Clinical trial on 5-AZA-2′-deoxycytidine in patients with acute leukemia

Momparler, Richard L.; Rivard, Georges E.; Gyger, M

doi:10.1016/0163-7258(85)90052-x

Pharmacology & Therapeutics

1985

DOI: 10.1016/0163-7258(85)90052-x

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Clinical trial on 5-AZA-2′-deoxycytidine in patients with acute leukemia

Richard L. Momparler

Georges E. Rivard

M Gyger

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1991

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Cited by 141 publications

(83 citation statements)

References 28 publications

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“…15 However, in patients starting therapy with an absolute neutrophil count of у0.5 × 10 9 /l an aplastic phase is unusual. [14][15][16] Here, we report the results of a phase I study of single agent decitabine with stem cell re-infusion for relapse after allogeneic progenitor cell transplant.…”

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confidence: 99%

“…7,13 Several phase I and II studies have demonstrated the efficacy of decitabine in achieving responses in patients with relapsed or refractory leukemia. [14][15][16] Of particular interest is the limited extramedullary toxicity associated with decitabine, with myelosuppression being the major drug-related toxicity. 15 However, in patients starting therapy with an absolute neutrophil count of у0.5 × 10 9 /l an aplastic phase is unusual.…”

mentioning

confidence: 99%

“…[14][15][16] Of particular interest is the limited extramedullary toxicity associated with decitabine, with myelosuppression being the major drug-related toxicity. 15 However, in patients starting therapy with an absolute neutrophil count of у0.5 × 10 9 /l an aplastic phase is unusual. [14][15][16] Here, we report the results of a phase I study of single agent decitabine with stem cell re-infusion for relapse after allogeneic progenitor cell transplant.…”

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confidence: 99%

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Decitabine with allogeneic peripheral blood stem cell transplantation in the therapy of leukemia relapse following a prior transplant: results of a phase I study

Ravandi

Kantarjian

Cohen

et al. 2001

Bone Marrow Transplant

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Summary:Relapse after allogeneic progenitor cell transplant is associated with a poor prognosis for patients with advanced leukemia, with few curative options available. Use of novel chemotherapeutic agents with limited toxicity is warranted. We investigated the role of decitabine, a pyrimidine analogue with significant anti-leukemic effect and limited toxicity, in this setting. Fourteen patients with advanced acute leukemia or transformed chronic myelogenous leukemia (CML) who had failed previous allogeneic transplant were treated. Decitabine at doses of 100 mg/m 2 to 150 mg/m 2 given every 12 h for 5 days was followed by infusion of stem cells from the original donor 2 to 5 days after the completion of chemotherapy. Dose of decitabine was escalated in cohorts of three patients based on the modified Fibonacci scheme. The primary study end-point was assessment of the toxicity of the regimen with secondary endpoints of response and survival. Eight patients responded with either a complete remission or partial hematological remission (absence of blasts in peripheral blood and bone marrow but with platelet count Ͻ100 × 10 9 /l). Toxicity was limited with no grade 3 or 4 toxicity directly attributable to the treatment. The median survival for all patients was 190 days (range 11 to 1215+ days). Decitabine at doses of 100 mg/m 2 to 150 mg/m 2 given every 12 h for 5 days, followed by stem cell infusion from the original donor was well tolerated, and was associated with acceptable myelosuppression. Current response data should encourage further study of this drug, either alone or in combination with other agents, for treatment of relapsed acute leukemia after an allogeneic transplant. Bone Marrow Transplantation (2001) 27, 1221-1225.

