Differential cytotoxicity of deoxyguanosine and 8-aminoguanosine for human leukemic cell lines and normal bone marrow progenitor cells

1984 ◽  
Vol 2 (2) ◽  
pp. 189-197 ◽  
Author(s):  
Nanneke J. De Fouw ◽  
David D. F. Ma ◽  
Rita Michalevicz ◽  
Douglas A. Gray ◽  
A. Victor Hoffbrand
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Cell Lines ◽  
Leukemic Cell ◽  
Normal Bone Marrow ◽  
Normal Bone ◽  
Bone Marrow Progenitor Cells ◽  
Human Leukemic Cell ◽  
Leukemic Cell Lines ◽  
Bone Marrow Progenitor

scholarly journals 2'-Deoxycytidine protects normal human bone marrow progenitor cells in vitro against the cytotoxicity of 3'-azido-3'-deoxythymidine with preservation of antiretroviral activity

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 1923-1928 ◽  
Author(s):  
K Bhalla ◽  
M Birkhofer ◽  
GR Li ◽  
S Grant ◽  
W MacLaughlin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
High Dose ◽  
Normal Bone Marrow ◽  
Normal Bone ◽  
Bone Marrow Progenitor Cells ◽  
Bone Marrow Progenitor ◽  
High Concentrations ◽  
Anti Hiv

Abstract Bone marrow cytotoxicity of 3′-azido-3′-deoxythymidine (AZT), an anti- human immunodeficiency virus (anti-HIV) drug, has been attributed to deoxyribonucleotide pool perturbations that might result in impaired DNA synthesis in normal bone marrow elements. We examined, in vitro, the effect of high, but clinically achievable and nontoxic, concentrations of 2′-deoxycytidine (dCyd) (greater than or equal to 100 mumol/L) on high-dose AZT mediated growth inhibition and intracellular biochemical perturbations in normal bone marrow progenitor cells. Colony formation by bone marrow progenitor cells in semisolid medium was significantly protected by dCyd against the inhibitory effects of co-administered, high concentrations of AZT (10 mumol/L). Also, dCyd significantly corrected AZT mediated depletion of intracellular thymidine triphosphate (dTTP) and dCyd triphosphate (dCTP) levels in normal bone marrow mononuclear cells (BMMC). Moreover, dCyd reduced the intracellular accumulation of AZT triphosphate (AZT-TP) and its DNA incorporation in BMMC. In contrast, co-administration of dCyd (100 mumol/L to 1 mmol/L) did not reverse AZT (10 mumol/L) mediated suppression of HIV infectivity in HUT-102 cells in culture, although a partial reduction in intracellular AZT-TP pools and its DNA incorporation as well as a correction of AZT mediated depletion of dTTP and dCTP pools was observed in these cells. These studies suggest that dCyd at high concentrations might ameliorate the bone marrow cytotoxicity of high-dose AZT without impairing its anti-HIV effect.

scholarly journals Loss of suppression of normal bone marrow colony formation by leukemic cell lines after differentiation is induced by chemical agents

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 100-106 ◽  
Author(s):  
HN Steinberg ◽  
AS Tsiftsoglou ◽  
SH Robinson
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Colony Formation ◽  
Leukemic Cell ◽  
K562 Cells ◽  
Leukemic Cells ◽  
Cell Phenotype ◽  
Normal Bone Marrow ◽  
Normal Bone ◽  
Leukemic Cell Lines

Abstract The human leukemic cell lines K562 and HL-60 were cocultured with normal bone marrow (BM) cells. Coculture with 10(4) K562 or HL-60 cells results in 50% inhibition of normal CFU-E and BFU-E colony formation. However, when the same number of K562 and HL-60 cells is first treated for two to five days with agents that induce their differentiation, a gradual loss in their capacity to inhibit CFU-E and BFU-E colony formation is observed. The inhibitory material in K562 cells is soluble and present in conditioned medium from cultures of these cells. The degree to which leukemic cell suppression of CFU-E and BFU-E growth is reversed is correlated with the time of exposure to the inducing agent. Suppression is no longer evident after five days of prior treatment with inducers. In fact, up to a 90% stimulation of CFU-E growth is observed in cocultures with K562 cells that have been pretreated with 30 to 70 mumol/L hemin for five days. K562 cells treated with concentrations of hemin as low as 30 mumol/L demonstrate increased hemoglobin synthesis and grow normally, but no longer have an inhibitory effect on CFU-E growth. Hence, reversal of normal BM growth inhibition must be caused by the more differentiated state of the K562 cells and not by a decrease in the number of these cells with treatment. Thus, induction of differentiation in cultured leukemic cells not only alters the malignant cell phenotype but also permits improved growth of accompanying normal marrow progenitor cells. Both are desired effects of chemotherapy.

