Minimal Toxicity to Myeloid Progenitor Cells of Weekly24-Hr Infusion of High-Dose 5-Fluorouracil: Direct Evidence from Colony Forming Unit-Granulocyte andMonocyte (CFU-GM) Clonogenic Assay

Abstract Bone marrow samples from sternum and iliac crests were harvested every 4 hours during 19 24-hour periods from 16 healthy male volunteers, and myeloid progenitor cells were cultured by the colony-forming unit- granulocyte-macrophage (CFU-GM) assay. A large interindividual variation was observed in the mean number of colonies during each 24- hour period, with the highest 24-hour mean colony number being about 600% greater than the lowest (range: 16 +/- 2.3 to 100.3 +/- 4.5). For each individual the difference between the lowest and highest colony number throughout the day ranged from 47.4% to 256.3% of the mean colony number of each series. A circadian stage-dependent variation in the number of colony-forming units of myeloid progenitor cells (CFU-GM) of human bone marrow was demonstrated, with values 150% higher, on the average, during the day as compared with the night. The overall data (891 CFU-GM replicates) exhibited a significant 24-hour rhythm (P less than .001) with an acrophase at midday (12.09 hours with 95% confidence limits from 10.32 to 13.49 hours) and a trough at midnight. This 24- hour variation was found to covary with DNA synthesis in the total proliferating bone marrow cell population. A seasonal effect on CFU-GM numbers was detected by ANOVA (P = .014) and by the least squares fit of a 1-year cosine (P = .015), with the highest number found in summer. The potential relevance of these findings should be examined in relation to cytotoxic cancer therapy, use of hematopoietic growth factors, and bone marrow transplantation.

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Deoxycytidine preferentially protects normal versus leukemic myeloid progenitor cells from cytosine arabinoside-mediated cytotoxicity

Blood ◽

10.1182/blood.v70.2.568.568 ◽

1987 ◽

Vol 70 (2) ◽

pp. 568-571 ◽

Cited By ~ 25

Author(s):

K Bhalla ◽

W MacLaughlin ◽

J Cole ◽

Z Arlin ◽

M Baker ◽

...

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Colony Formation ◽

Mononuclear Cells ◽

Leukemic Cells ◽

High Dose ◽

Bone Marrow Mononuclear Cells ◽

Myeloid Progenitor ◽

Myeloid Progenitor Cells

Abstract We examined the ability of high concentrations of the naturally occurring nucleoside deoxycytidine (dCyd) to reverse the cytotoxicity of high (eg, greater than or equal to 10(-5) mol/L) concentrations of 1- B-D arabinofuranosylcytosine (Ara-C) toward normal (CFU-GM) and leukemic myeloid progenitor cells (L-CFU). Leukemic myeloblasts from patients with acute nonlymphocytic leukemia (ANLL) and normal human bone marrow mononuclear cells were cultured in soft agar in the continuous presence of 10(-5) to 5 X 10(-5) mol/L of Ara-C together with dCyd (10(-4) to 5 X 10(-3) mol/L). Administration of 10(-5) mol/L of Ara-C alone eradicated colony formation in all samples tested. Coadministration of 10(-3) mol/L of dCyd restored 72.2% of control colony formation for CFU-GM, but only 10.9% for L-CFU. When higher concentrations of Ara-C (eg, 5 X 10(-5) mol/L) were administered, dCyd- mediated protection toward CFU-GM decreased, but remained significantly greater than that observed for L-CFU. Incubation with 10(-3) mol/L of dCyd reduced the 4-hour intracellular accumulation of the triphosphate derivative of Ara-C (Ara-CTP) in both normal and leukemic cells by greater than 98%; under identical conditions, a significant expansion of the intracellular of the triphosphate derivative of dCyd (dCTP) pools was observed in normal bone marrow mononuclear cells but not in leukemic blasts. This finding was associated with a greater reduction in Ara-C DNA incorporation in normal elements. These in vitro studies suggest that dCyd may preferentially protect normal v leukemic myeloid progenitor cells from the lethal actions of high-dose Ara-C.

