Pentoxifylline, Ciprofloxacin and Dexamethasone Improve the Ineffective Hematopoiesis in Myelodysplastic Syndrome Patients

Raza, Azra; Qawi, Huma; Andric, Tanja; Dar, Saleem; Lisak, Laurie; Huang, Ran; Venugopal, Parameswaran; Gezer, Sefer; Gregory, Stephanie A.; Hsu, Wei-Tong; Loew, Jerome; Robin, Erwin; Rifkin, S.; Shah, Rohit; Divgi, Ajit B.; Taylor, Robert L.; Grosset, Alan

doi:10.1080/10245332.2000.11746517

Cited by 17 publications

(11 citation statements)

References 16 publications

(17 reference statements)

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“…The demonstration of TNF-␣-inducible DNA fragmentation pattern in MDS may indicate that perhaps anti-TNF-␣ (or anticytokine) therapy could be of special benefit to these patients. Indeed, our recent clinical studies in MDS patients demonstrating a favorable clinical response to an anticytokine regimen comprised of pentoxifylline, ciprofloxacin, dexamethasone, and amifostine are compatible with our present biologic observations in the BMs of these patients [36].…”

Section: Fig 7 Double Labeling Of Dna Breaks Produced By Known Endosupporting

confidence: 91%

Evidence for involvement of tumor necrosis factor‐α in apoptotic death of bone marrow cells in myelodysplastic syndromes

et al. 1999

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We previously reported excessive apoptosis and high levels of tumor necrosis factor-alpha (TNF-alpha) in the bone marrows of patients with myelodysplastic syndromes (MDS), using histochemical techniques. The present studies provide further circumstantial evidence for the involvement of TNF-alpha in apoptotic death of the marrow cells in MDS. Using our newly developed in situ double-labeling technique that sequentially employs DNA polymerase (DNA Pol) followed by terminal deoxynucleotidyl transferase (TdT) to label cells undergoing apoptosis, we have characterized DNA fragmentation patterns during spontaneous apoptosis in MDS bone marrow and in HL60 cells treated with TNF-alpha or etoposide (VP16). Clear DNA laddering detected by gel electrophoresis in MDS samples confirmed the unique length of apoptotic DNA fragments (180-200 bp). Surprisingly, however, phenotypically heterogeneous population of MDS cells as well as the homogenous population of HL60 cells showed three distinct labeling patterns after double labeling--only DNA-Pol reaction, only TdT reaction, and a combined DNA Pol + TdT reaction, albeit in different cohorts of cells. Each labeling pattern was found at all morphological stages of apoptosis. MDS mononuclear cells, during spontaneous apoptosis in 4 hr cultures, showed highest increase in double-labeled cells (DNA Pol + TdT reaction). Interestingly, this was paralleled by TNF-alpha-induced apoptosis in HL60 cells. In contrast, VP16 treatment of HL60 cells led to increased apoptosis in cells showing only TdT reaction. The double-labeling technique was applied to normal bone marrow and peripheral blood mononuclear cells after treatment with known endonucleases that specifically cause 3' recessed (BamHI), 5' recessed (PstI), or blunt ended (DraI) double-stranded DNA breaks. It was found that the DNA-Pol reaction in MDS and HL60 cells corresponds to 3' recessed DNA fragments, the TdT reaction to 5' recessed and/or blunt ended fragments, and a combined "DNA Pol + TdT reaction" corresponds to a copresence of 3' recessed with 5' recessed and/or blunt ended fragments. Clearly, therefore, apoptotic DNA fragments, in spite of a unique length, may have differently staggered ends that could be cell (or tissue) specific and be selectively triggered by different inducers of apoptosis. The presence of TNF-alpha-inducible apoptotic DNA fragmentation pattern in MDS supports its involvement in these disorders and suggests that anti-TNF-alpha (or anticytokine) therapy may be of special benefit to MDS patients, where no definitive treatment is yet available.

