A meta-analysis of CAG (cytarabine, aclarubicin, G-CSF) regimen for the treatment of 1029 patients with acute myeloid leukemia and myelodysplastic syndrome

Wei, Guoqing; Ni, Wanmao; Chiao, Jen Wei; Cai, Zhen; Huang, He; Liu, Delong

doi:10.1186/1756-8722-4-46

Cited by 80 publications

(73 citation statements)

References 25 publications

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“…These poor outcomes may be due to drug resistance, comorbidity, Eastern Cooperative Oncology Group performance status or treatment-associated mortality (4,5). The cytarabine, aclarubicin and granulocyte colony-stimulating factor (G-CSF) (CAG) treatment regimen was initially applied to these patients groups in Japan (6), and widespread popularization in Asia followed (7). Although the CAG regimen has demonstrated marked therapeutic efficacy (6), the definite mechanisms underlying the CAG protocol remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line

Sheng

Wan

Zhong

et al. 2016

Experimental and Therapeutic Medicine

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Combining cytarabine, aclarubicin and granulocyte colony-stimulating factor (G-CSF) has demonstrated marked efficacy in the treatment of elderly and relapsed/refractory patients with acute myeloid leukemia (AML); however, the role of G-CSF remains poorly understood. The present study aimed to investigate the ability of G-CSF to overcome stromal-mediated drug resistance and the underlying molecular mechanism. Two types of co-culture models were established in the HS-5 human bone marrow/stromal and HL-60 human promyelocytic leukemia cell lines, in order to imitate the interactions between stromal and leukemia cells , which is mediated by the stromal cell-derived factor (SDF)-1α signaling axis. In the present study, HL-60 cells were attracted and adhered to HS-5 cells using migration assay and flow cytometry, respectively; however, these interactions were inhibited by treatment with G-CSF and/or the C-X-C chemokine receptor type 4 (CXCR4) antagonist, AMD3100. Co-culture with HS-5 cells, including direct and indirect contact, protected HL-60 cells against spontaneous apoptosis or drug-induced apoptosis; however, these protective effects were disrupted by treatment with G-CSF and/or AMD3100. Notably, G-CSF and/or AMD3100 did not alter cell viability or apoptosis when HL-60 cells were cultured with medium alone. In addition, G-CSF significantly reduced the expression levels of surface CXCR4 protein, total CXCR4 protein and CXCR4 mRNA, and significantly upregulated the expression of microRNA (miR)-146a. Conversely, AMD3100 significantly reduced surface CXCR4 expression levels, but not the total CXCR4, CXCR4 mRNA or miR-146a expression levels. The results of the present study suggested that interfering with the CXCR4/SDF-1α signaling axis via G-CSF inhibited the migration and adhesion of HL-60 cells to HS-5 cells and eliminated HS5 cell-mediated protective effects. Furthermore, G-CSF administration reduced CXCR4 expression levels by upregulating the expression of miR-146a, whereas AMD3100 appeared to be predominantly dependent on receptor internalization. Therefore, a G-CSF/miR-146a/CXCR4 pathway may explain how G-CSF inhibits CXCR4/SDF-1α signaling and overcomes stromal cell-mediated drug resistance in acute myeloid leukemia.

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Section: Introductionmentioning

confidence: 99%

Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line

Sheng

Wan

Zhong

et al. 2016

Experimental and Therapeutic Medicine

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“…These compounds, produced by Streptomyces bacteria, are among the most effective anticancer drugs available and are currently included in 500 clinical trials worldwide (4). Doxorubicin is widely used as a first-choice chemotherapeutic agent for many tumors, including various carcinomas and sarcomas (5), whereas aclacinomycin A has been used in the treatment of hematological malignancies (6). The biological activity of doxorubicin and aclacinomycin is mediated through topoisomerase II (7), while additional mechanisms of these drugs include the recently discovered histone eviction activity (4).…”

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confidence: 99%

Divergent evolution of an atypical S -adenosyl- l -methionine–dependent monooxygenase involved in anthracycline biosynthesis

