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

Blood ◽  
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.

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

Blood ◽  
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

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.

scholarly journals The influence in vivo of murine colony-stimulating factor-1 on myeloid progenitor cells in mice recovering from sublethal dosages of cyclophosphamide

Blood ◽  
1987 ◽  
Vol 69 (3) ◽  
pp. 913-918 ◽  
Author(s):  
HE Broxmeyer ◽  
DE Williams ◽  
S Cooper ◽  
A Waheed ◽  
RK Shadduck
Keyword(s):  
Progenitor Cells ◽  
Colony Formation ◽  
Colony Stimulating Factor ◽  
Myeloid Progenitor ◽  
Accessory Cells ◽  
Myeloid Progenitor Cells ◽  
In Vivo Administration ◽  
Stimulating Factor

Abstract Pure murine colony-stimulating factor-1 (CSF-1) was assessed for its effects in vivo in mice pretreated seven days earlier with a sublethal dosage of cyclophosphamide. The multipotential (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells in these mice were in a slowly cycling or noncycling state. Intravenous administration of 20,000 units of CSF-1 to these mice stimulated the hematopoietic progenitors into a rapidly cycling state in the marrow and spleen within three hours. Significant increases in absolute numbers of marrow and spleen CFU-GM and spleen BFU-E and CFU-GEMM were also detected. No endotoxin was detected in the CSF-1 preparation by Limulus lysate assay, and treatment of CSF-1 at 100 degrees C for 20 to 30 minutes completely inactivated the in vitro and in vivo stimulating effects. The effects of CSF-1 were not mimicked by the in vivo administration of 0.1 to 10 ng Escherichia coli lipopolysaccharide. These results suggest that the effects of CSF-1 in vivo were not due to contaminating endotoxin or to a nonspecific protein effect. CSF-1 did not enhance colony formation by BFU-E or stimulate colony formation by CFU-GEMM in vitro, thus suggesting that at least some of the effects of CSF-1 noted in vivo are probably indirect and mediated by accessory cells.

scholarly journals Enhancing and suppressing effects of recombinant murine macrophage inflammatory proteins on colony formation in vitro by bone marrow myeloid progenitor cells

Blood ◽  
1990 ◽  
Vol 76 (6) ◽  
pp. 1110-1116 ◽  
Author(s):  
HE Broxmeyer ◽  
B Sherry ◽  
L Lu ◽  
S Cooper ◽  
KO Oh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Colony Formation ◽  
Pokeweed Mitogen ◽  
Myeloid Progenitor ◽  
Hla Dr ◽  
Myeloid Progenitor Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Inflammatory Proteins ◽  
Macrophage Colony

Abstract Purified recombinant (r) macrophage inflammatory proteins (MIPs) 1 alpha, 1 beta, and 2 were assessed for effects on murine (mu) and human (hu) marrow colony-forming unit-granulocyte-macrophage (CFU-GM) and burst-forming unit-erythroid (BFU-E) colonies. Recombinant MIP-1 alpha, -1 beta, and -2 enhanced muCFU-GM colonies above that stimulated with 10 to 100 U natural mu macrophage-colony-stimulating factor (M-CSF) or rmuGM-CSF, with enhancement seen on huCFU-GM colony formation stimulated with suboptimal rhuM-CSF or rhuGM-CSF; effects were neutralized by respective MIP-specific antibodies. Macrophage inflammatory proteins had no effects on mu or huBFU-E colonies stimulated with erythropoietin (Epo). However, natural MIP-1 and rMIP-1 alpha, but not rMIP-1 beta or -2, suppressed muCFU-GM stimulated with pokeweed mitogen spleen-conditioned medium (PWMSCM), huCFU-GM stimulated with optimal rhuGM-CSF plus rhu interleukin-3 (IL-3), muBFU- E and multipotential progenitors (CFU-GEMM) stimulated with Epo plus PWMSCM, and huBFU-E and CFU-GEMM stimulated with Epo plus rhuIL-3 or rhuGM-CSF. The suppressive effects of natural MIP-1 and rMIP-1 alpha were also apparent on a population of BFU-E, CFU-GEMM, and CFU-GM present in cell-sorted fractions of human bone marrow (CD34 HLA-DR+) highly enriched for progenitors with cloning efficiencies of 42% to 75%. These results, along with our previous studies, suggest that MIP-1 alpha, -1 beta, and -2 may have direct myelopoietic enhancing activity for mature progenitors, while MIP-1 alpha may have direct suppressing activity for more immature progenitors.

