Effect of low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor priming (CAG regimen) on the outcome of elderly patients with acute myeloid leukemia

Shen, Qian; Li, Jianyong; Tian, Tian; Shen, Yongchun; Jiang, Yuanqiang; Liu, Hua; Wu, Haoran; Zhang, Sujiang; Xu, Wei

doi:10.1016/j.leukres.2007.02.009

Cited by 32 publications

(24 citation statements)

References 20 publications

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“…The observation that some patients respond to this treatment without developing marrow hypoplasia may support the presence of a clinically relevant differentiation-inducing effect, but could also be explained by a weak and selective cytotoxic effect. However, even low-dose cytarabine is associated with hematological toxicity and treatment-related mortality (Tables 1, 2), observations strongly supporting the view that even low-dose therapy mainly acts through its cytotoxic effect on the leukemia cells [73][74][75][76][77][78][79][80][81][82][83][84][85][86]. However, such observations should be interpreted with great care as both mechanisms may be operative and the relative contribution of differentiation versus cytotoxicity will then be difficult to define for individual patients.…”

Section: Low Dose Cytarabine -Cytotoxicity or Differentiation?mentioning

confidence: 95%

“…This treatment can be given alone or in combination with other cytotoxic agents, growth factors or all-trans retinoic acid (ATRA) [2]. The results from studies of low-dose cytarabine therapy in human AML are summarized in Tables 1 and 2 [73][74][75][76][77][78][79][80][81][82][83][84][85][86]. This therapeutic approach can induce complete hematological remissions for a subset of patients, and these responses may last for several months.…”

Section: Low Dose Cytarabine -Cytotoxicity or Differentiation?mentioning

confidence: 99%

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The Combination of Conventional Chemotherapy with New Targeted Therapy in Hematologic Malignancies: The Safety and Efficiency of Low- Dose Cytarabine Supports its Combination with New Therapeutic Agents in Early Clinical Trials

Fredly¹,

Ersvær²,

Stapnes³

et al. 2009

CCTR

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Cytarabine (cytosine arabinoside) is commonly used in the treatment of hematologic malignancies, including both myeloid and lymphoid disorders. The cytotoxic effect of the drug depends on conversion to its triphosphate form in the targeted cells, and the intracellular levels of this active form depend on the balance between phosphorylating and dephosphorylating enzymes. The sensitivity to cytarabine-triphosphate induced cytotoxicity is in addition dependent on the balance between pro-and antiapoptotic signalling in the malignant cells, especially the balance between various members of the bcl-2 family. Even though differentiation induction has been claimed to be important in low-dose cytarabine, most clinical studies suggest that the cytotoxic affect is most important even in this therapeutic strategy. The clinical experience with the low-dose therapy is based on studies in hematological malignancies, mainly acute myeloid leukemia and myelodysplastic syndromes. These studies clearly document the clinical efficiency of low-dose therapy. However, even this low-dose strategy has a risk of severe hematological toxicity and eventually serious or fatal infections especially in elderly patients. Our understanding of the molecular mechanisms behind chemoresistance and chemosensitivity to cytarabine thereby forms the scientific basis for the design of future clinical studies where cytarabine can be combined with new targeted therapy. Low-dose cytarabine may then represent an efficient alternative with an acceptable toxicity even when combined with new anticancer agents in early clinical studies. However, the possibility of pharmacological interactions with the intracellular metabolism of cytarabine by these new agents has to be considered when combination regimens are designed.

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Section: Low Dose Cytarabine -Cytotoxicity or Differentiation?mentioning

confidence: 95%

Section: Low Dose Cytarabine -Cytotoxicity or Differentiation?mentioning

confidence: 99%

The Combination of Conventional Chemotherapy with New Targeted Therapy in Hematologic Malignancies: The Safety and Efficiency of Low- Dose Cytarabine Supports its Combination with New Therapeutic Agents in Early Clinical Trials

Fredly¹,

Ersvær²,

Stapnes³

et al. 2009

CCTR

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“…Our previous studies revealed that the standard-dose of CAG regimen consisting of low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (G-CSF) priming as an induction therapy was well-tolerated by patients and led to a complete remission (CR) rate of 50.0% in patients aged ≥ 70 years, and a CR rate of 40.0% in patients with unfavorable cytogenetic aberrations [14]. In this study, we conducted a phase II trial that evaluated the efficacy and safety of decitabine in combination with modified CAG regimen (low-dose cytarabine and aclarubicin) in elderly patients with AML.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin in newly diagnosed elderly patients with acute myeloid leukemia

