:Alprostadil / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects; D003841:Deoxycytidine / Q000494:pharmacology*; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005293:Ferritins / Q000037:antagonists & inhibitors*; D006098:Granulocytes / Q000166:cytology; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D006801:Humans; D066298:In Vitro Techniques; D008264:Macrophages / Q000166:cytology; D013767:Tetrahydrouridine / Q000494:pharmacology
D003845:Deoxycytosine Nucleotides; D000949:Histocompatibility Antigens Class II; D003841:Deoxycytidine; D013767:Tetrahydrouridine; C024107:2'-deoxycytidine 5'-triphosphate; D005293:Ferritins; D000527:Alprostadil