Identification of Pathogenetically Important Genes within the Common Deleted Region (CDR) of the 5q- Syndrome.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3439-3439
Author(s):  
Soren Lehmann ◽  
Sophie Raynaud ◽  
Julian C. Desmond ◽  
Phillip H. Koeffler
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Leukemic Cell ◽  
Refractory Anemia ◽  
Normal Bone Marrow ◽  
Expression Data ◽  
Hematopoietic Stem ◽  
Normal Bone ◽  
Leukemic Cell Lines ◽  
Biological Studies

Abstract The 5q- syndrome is characterized by refractory anemia, normal or high platelet count, hypolobulated megakaryocytes, a good prognosis and a low risk of leukemic transformation. Although the CDR has been defined to a 1.5 Mb interval on the long arm on chromosome 5 (5q33.1), the molecular pathogenesis of the disease is still unknown. The CDR contains 39 known-genes of which 33 have been shown to be expressed in hematopoietic stem cells. In order to elucidate the molecular mechanisms behind the 5q- syndrome, we performed real-time quantitative PCR on these 33 genes. Samples from the bone marrow of 12 patients with a sole deletion of 5q and 14 patients with MDS with normal karyotype were initially analyzed. The genes that showed the most pronounced decrease in expression in the 5q- samples were: SLC36A1 (89% down-regulated compared to non 5q-), G3BP (79%), ATOX1 (76%), CSF1R (76%), RPS14 (74%), PDGFRB (73%), TNIP1 (72%), SPARC (71%), ANAX6 (69%), NSDT (66%) and TIGD (60%). SPARC expression was found to be higher in both types of MDS samples compared to normal bone marrow (n=18) as well as compared to seven leukemic cell lines (HL-60, NB4, HEL, KG1, K562, U937 and TP-1). ATOX1 expression was highly over-expressed (20- to 80-fold) in the leukemic cell lines and modestly but significantly higher in normal bone marrow compared to both types of MDS. For G3BP, the expression was similar in normal bone marrow compared to the non-5q- samples but 1- to 10-fold higher in the cell lines. RPS14 was down-regulated in both types of MDS compared to normal bone marrow and leukemic cell lines. Thus, we have identified the most significantly down-regulated genes within the CDR of the 5q- syndrome. Based on our expression data, their known biological functions and on publicly available tissue expression data, genes such as G3BP, ATOX1, TNIP1, RPS14 and CSF1R are interesting targets for further studies. Biological studies are currently being performed on these genes with respect to their role during hematopoiesis with special focus on erythropoiesis.

scholarly journals Loss of suppression of normal bone marrow colony formation by leukemic cell lines after differentiation is induced by chemical agents

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 100-106
Author(s):  
HN Steinberg ◽  
AS Tsiftsoglou ◽  
SH Robinson
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Colony Formation ◽  
Leukemic Cell ◽  
K562 Cells ◽  
Leukemic Cells ◽  
Cell Phenotype ◽  
Normal Bone Marrow ◽  
Normal Bone ◽  
Leukemic Cell Lines