scholarly journals Deoxycytidine stimulates the in vitro growth of normal CFU-GM and reverses the negative regulatory effects of acidic isoferritin and prostaglandin E1

Blood ◽  
1986 ◽  
Vol 68 (5) ◽  
pp. 1136-1141 ◽  
Author(s):  
K Bhalla ◽  
J Cole ◽  
W MacLaughlin ◽  
M Baker ◽  
Z Arlin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Prostaglandin E1 ◽  
S Phase ◽  
In Vitro Growth ◽  
Inhibitory Effects ◽  
Initial Exposure ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

Abstract 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.

scholarly journals Application of hyperthermia to the treatment of human acute leukemia: purging human leukemic progenitor cells by heat

Blood ◽  
1986 ◽  
Vol 67 (3) ◽  
pp. 802-804 ◽  
Author(s):  
Y Moriyama ◽  
M Narita ◽  
K Sato ◽  
M Urushiyama ◽  
S Koyama ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Progenitor Cells ◽  
Autologous Bone Marrow Transplantation ◽  
Leukemic Cell ◽  
Autologous Bone Marrow ◽  
Leukemic Cells ◽  
Neoplastic Disease ◽  
Myeloid Progenitor Cells

Abstract The application of hyperthermia to the treatment of neoplastic disease has focused on solid tumors. Since the hyperthermic sensitivity of human acute leukemia cells is not known, we have studied the in vitro response of human leukemic progenitor cells (L-CFU) to hyperthermia using a quantitative assay system for L-CFU. Human L-CFU were found to be more sensitive than committed normal myeloid progenitor cells to hyperthermic killing (41 to 42 degrees C). In addition, in the five acute myelogenous leukemic patients studied, it was shown that their leukemic progenitor cells--all types were studied according to the French-American-British diagnosis--were unable to form colonies when exposed to a temperature of 42 degrees C for 60 minutes, whereas the residual normal clones suppressed by the leukemic cell population were found to recover and to form more colonies in vitro as compared with untreated leukemic marrows. This strongly suggests that in vitro hyperthermia may selectively purge residual leukemic cells, especially L-CFU in stored remission bone marrow before autologous bone marrow transplantation.

Altered Development and Cytokine Responses of Myeloid Progenitors in the Absence of Transcription Factor, Interferon Consensus Sequence Binding Protein

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3764-3771 ◽  
Author(s):  
Marina Scheller ◽  
John Foerster ◽  
Clare M. Heyworth ◽  
Jeffrey F. Waring ◽  
Jürgen Löhler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transcription Factor ◽  
Progenitor Cells ◽  
Fetal Liver ◽  
Binding Protein ◽  
Marrow Cell ◽  
Consensus Sequence ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

Abstract Mice deficient for the transcription factor, interferon consensus sequence binding protein (ICSBP), are immunodeficient and develop disease symptoms similar to human chronic myeloid leukemia (CML). To elucidate the hematopoietic disorder of ICSBP−/− mice, we investigated the growth, differentiation, and leukemogenic potential of ICSBP−/−myeloid progenitor cells in vitro, as well as by cell-transfers in vivo. We report that adult bone marrow, as well as fetal liver of ICSBP-deficient mice harbor increased numbers of progenitor cells, which are hyperresponsive to both granulocyte macrophage colony-stimulating factor (GM-CSF) and G-CSF in vitro. In contrast, their response to M-CSF is strongly reduced and, surprisingly, ICSBP−/− colonies formed in the presence of M-CSF are mostly of granulocytic morphology. This disproportional differentiation toward cells of the granulocytic lineage in vitro parallels the expansion of granulocytes in ICSBP−/− mice and correlates with a 4-fold reduction of M-CSF receptor expressing cells in bone marrow. Cell transfer studies showed an intrinsic leukemogenic potential and long-term reconstitution capability of ICSBP−/− progenitors. Further experiments demonstrated strongly reduced adhesion of colony-forming cells from ICSBP−/− bone marrow to fibronectin. In summary, ICSBP−/− myeloid progenitor cells share several abnormal features with CML progenitors, suggesting that the distal parts of signaling pathways of these two disorders are overlapping.