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Decitabine with allogeneic peripheral blood stem cell transplantation in the therapy of leukemia relapse following a prior transplant: results of a phase I study

Ravandi

Kantarjian

Cohen

et al. 2001

Bone Marrow Transplant

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“…After incorporation into DNA, as a fraudulent cytosine base, Aza-dC induces hypomethylation of DNA (Bouchard et al, 1983), which has been associated with altered gene expression (Ley et al, 1982), induction of differentiation (Creusot et al, 1982;Momparler et al, 1985) and probably cell death. The mechanisms by which Aza-dC induces cytotoxicity are entirely speculative.…”

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confidence: 99%

“…5-Aza-2-deoxycytidine (Aza-dC), an analogue of deoxycytidine, has shown antineoplastic activity against some murine and human leukaemias (Momparler & Gonzales, 1978;Vesely & Cihak, 1977;Momparler et al, 1985). To acquire cytotoxic activity, Aza-dC has to be phosphorylated into its triphosphate form, Aza-dCTP, by kinase enzymes of the salvage pathway for nucleotide synthesis.…”

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confidence: 99%

The antileukaemic activity of 5-Aza-2 deoxycytidine (Aza-dC) in patients with relapsed and resistant leukaemia

Richel¹,

Colly²,

Kluin-Nelemans³

et al. 1991

Br J Cancer

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In the present study we demonstrate that Aza-dC in combination with Amsacrine has major antileukaemic properties in patients who have not already received extensive Ara-C therapy. Eight out of 11 patients in their first relapse of acute leukaemia achieved complete remission. Cross resistance between Ara-C and Aza-dC was revealed by the lack of antileukaemic activity in five patients with with Ara-C resistant leukaemia. Combination therapy with Aza-dC/Ams-acrine induced a considerable period of a granulocytopenia (28-35 days), while the toxic effect on erythro- and megakaryopoiesis was comparable to that reported for high dose Ara-C/Amsacrine chemotherapy. Remarkable is the long disappearance time for leukaemic blast cells in bone marrow, i.e. 3-5 weeks in some cases. Analysis of cell membrane markers showed a loss of the early differentiation antigens CD34 and CD33 from leukaemic bone marrow cells after 7 days of Aza-dC treatment, which is suggestive of leukaemic cell differentiation. In the small group of patients tested for DNA hypomethylation no association existed between the degree of hypomethylation and clinical response. Non-haematologic side effects were considerable in patients receiving the highest dosages of Aza-dC and consisted of severe, although usually reversible, gastrointestinal and neurological complications. In comparison with Ara-C, Aza-dC causes less nausea and vomiting and is therefore better tolerated.

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DNA methylation and cancer

2000

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The methylation of DNA is an epigenetic modification that can play an important role in the control of gene expression in mammalian cells. The enzyme involved in this process is DNA methyltransferase, which catalyzes the transfer of a methyl group from S-adenosyl-methionine to cytosine residues to form 5-methylcytosine, a modified base that is found mostly at CpG sites in the genome. The presence of methylated CpG islands in the promoter region of genes can suppress their expression. This process may be due to the presence of 5-methylcytosine that apparently interferes with the binding of transcription factors or other DNA-binding proteins to block transcription. In different types of tumors, aberrant or accidental methylation of CpG islands in the promoter region has been observed for many cancer-related genes resulting in the silencing of their expression. How this aberrant hypermethylation takes place is not known. The genes involved include tumor suppressor genes, genes that suppress metastasis and angiogenesis, and genes that repair DNA suggesting that epigenetics plays an important role in tumorigenesis. The potent and specific inhibitor of DNA methylation, 5-aza-2'-deoxycytidine (5-AZA-CdR) has been demonstrated to reactivate the expression most of these "malignancy" suppressor genes in human tumor cell lines. These genes may be interesting targets for chemotherapy with inhibitors of DNA methylation in patients with cancer and this may help clarify the importance of this epigenetic mechanism in tumorigenesis.

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Clinical trial on 5-AZA-2′-deoxycytidine in patients with acute leukemia

Cited by 141 publications

References 28 publications

Decitabine with allogeneic peripheral blood stem cell transplantation in the therapy of leukemia relapse following a prior transplant: results of a phase I study

Decitabine with allogeneic peripheral blood stem cell transplantation in the therapy of leukemia relapse following a prior transplant: results of a phase I study

The antileukaemic activity of 5-Aza-2 deoxycytidine (Aza-dC) in patients with relapsed and resistant leukaemia

DNA methylation and cancer

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