The human leukemic cell lines K562 and HL-60 were cocultured with normal bone marrow (BM) cells. Coculture with 10(4) K562 or HL-60 cells results in 50% inhibition of normal CFU-E and BFU-E colony formation. However, when the same number of K562 and HL-60 cells is first treated for two to five days with agents that induce their differentiation, a gradual loss in their capacity to inhibit CFU-E and BFU-E colony formation is observed. The inhibitory material in K562 cells is soluble and present in conditioned medium from cultures of these cells. The degree to which leukemic cell suppression of CFU-E and BFU-E growth is reversed is correlated with the time of exposure to the inducing agent. Suppression is no longer evident after five days of prior treatment with inducers. In fact, up to a 90% stimulation of CFU-E growth is observed in cocultures with K562 cells that have been pretreated with 30 to 70 mumol/L hemin for five days. K562 cells treated with concentrations of hemin as low as 30 mumol/L demonstrate increased hemoglobin synthesis and grow normally, but no longer have an inhibitory effect on CFU-E growth. Hence, reversal of normal BM growth inhibition must be caused by the more differentiated state of the K562 cells and not by a decrease in the number of these cells with treatment. Thus, induction of differentiation in cultured leukemic cells not only alters the malignant cell phenotype but also permits improved growth of accompanying normal marrow progenitor cells. Both are desired effects of chemotherapy.

scholarly journals 2'-Deoxycytidine protects normal human bone marrow progenitor cells in vitro against the cytotoxicity of 3'-azido-3'-deoxythymidine with preservation of antiretroviral activity

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 1923-1928
Author(s):  
K Bhalla ◽  
M Birkhofer ◽  
GR Li ◽  
S Grant ◽  
W MacLaughlin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
High Dose ◽  
Normal Bone Marrow ◽  
Normal Bone ◽  
Bone Marrow Progenitor Cells ◽  
Bone Marrow Progenitor ◽  
High Concentrations ◽  
Anti Hiv

Bone marrow cytotoxicity of 3′-azido-3′-deoxythymidine (AZT), an anti- human immunodeficiency virus (anti-HIV) drug, has been attributed to deoxyribonucleotide pool perturbations that might result in impaired DNA synthesis in normal bone marrow elements. We examined, in vitro, the effect of high, but clinically achievable and nontoxic, concentrations of 2′-deoxycytidine (dCyd) (greater than or equal to 100 mumol/L) on high-dose AZT mediated growth inhibition and intracellular biochemical perturbations in normal bone marrow progenitor cells. Colony formation by bone marrow progenitor cells in semisolid medium was significantly protected by dCyd against the inhibitory effects of co-administered, high concentrations of AZT (10 mumol/L). Also, dCyd significantly corrected AZT mediated depletion of intracellular thymidine triphosphate (dTTP) and dCyd triphosphate (dCTP) levels in normal bone marrow mononuclear cells (BMMC). Moreover, dCyd reduced the intracellular accumulation of AZT triphosphate (AZT-TP) and its DNA incorporation in BMMC. In contrast, co-administration of dCyd (100 mumol/L to 1 mmol/L) did not reverse AZT (10 mumol/L) mediated suppression of HIV infectivity in HUT-102 cells in culture, although a partial reduction in intracellular AZT-TP pools and its DNA incorporation as well as a correction of AZT mediated depletion of dTTP and dCTP pools was observed in these cells. These studies suggest that dCyd at high concentrations might ameliorate the bone marrow cytotoxicity of high-dose AZT without impairing its anti-HIV effect.

scholarly journals Clonal analysis of the response of human myeloid leukemic cell lines to colony-stimulating activity

Blood ◽  
1981 ◽  
Vol 58 (2) ◽  
pp. 285-292 ◽  
Author(s):  
FW Ruscetti ◽  
SJ Collins ◽  
AM Woods ◽  
RC Gallo
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Colony Formation ◽  
Leukemic Cell ◽  
Conditioned Media ◽  
Normal Bone Marrow ◽  
Normal Bone ◽  
Leukemic Cell Lines ◽  
Growth Promoting ◽  
Myeloid Leukemic Cell

