Effect of Cytarabine and Decitabine in Combination in Human Leukemic Cell Lines

Qin, Taichun; Youssef, Emile M.; Jelı́nek, Jaroslav; Chen, Rong; Yang, Allen S.; Garcia‐Manero, Guillermo; Issa, Jean–Pierre J.

doi:10.1158/1078-0432.ccr-06-2762

Cited by 119 publications

(106 citation statements)

References 24 publications

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“…The chemosensitizing effect of demethylating agents has been previously described in several cancer cell lines (46)(47)(48). These studies showed that 5-aza and its analogues increase the apoptotic index of cancer cells exposed to various DNA-damaging agents, including irinotecan.…”

Section: Molecular Cancer Therapeuticsmentioning

confidence: 83%

Epigenetic mechanisms of irinotecan sensitivity in colorectal cancer cell lines

Crea

Giovannetti

Cortesi

et al. 2009

Molecular Cancer Therapeutics

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Irinotecan is a topoisomerase-I (Top-I) inhibitor used for the treatment of colorectal cancer. DNA demethylating agents, including 5-azacytidine (5-aza), display synergistic antitumor activity with several chemotherapy drugs. 5-Aza may enhance irinotecan cytotoxicity by at least one of the following mechanisms: (a) Top-I promoter demethylation, (b) activation of genes involved in Top-I transcriptional regulation (p16 or Sp1), and (c) modulation of the cell cycle and apoptosis after DNA damage. The growth-inhibitory effects of SN38, the active metabolite of irinotecan, 5-aza, and their combinations, were studied in four colorectal cancer cell lines. The effects of treatments on cell cycle were analyzed by flow cytometry, and apoptosis was measured by fluorescence microscopy. Top-I, Sp1, and p53 expression modulated by 5-aza were measured by real-time PCR. Methylation of Top-I, p16, 14-3-3σ, and hMLH1 promoters before and after 5-aza treatment were measured by MethyLight PCR and DNA bisulfite sequencing. Low-dose 5-aza significantly enhanced the apoptotic effect of irinotecan in all colorectal cancer cells, whereas a synergistic cytotoxic effect was observed only in p53-mutated cells (HT29, SW620, and WiDr). This synergistic effect was significantly correlated with Top-I upregulation by 5-aza, and coupled to p16 demethylation and Sp1 up-regulation. p16 demethylation was also associated with enhanced cell cycle arrest after irinotecan treatment. In contrast, 5-aza down-regulated Top-I expression in the p53 wild-type LS174T cells in a p53-dependent manner, thereby reducing SN38 cytotoxicity. In conclusion, 5-aza modulates Top-I expression by several mechanisms involving Sp1, p16, and p53. If confirmed in other models, these results suggest that p16 and p53 status affects the 5-aza-irinotecan interaction.

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Section: Molecular Cancer Therapeuticsmentioning

confidence: 83%

Epigenetic mechanisms of irinotecan sensitivity in colorectal cancer cell lines

Crea

Giovannetti

Cortesi

et al. 2009

Molecular Cancer Therapeutics

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“…The antitumoral activity of decitabine was evaluated in vitro in several leukemic cell lines and solid tumors, where the 50% inhibitory concentration ranged from 10 nM to 10 mM. Concentrations of decitabine optimal to induce DNA hypomethylation reached a plateau above concentrations of 0.5 mM to 1 mM, whereas higher concentrations increased cytotoxicity [16][17][18][19].…”

Section: Nonclinical Aspects and Clinical Pharmacologymentioning

confidence: 99%

The European Medicines Agency Review of Decitabine (Dacogen) for the Treatment of Adult Patients With Acute Myeloid Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

et al. 2016

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On September 20, 2012, a marketing authorization valid throughout the European Union (EU) was issued for decitabine for the treatment of adult patients aged 65 years and older with newly diagnosed de novo or secondary acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy. Decitabine is a pyrimidine analog incorporated into DNA, where it irreversibly inhibits DNA methyltransferases through covalent adduct formation with the enzyme.The use of decitabine was studied in an open-label, randomized, multicenter phase III study (DACO-016) in patients with newly diagnosed de novo or secondary AML. Decitabine (n 5 242) was compared with patient's choice with physician's advice (n 5 243) of low-dose cytarabine or supportive care alone. The primary endpoint of the study was overall survival. The median overall survival in the intent-to-treat (ITT) population was 7.7 months among patients treated with decitabine compared with 5.0 months for those in the control arm (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69-1.04; p 5 .1079). Mature survival data after an additional year of follow-up were consistent with these results, with a median overall survival of 7.7 months in patients treated with decitabine and 5.0 months in the control arm (HR, 0.82; 95% CI, 0.68-0.99; p 5 .0373). Secondary endpoints, including response rates, progressionfree survival, and event-free survival, were increased in favor of decitabine when compared with control treatment. The most common adverse drug reactions reported during treatment with decitabine are pyrexia, anemia, thrombocytopenia, febrile neutropenia, neutropenia, nausea, and diarrhea. This paper summarizes the scientific review of the application leading to approval of decitabine in the EU. The detailed scientific assessment report and product information (including the summary of product characteristics) for this product are available on the EMA website (http://www.ema.europa.eu). The Oncologist 2016;21:692-700