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Deoxycytidine preferentially protects normal versus leukemic myeloid progenitor cells from cytosine arabinoside-mediated cytotoxicity

Blood ◽

10.1182/blood.v70.2.568.bloodjournal702568 ◽

1987 ◽

Vol 70 (2) ◽

pp. 568-571

Author(s):

K Bhalla ◽

W MacLaughlin ◽

J Cole ◽

Z Arlin ◽

M Baker ◽

...

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Colony Formation ◽

Mononuclear Cells ◽

Leukemic Cells ◽

High Dose ◽

Bone Marrow Mononuclear Cells ◽

Myeloid Progenitor ◽

Myeloid Progenitor Cells

We examined the ability of high concentrations of the naturally occurring nucleoside deoxycytidine (dCyd) to reverse the cytotoxicity of high (eg, greater than or equal to 10(-5) mol/L) concentrations of 1- B-D arabinofuranosylcytosine (Ara-C) toward normal (CFU-GM) and leukemic myeloid progenitor cells (L-CFU). Leukemic myeloblasts from patients with acute nonlymphocytic leukemia (ANLL) and normal human bone marrow mononuclear cells were cultured in soft agar in the continuous presence of 10(-5) to 5 X 10(-5) mol/L of Ara-C together with dCyd (10(-4) to 5 X 10(-3) mol/L). Administration of 10(-5) mol/L of Ara-C alone eradicated colony formation in all samples tested. Coadministration of 10(-3) mol/L of dCyd restored 72.2% of control colony formation for CFU-GM, but only 10.9% for L-CFU. When higher concentrations of Ara-C (eg, 5 X 10(-5) mol/L) were administered, dCyd- mediated protection toward CFU-GM decreased, but remained significantly greater than that observed for L-CFU. Incubation with 10(-3) mol/L of dCyd reduced the 4-hour intracellular accumulation of the triphosphate derivative of Ara-C (Ara-CTP) in both normal and leukemic cells by greater than 98%; under identical conditions, a significant expansion of the intracellular of the triphosphate derivative of dCyd (dCTP) pools was observed in normal bone marrow mononuclear cells but not in leukemic blasts. This finding was associated with a greater reduction in Ara-C DNA incorporation in normal elements. These in vitro studies suggest that dCyd may preferentially protect normal v leukemic myeloid progenitor cells from the lethal actions of high-dose Ara-C.

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Colony-forming unit-granulocyte-macrophage and DNA synthesis of human bone marrow are circadian stage-dependent and show covariation

Blood ◽

10.1182/blood.v79.9.2281.bloodjournal7992281 ◽

1992 ◽

Vol 79 (9) ◽

pp. 2281-2287 ◽

Cited By ~ 50

Author(s):

R Smaaland ◽

OD Laerum ◽

RB Sothern ◽

O Sletvold ◽

R Bjerknes ◽

...

Keyword(s):

Bone Marrow ◽

Dna Synthesis ◽

Progenitor Cells ◽

Human Bone ◽

Human Bone Marrow ◽

Colony Forming Unit ◽

Myeloid Progenitor ◽

Myeloid Progenitor Cells ◽

Colony Number ◽

The Mean

Bone marrow samples from sternum and iliac crests were harvested every 4 hours during 19 24-hour periods from 16 healthy male volunteers, and myeloid progenitor cells were cultured by the colony-forming unit- granulocyte-macrophage (CFU-GM) assay. A large interindividual variation was observed in the mean number of colonies during each 24- hour period, with the highest 24-hour mean colony number being about 600% greater than the lowest (range: 16 +/- 2.3 to 100.3 +/- 4.5). For each individual the difference between the lowest and highest colony number throughout the day ranged from 47.4% to 256.3% of the mean colony number of each series. A circadian stage-dependent variation in the number of colony-forming units of myeloid progenitor cells (CFU-GM) of human bone marrow was demonstrated, with values 150% higher, on the average, during the day as compared with the night. The overall data (891 CFU-GM replicates) exhibited a significant 24-hour rhythm (P less than .001) with an acrophase at midday (12.09 hours with 95% confidence limits from 10.32 to 13.49 hours) and a trough at midnight. This 24- hour variation was found to covary with DNA synthesis in the total proliferating bone marrow cell population. A seasonal effect on CFU-GM numbers was detected by ANOVA (P = .014) and by the least squares fit of a 1-year cosine (P = .015), with the highest number found in summer. The potential relevance of these findings should be examined in relation to cytotoxic cancer therapy, use of hematopoietic growth factors, and bone marrow transplantation.