Grocholski

Dinis

Niiranen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Bacterial secondary metabolic pathways are responsible for the biosynthesis of thousands of bioactive natural products. Many enzymes residing in these pathways have evolved to catalyze unusual chemical transformations, which is facilitated by an evolutionary pressure promoting chemical diversity. Such divergent enzyme evolution has been observed in S-adenosyl-l-methionine (SAM)-dependent methyltransferases involved in the biosynthesis of anthracycline anticancer antibiotics; whereas DnrK from the daunorubicin pathway is a canonical 4-O-methyltransferase, the closely related RdmB (52% sequence identity) from the rhodomycin pathways is an atypical 10-hydroxylase that requires SAM, a thiol reducing agent, and molecular oxygen for activity. Here, we have used extensive chimeragenesis to gain insight into the functional differentiation of RdmB and show that insertion of a single serine residue to DnrK is sufficient for introduction of the monooxygenation activity. The crystal structure of DnrK-Ser in complex with aclacinomycin T and S-adenosyl-l-homocysteine refined to 1.9-Å resolution revealed that the inserted serine S297 resides in an α-helical segment adjacent to the substrate, but in a manner where the side chain points away from the active site. Further experimental work indicated that the shift in activity is mediated by rotation of a preceding phenylalanine F296 toward the active site, which blocks a channel to the surface of the protein that is present in native DnrK. The channel is also closed in RdmB and may be important for monooxygenation in a solvent-free environment. Finally, we postulate that the hydroxylation ability of RdmB originates from a previously undetected 10-decarboxylation activity of DnrK.

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“…The CAG regimen, which was originally designed in Japan, rapidly became popularized in China for the treatment of acute myeloid leukemia and myelodysplastic syndrome patients due to the relatively mild toxicity exhibited by the regimen. The CR rate of acute myeloid leukemia patients treated with the CAG regimen (56.7%) appears to be marginally lower than the CR rate of patients treated with the standard daunorubicin and cytarabine regimen (DA; 45 mg/m 2 daunorubicin and 100-200 mg/m 2 cytarabine; 57-65%) (13). However, no randomized control trial studies regarding the efficacy of the CAG and DA regimens have been performed.…”

Section: Discussionmentioning

confidence: 98%

Concurrent chronic neutrophilic leukemia blast crisis and multiple myeloma: A case report and literature review

Shi

et al. 2015

Oncology Letters

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Abstract. The current study presents the case of a 78-year-old male with concurrent chronic neutrophilic leukemia (CNL) and multiple myeloma (MM) who developed acute myeloid leukemia after two years of treatment with hydroxyurea, cyclophosphamide, prednisone and thalidomide. The patient presented with mature neutrophilic leukocytosis, hepatosplenomegaly, a high neutrophil alkaline phosphatase score and an absence of the Philadelphia chromosome or the BCR-ABL fusion gene. A bone marrow aspirate smear and biopsy indicated that the CNL coexisted with a plasma cell neoplasm. In addition, monoclonal λ-paraproteinemia was detected by serum protein immunofixation electrophoresis, and bone lesions were identified in multiple vertebrae. The patient achieved complete remission following one cycle of induction chemotherapy with the decitabine regimen in combination with the low-dose cytarabine, aclarubicin and granulocyte-colony stimulating factor (CAG) priming regimen. The occurrence of CNL and MM concurrently is extremely rare and thus, it has only been reported in a small number of cases. The occurrence of CNL and MM in the same patient as two distinct hematological malignancies indicates the neoplastic transformation of a pluripotent stem cell. Decitabine combined with the CAG priming regimen may present a good therapeutic strategy for elderly patients with secondary acute myeloid leukemia.

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A meta-analysis of CAG (cytarabine, aclarubicin, G-CSF) regimen for the treatment of 1029 patients with acute myeloid leukemia and myelodysplastic syndrome

Cited by 80 publications

References 25 publications

Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line

Granulocyte colony-stimulating factor inhibits CXCR4/SDF-1α signaling and overcomes stromal-mediated drug resistance in the HL-60 cell line

Divergent evolution of an atypical S -adenosyl- l -methionine–dependent monooxygenase involved in anthracycline biosynthesis

Concurrent chronic neutrophilic leukemia blast crisis and multiple myeloma: A case report and literature review

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