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“…13,14 DNA-hypomethylating agents can sensitize resistant cancer cells to cytotoxic agents, [25][26][27][28] but this approach has been sparsely studied in clinical trials. Nonetheless, the use of an epigenetic modifier for chemosensitization appears to be safe, 29,30 and was reported to have restored cytarabine sensitivity to a cohort of younger patients with refractory acute lymphoblastic leukemia.…”

Section: Introductionmentioning

confidence: 99%

Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML

Scandura

Roboz

Moh

et al. 2011

Blood

119

100

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We conducted an open-label phase 1 study exploring the feasibility, safety, and biologic activity of epigenetic priming with decitabine before standard induction chemotherapy in patients with less-thanfavorable risk of acute myelogenous leukemia (AML). We directly compared the clinical and DNA-hypomethylating activity of decitabine delivered at 20 mg/m 2 by either a 1-hour infusion (Arm A) or a continuous infusion (Arm B) for 3, 5, or 7 days before a single, standard induction with infusional cytarabine (100 mg/m 2 for 7 days) and daunorubicin (60 mg/m 2 ؋ 3 doses). Toxicity was similar to that of standard induction chemotherapy alone. Although we did not identify a maximum tolerated dose, there was more gastrointestinal toxicity with 7 days of decitabine priming. Decitabine induced DNA hypomethylation at all dose levels and there was a trend toward greater hypomethylation in CD34 ؉ bone marrow cells when decitabine was delivered by a short pulse (Arm A). Twenty-seven subjects (90%) responded to therapy: 17 with complete remission (57%) and 10 with partial remission (33%). Of the patients with partial remission to protocol treatment, 8 achieved remission to their next therapy, bringing the overall complete remission rate to 83%. We conclude that epigenetic priming of intensive chemotherapy can be safely delivered in an attempt to improve response rates. This trial was registered at www.clinicaltrials. gov as NCT00538876. (Blood. 2011;118(6): 1472-1480) IntroductionComplete remission (CR) is required for the cure of patients with acute myelogenous leukemia (AML). Modern treatment has improved the survival of patients with AML and favorable molecular features, but the majority of patients do not have these favorable features. Standard therapy for younger patients with suboptimalrisk AML is associated with only 19%-37% long-term survival, and 17%-38% of these patients have persistent AML after standard induction chemotherapy. 1-3 Accordingly, new treatment strategies to improve induction success rates are needed to increase survival.Aberrant DNA methylation is a common means by which tumor suppressor genes (TSGs) are inactivated during carcinogenesis. 4,5 Unlike genetic mechanisms of inactivation such as gene deletion or mutation, the epigenetic silencing of TSGs by DNA methylation is potentially reversible. This has led to broad interest by cancer biologists and oncologists in the study of DNA methylation and provides the rationale for incorporating DNA-hypomethylating agents into cancer therapy.Acquired abnormalities of DNA methylation are frequently observed in AML and are particularly prevalent among patients with adverse risk features. 6,7 Decitabine has single-agent activity in patients with poor-risk, relapsed, and resistant AML. [8][9][10][11][12] This antileukemic activity is believed to result from the epigenetic induction of differentiation and cytotoxicity, 13,14 but a link between clinical outcomes and the decitabine-induced hypomethylation of specific genomic loci has not yet been established. 10,[15]...

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Effect of Cytarabine and Decitabine in Combination in Human Leukemic Cell Lines

Cited by 119 publications

References 24 publications

Epigenetic mechanisms of irinotecan sensitivity in colorectal cancer cell lines

Epigenetic mechanisms of irinotecan sensitivity in colorectal cancer cell lines

The European Medicines Agency Review of Decitabine (Dacogen) for the Treatment of Adult Patients With Acute Myeloid Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML

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