Chen

Zhu

et al. 2015

Oncotarget

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PurposeThis prospective phase II, open label, study was designed to assess the efficacy and safety of D-CAG induction treatment for elderly patients with newly diagnosed AML.Experimental DesignAll patients in this study were treated with decitabine of 15 mg/m2 for 5 days and G-CSF for priming, in combination with cytarabine of 10-mg/m2 q12h for 7 days and aclarubicin of 10 mg/day for 4 days (D-CAG).ResultsAmong 85 evaluable patients, overall response rate (ORR) and complete remission (CR) were 82.4% and 64.7%, respectively, after 1 cycle of therapy. The ORR in patients aged <70 years was 83.0% and 81.6% in patients aged ≥70 years. There was a significantly longer median overall survival (OS) in patients with response (16 months) than in those without response (7 months, p< 0.0001). The OS for patients aged ≥70 years and 60-69 years was 10 months and 12 months, respectively (p=0.4994). The two-year OS probability was 19.2% and the twenty-month survival rate was 33.8%. Induction mortality of D-CAG treated elderly patients with AML is 4.4%.ConclusionD-CAG regimen was well tolerated and showed a promising clinic efficacy in elderly patients with AML (≥70 years).

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“…There are several human leukemia cell lines available, and only K562 cell line was selected to mimic the clinical situation, since this cell line was found to have higher baseline levels of M2 expression (data not shown), which is similar to those responders of AML patients treated with GTI-2040 and high-dose Ara-C (14). Ara-C is one of the most effective anticancer agents for the treatment of AML, and its therapeutic effect at low or high doses has been extensively studied (24)(25)(26)(27)(28)(29)(30)(31). It has been reported that the metabolism of Ara-C in vitro was greatly enhanced by RNR inhibitors, such as amidox and trimidox (32)(33)(34).…”

Section: Discussionmentioning

confidence: 60%

Biochemical Modulation of Aracytidine (Ara-C) Effects by GTI-2040, a Ribonucleotide Reductase Inhibitor, in K562 Human Leukemia Cells

Chen

Aimiuwu

Xie

et al. 2010

AAPS J

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Abstract. GTI-2040 is a potent antisense to the M2 subunit of the ribonucleotide reductase (RNR), an enzyme involved in the de novo synthesis of nucleoside triphosphates. We hypothesized that combination of GTI-2040 with the cytarabine (Ara-C) could result in an enhanced cytotoxic effect with perturbed intracellular deoxynucleotide/nucleotide (dNTP/NTP) pools including Ara-C triphosphate (Ara-CTP). This study aims to provide a direct experimental support of this hypothesis by monitoring the biochemical modulation effects, intracellular levels of Ara-CTP, dNTPs/NTPs following the combination treatment of Ara-C, and GTI-2040 in K562 human leukemia cells. GTI-2040 was introduced into cells via electroporation. A hybridization-ligation ELISA was used to quantify intracellular GTI-2040 concentrations. Real-time PCR and Western blot methods were used to measure the RNR M2 mRNA and protein levels, respectively. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay was used to measure the cytotoxicity following various drug treatments. A non-radioactive HPLC-UV method was used for measuring the intracellular Ara-CTP, while a LC-MS/ MS method was used to quantify intracellular dNTP/NTP pools. GTI-2040 was found to downregulate M2 mRNA and protein levels in a dose-dependent manner and showed significant decrease in dNTP but not NTP pool. When combining GTI-2040 with Ara-C, a synergistic cytotoxicity was observed with no further change in dNTP/NTP pools. Importantly, pretreatment of K562 cells with GTI-2040 was found to increase Ara-CTP level for the first time, and this effect may be due to inhibition of RNR by GTI-2040. This finding provides a laboratory justification for the current phase I/II evaluation of GTI-2040 in combination with Ara-C in patients with acute myeloid leukemia.

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Effect of low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor priming (CAG regimen) on the outcome of elderly patients with acute myeloid leukemia

Cited by 32 publications

References 20 publications

The Combination of Conventional Chemotherapy with New Targeted Therapy in Hematologic Malignancies: The Safety and Efficiency of Low- Dose Cytarabine Supports its Combination with New Therapeutic Agents in Early Clinical Trials

The Combination of Conventional Chemotherapy with New Targeted Therapy in Hematologic Malignancies: The Safety and Efficiency of Low- Dose Cytarabine Supports its Combination with New Therapeutic Agents in Early Clinical Trials

Efficacy and safety of decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin in newly diagnosed elderly patients with acute myeloid leukemia

Biochemical Modulation of Aracytidine (Ara-C) Effects by GTI-2040, a Ribonucleotide Reductase Inhibitor, in K562 Human Leukemia Cells

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