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Bone marrow lymphoid and myeloid progenitor cells are suppressed in 7,12-dimethylbenz(a)anthracene (DMBA) treated mice

Toxicology ◽

10.1016/j.tox.2010.02.009 ◽

2010 ◽

Vol 271 (1-2) ◽

pp. 27-35 ◽

Cited By ~ 11

Author(s):

A.U. N’jai ◽

M. Larsen ◽

L. Shi ◽

C.R. Jefcoate ◽

C.J. Czuprynski

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Myeloid Progenitor ◽

Myeloid Progenitor Cells

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Increased Levels of Myeloid Progenitor Cells in the Blood of Patients with Metastatic Invasion of the Marrow

Scandinavian Journal of Haematology ◽

10.1111/j.1600-0609.1983.tb00652.x ◽

2009 ◽

Vol 31 (3) ◽

pp. 275-279 ◽

Cited By ~ 3

Author(s):

Alain Delforge ◽

Jean P. De Caluwe ◽

Elisabeth Rongé-Collard ◽

Marie A. Mattelaer ◽

Théodore Spiro ◽

...

Keyword(s):

Progenitor Cells ◽

Myeloid Progenitor ◽

Myeloid Progenitor Cells

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Kell Expression on Myeloid Progenitor Cells

Leukemia & Lymphoma ◽

10.1080/10428190290011949 ◽

2002 ◽

Vol 43 (3) ◽

pp. 479-485 ◽

Cited By ~ 7

Author(s):

T. Wagner ◽

G. Lanzer ◽

K. Geissler

Keyword(s):

Progenitor Cells ◽

Myeloid Progenitor ◽

Myeloid Progenitor Cells

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Expression of Ia antigens on myeloid progenitor cells in chronic myeloid leukemia: direct analysis using partially purified colony- forming cells

Blood ◽

10.1182/blood.v65.2.414.bloodjournal652414 ◽

1985 ◽

Vol 65 (2) ◽

pp. 414-422

Author(s):

SA Cannistra ◽

JF Daley ◽

P Larcom ◽

JD Griffin

Keyword(s):

Cell Cycle ◽

Chronic Myeloid Leukemia ◽

Progenitor Cells ◽

Myeloid Leukemia ◽

Antigen Expression ◽

Colony Stimulating Factors ◽

Myeloid Progenitor ◽

Hla Dr ◽

Ia Antigens ◽

Myeloid Progenitor Cells

The regulation of Ia (HLA-DR) antigen expression on myeloid progenitor cells may be closely related to the control of myelopoiesis in both normal individuals and chronic myeloid leukemia (CML) patients. In an effort to study directly the expression and behavior of Ia surface molecules on myeloid progenitor cells, we used an immunologic purification technique to enrich these cells approximately 100-fold from the peripheral blood of CML patients. The majority of cells in this blast population expressed HLA-DR antigens. Thirty percent to 40% of cells could form a granulocyte or monocyte colony in agar, and these cells tended to express the highest levels of HLA-DR. The number of HLA- DR molecules per cell increased about twofold as the cells tranversed the cell cycle from G0/G1 to G2/M. This was true for unstimulated cells or cells exposed to colony-stimulating factors. Some of this increase was related to a corresponding increase in cell size and is also seen with other cell surface antigens such as beta-2-microglobulin. Ia antigen expression was not modified by culture with colony-stimulating factors, fetal calf serum, or serum-free, prostaglandin-free medium for periods of up to 24 hours. These results demonstrate that Ia antigens are expressed on the myeloid progenitor cells of CML, are increased in the S and G2/M phases of the cell cycle, and are stable under most in vitro culture conditions for at least 24 hours of culture.

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