Abstract The recent development of two continuously proliferating human myeloid leukemic cell lines (HL-60 and KG-1) that response to CSA provides an opportunity for a detailed study of the interaction of CSA with leukemic myeloid cells. Here we report on the colony-forming ability of HL-60 and KG-1 over an extended culture life of the cells. Several different sources of human CSA of different stages of purity enhanced colony formation of these cells. CSA, obtained from conditioned media from an SV-40 transformed human trophoblast, was partially purified, and its activity for normal bone marrow copurified with the activity that stimulated HL-60 colony formation. Over 100 clones of HL-60 were developed and tested for their response to CSA. All responded to CSA by showing an increase in colony size and number. However, none of the colonies formed from any of the 100 clones differentiated in response to CSA despite the fact that many chemical can induce differentiation of HL-60. since HL-60 forms spontaneous colonies without the addition of any exogenous stimulating factors, HL-60 conditioned media and cell extracts were tested for the production by these cells of their own endogenous growth-promoting activity (such as a CSA-like molecule). No growth-promoting endogenous activity was found that stimulated normal bone marrow or HL-60 colony formation even after concentration and fractionation methods were employed. These experiments suggest that: (1) the effect of CSA markedly favors proliferation over differentiation in these cell lines; (2) CSA is unlikely to suppress growth of the age of the type of leukemic myeloid cells that HL-60 and KG-1 represent; and (3) if HL-60 cells produce their own growth- promoting factor it is not detectable in the media.

scholarly journals Clonal analysis of the response of human myeloid leukemic cell lines to colony-stimulating activity

Blood ◽  
1981 ◽  
Vol 58 (2) ◽  
pp. 285-292
Author(s):  
FW Ruscetti ◽  
SJ Collins ◽  
AM Woods ◽  
RC Gallo
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Colony Formation ◽  
Leukemic Cell ◽  
Conditioned Media ◽  
Normal Bone Marrow ◽  
Normal Bone ◽  
Leukemic Cell Lines ◽  
Growth Promoting ◽  
Myeloid Leukemic Cell

The recent development of two continuously proliferating human myeloid leukemic cell lines (HL-60 and KG-1) that response to CSA provides an opportunity for a detailed study of the interaction of CSA with leukemic myeloid cells. Here we report on the colony-forming ability of HL-60 and KG-1 over an extended culture life of the cells. Several different sources of human CSA of different stages of purity enhanced colony formation of these cells. CSA, obtained from conditioned media from an SV-40 transformed human trophoblast, was partially purified, and its activity for normal bone marrow copurified with the activity that stimulated HL-60 colony formation. Over 100 clones of HL-60 were developed and tested for their response to CSA. All responded to CSA by showing an increase in colony size and number. However, none of the colonies formed from any of the 100 clones differentiated in response to CSA despite the fact that many chemical can induce differentiation of HL-60. since HL-60 forms spontaneous colonies without the addition of any exogenous stimulating factors, HL-60 conditioned media and cell extracts were tested for the production by these cells of their own endogenous growth-promoting activity (such as a CSA-like molecule). No growth-promoting endogenous activity was found that stimulated normal bone marrow or HL-60 colony formation even after concentration and fractionation methods were employed. These experiments suggest that: (1) the effect of CSA markedly favors proliferation over differentiation in these cell lines; (2) CSA is unlikely to suppress growth of the age of the type of leukemic myeloid cells that HL-60 and KG-1 represent; and (3) if HL-60 cells produce their own growth- promoting factor it is not detectable in the media.

scholarly journals The effects of alkyl-lysophospholipids on leukemic cell lines. I. Differential action on two human leukemic cell lines, HL60 and K562

Blood ◽  
1981 ◽  
Vol 57 (4) ◽  
pp. 794-797 ◽  
Author(s):  
T Tidwell ◽  
G Guzman ◽  
WR Vogler
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Leukemic Cell ◽  
Short Term ◽  
Cell Numbers ◽  
Human Leukemic Cell ◽  
Leukemic Cell Lines ◽  
Low Concentrations ◽  
Bone Marrow Cultures ◽  
Differential Action

Abstract The action of an alkyl-lysophospholipid (ALP), ET180CH3, on clonogenicity, 3H-TdR uptake, and cell numbers was tested in two human leukemic cell lines, HL60 and K562, and short-term human leukemic bone marrow cultures. ALP eliminated clonogenicity in HL60 but not in K562 cultures; 3H-TdR uptake and cell numbers were depressed at low concentrations of ET180CH3 in HL60, but not K562 cultures. The action of the lysophospholipid analog on human leukemic bone marrow short-term cultures at low concentrations was similar to its action on HL60 cultures; clonogenicity and 3H-TdR uptake were depressed, but cell numbers were not significantly affected. The demonstration of differential action of ALP on two cell lines should significantly simplify the investigation of the mechanism of the reported differential action of ET180CH3 on normal and leukemic cell membranes.

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