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Section: Fig 7 Double Labeling Of Dna Breaks Produced By Known Endosupporting

confidence: 91%

Evidence for involvement of tumor necrosis factor‐α in apoptotic death of bone marrow cells in myelodysplastic syndromes

et al. 1999

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“…In response to this therapy, most patients showed a significant improvement in cytopenia(s) [158]. In some of them, hematologic remission and even cytogenetic responses were observed [158]. In a more recent study, anti-cytokine therapy with pentoxifylline and dexamethasone was combined with amifostine with similar beneficial effects [159].…”

Section: Experimental Treatment Low Dose Chemotherapy and Targeted mentioning

confidence: 98%

“…In one recent study, MDS patients were treated with a combination of pentoxifylline (inhibits TNF production in various cells), ciprofloxacine, and dexamethasone [158]. In response to this therapy, most patients showed a significant improvement in cytopenia(s) [158].…”

Section: Experimental Treatment Low Dose Chemotherapy and Targeted mentioning

confidence: 98%

“…Another interesting approach in MDS is to interefere with the production or the effects of disease-promoting cytokines, such as TNF-alpha (anti-cytokine therapy) [156][157][158]. In one recent study, MDS patients were treated with a combination of pentoxifylline (inhibits TNF production in various cells), ciprofloxacine, and dexamethasone [158].…”

Section: Experimental Treatment Low Dose Chemotherapy and Targeted mentioning

confidence: 99%

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Pathogenesis, classification, and treatment of myelodysplastic syndromes (MDS)

Valent

Wimazal

Schwarzinger

et al. 2003

Wien Klin Wochenschr

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Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal myeloid disorders characterized by morphologic dysplasia in one or more cell lineages. Dysplasia in MDS is associated with insufficient production of blood cells and consecutive cytopenia(s). The natural course and prognosis of MDS vary among patients and depend on genetic defects that occur during clonal evolution. In a significant group of patients (roughly 30%) progression to secondary leukemia is observed. These patients appear to have a grave prognosis. The treatment of patients with MDS has to be adjusted to the individual situation and age in each case. In many patients, control of blast cell production by palliative cytoreduction, continuous support with red blood cells, as well as other supportive measures, seem appropriate. In other patients, however, curative therapy (chemotherapy, stem cell transplantation) should be considered. The final decision to offer curative therapy must be based on many different factors including age and the overall situation of the patient. Recently established scoring systems aimed at predicting survival and evolution of leukemia in MDS may be helpful in this regard.

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“…In vivo studies using either soluble TNF-α receptor (Enbrel) or anti-cytokine drug combinations such as pentoxifylline, ciprofloxacin and dexamethasone, although successfully reducing serum cytokine levels, have been less encouraging [184, 185, 186]. …”

Section: Therapy In Early Mds: Blocking Apoptosismentioning

confidence: 99%

The Myelodysplastic Syndromes: A Matter of Life or Death

Parker

Mufti

2003

Acta Haematol

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Apoptosis is upregulated in early myelodysplastic syndromes (MDS) and may contribute to the peripheral cytopenias commonly observed. Conversely, leukemic progression is associated with abrogation of programmed cell death (PCD). The stage of hematopoietic cell maturation at which defects in PCD arise and the underlying causes of apoptosis dysregulation remain unknown. This paper outlines the apoptotic process in normal hematopoietic cells and summarizes current data regarding the role, potential causes and clinical implications of altered apoptosis in MDS.

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Pentoxifylline, Ciprofloxacin and Dexamethasone Improve the Ineffective Hematopoiesis in Myelodysplastic Syndrome Patients

Cited by 17 publications

References 16 publications

Evidence for involvement of tumor necrosis factor‐α in apoptotic death of bone marrow cells in myelodysplastic syndromes

Evidence for involvement of tumor necrosis factor‐α in apoptotic death of bone marrow cells in myelodysplastic syndromes

Pathogenesis, classification, and treatment of myelodysplastic syndromes (MDS)

The Myelodysplastic Syndromes: A Matter of Life or Death

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