scholarly journals Inhibitory effect of 2-chlorodeoxyadenosine on granulocytic, erythroid, and T-lymphocytic colony growth

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2583-2587 ◽  
Author(s):  
AL Petzer ◽  
R Bilgeri ◽  
U Zilian ◽  
M Haun ◽  
FH Geisen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
T Lymphocyte ◽  
Human Lymphocytes ◽  
Maturation Stage ◽  
Dependent Manner ◽  
Myeloid Progenitor ◽  
Marked Inhibition ◽  
Myeloid Progenitor Cells

Abstract Previous studies have shown that 2-chloro-2′-deoxyadenosine (CdA) is markedly toxic to normal and malignant human lymphocytes in vitro and in vivo. Recent clinical trials have shown that CdA is a very promising drug for the treatment of lymphoid malignancies. The present investigations were designed to test the effect of CdA on the in vitro clonal growth of both myeloid progenitors and T-lymphocyte colony- forming cells (CFU-TL) obtained from normal human bone marrow and peripheral blood. Cells were exposed to CdA in doses up to 1280 nmol/L. To reduce indirect effects of CdA mediated by accessory cells, monocyte- and T-lymphocyte-depleted bone marrow cells were used for our investigations. The results show a marked inhibition of myeloid progenitor and lymphocyte colony-forming cells in a dose-dependent manner, correlating with maturation stage in that the immature progenitor cells are more sensitive to this drug. Furthermore, our studies suggest that a sequence of metabolic events previously described for lymphocytes may be operative in myeloid progenitor cells because a minimal exposure time of 48 hours is required to obtain a marked inhibition. CdA toxicity was proposed to be linked with phosphorylation by deoxycytidine-kinase (E.C. 2.7.1.74), the levels of which have been found to be high in lymphocytes, but low in granulocytes. However, the marked inhibition of myeloid progenitor cells shown in these studies suggests that other factors such as modulation of the effect of CdA by the ambient levels of other deoxynucleosides might influence the apparent sensitivity of myeloid cells.

scholarly journals Application of hyperthermia to the treatment of human acute leukemia: purging human leukemic progenitor cells by heat

Blood ◽  
1986 ◽  
Vol 67 (3) ◽  
pp. 802-804
Author(s):  
Y Moriyama ◽  
M Narita ◽  
K Sato ◽  
M Urushiyama ◽  
S Koyama ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Progenitor Cells ◽  
Autologous Bone Marrow Transplantation ◽  
Leukemic Cell ◽  
Autologous Bone Marrow ◽  
Leukemic Cells ◽  
Neoplastic Disease ◽  
Myeloid Progenitor Cells

The application of hyperthermia to the treatment of neoplastic disease has focused on solid tumors. Since the hyperthermic sensitivity of human acute leukemia cells is not known, we have studied the in vitro response of human leukemic progenitor cells (L-CFU) to hyperthermia using a quantitative assay system for L-CFU. Human L-CFU were found to be more sensitive than committed normal myeloid progenitor cells to hyperthermic killing (41 to 42 degrees C). In addition, in the five acute myelogenous leukemic patients studied, it was shown that their leukemic progenitor cells--all types were studied according to the French-American-British diagnosis--were unable to form colonies when exposed to a temperature of 42 degrees C for 60 minutes, whereas the residual normal clones suppressed by the leukemic cell population were found to recover and to form more colonies in vitro as compared with untreated leukemic marrows. This strongly suggests that in vitro hyperthermia may selectively purge residual leukemic cells, especially L-CFU in stored remission bone marrow before autologous bone marrow transplantation.

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