S110, a 5-Aza-2′-Deoxycytidine–Containing Dinucleotide, Is an Effective DNA Methylation Inhibitor <i>In vivo</i> and Can Reduce Tumor Growth

Chuang, Jody C.; Warner, Steven L.; Vollmer, David; Vankayalapati, Hariprasad; Redkar, Sanjeev; Bearss, David J.; Qiu, Xianyang; Yoo, Christine B.; Jones, Peter A.

doi:10.1158/1535-7163.mct-09-1048

Cited by 140 publications

(88 citation statements)

References 27 publications

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“…In addition, CP-4200 also causes widespread DNA demethylation and reactivation of tumor suppressor genes under conditions where inhibition of hENTdependent drug transport completely blocked the demethylating effects of 5-azacytidine (MR and FL, unpublished data). Both CP-4200 and S110 have shown significant in vivo activity in mouse tumor models (Brueckner et al, 2010;Chuang et al, 2010), which further illustrates the potential of the azacytosine scaffold for continued preclinical development. Importantly, the development of chemically modified azacytosine derivatives might also allow the targeting of tumor entities that are insensitive to 5-azacytidine and decitabine.…”

Section: Metabolic Activation and Cellular Transport Of Dnmt Inhibitorsmentioning

confidence: 82%

Epigenetic cancer therapy: rationales, targets and drugs

2011

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The fundamental role of altered epigenetic modification patterns in tumorigenesis establishes epigenetic regulatory enzymes as important targets for cancer therapy. Over the past few years, several drugs with an epigenetic activity have received approval for the treatment of cancer patients, which has led to a detailed characterization of their modes of action. The results showed that both established drug classes, the histone deacetylase (HDAC) inhibitors and the DNA methyltransferase inhibitors, show substantial limitations in their epigenetic specificity. HDAC inhibitors are highly specific drugs, but the enzymes have a broad substrate specificity and deacetylate numerous proteins that are not associated with epigenetic regulation. Similarly, the induction of global DNA demethylation by non-specific inhibition of DNA methyltransferases shows pleiotropic effects on epigenetic regulation with no apparent tumor-specificity. Second-generation azanucleoside drugs have integrated the knowledge about the cellular uptake and metabolization pathways, but do not show any increased specificity for cancer epigenotypes. As such, the traditional rationale of epigenetic cancer therapy appears to be in need of refinement, as we move from the global inhibition of epigenetic modifications toward the identification and targeting of tumor-specific epigenetic programs. Recent studies have identified epigenetic mechanisms that promote self-renewal and developmental plasticity in cancer cells. Druggable somatic mutations in the corresponding epigenetic regulators are beginning to be identified and should facilitate the development of epigenetic therapy approaches with improved tumor specificity.

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Section: Metabolic Activation and Cellular Transport Of Dnmt Inhibitorsmentioning

confidence: 82%

Epigenetic cancer therapy: rationales, targets and drugs

2011

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“…However, the short plasma half‐life of S‐phase–dependent drugs such as decitabine and 5‐azacitidine limits their incorporation into the DNA of replicating leukemia cells. Guadecitabine (SGI‐110 or 2′‐deoxy‐5‐azacytidylyl‐(3′→5′)‐2′‐deoxyguanosine sodium salt), a next‐generation HMA that is resistant to cytidine deaminase, the main enzyme responsible for decitabine degradation, is designed to extend exposure to decitabine, its active metabolite 7, 8, 9. Guadecitabine is a dinucleotide of decitabine and deoxyguanosine linked by a phosphodiester bond.…”

Section: Introductionmentioning

confidence: 99%

Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia

Roboz

Kantarjian

Yee

et al. 2017

Cancer

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BACKGROUNDOutcomes for patients with relapsed or refractory acute myeloid leukemia (AML) are poor. Guadecitabine, a next‐generation hypomethylating agent, could be useful in treating such patients.METHODSIn this multicenter, open‐label, phase 2 dose‐expansion study, AML patients from 10 North American medical centers were first randomized (1:1) to receive subcutaneous guadecitabine at 60 or 90 mg/m2 on 5 consecutive days in each 28‐day cycle (5‐day regimen). Subsequently, another cohort was treated for 10 days with 60 mg/m2 (10‐day regimen).RESULTSBetween June 15, 2012, and August 19, 2013, 108 patients with previously treated AML consented to enroll in the study, and 103 of these patients were treated; 5 patients did not receive the study treatment. A total of 103 patients were included in the safety and efficacy analyses (24 and 26 patients who were randomly assigned to 60 and 90 mg/m2/d, respectively [5‐day regimen] and 53 patients who were assigned to 60 mg/m2/d [10‐day regimen]). The 90 mg/m2 dose showed no benefit in clinical outcomes in comparison with 60 mg/m2 in the randomized cohort. Composite complete response (CRc) and complete response (CR) rates were higher with the 10‐day regimen versus the 5‐day regimen (CRc, 30.2% vs 16.0%; P = .1061; CR, 18.9% vs 8%; P = .15). Adverse events (grade ≥ 3) were mainly hematologic, with a higher incidence on the 10‐day regimen. Early all‐cause mortality was low and similar between regimens. Twenty patients (8 on the 5‐day regimen and 12 on the 10‐day regimen) were bridged to hematopoietic cell transplantation.CONCLUSIONSGuadecitabine has promising clinical activity and an acceptable safety profile and thus warrants further development in this population. Cancer 2018;124:325‐34. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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“…The current DNA-demethylating agents have a short half-life, and the means to extend tumor exposure but maintain low-dose scenarios are needed. In this regard, SGI-110, a novel compound with a pro-drug mechanism that releases decitabine as the final product (101,102), has shown promising activity in early clinical trials in myeloid malignancies. An additional consideration is the route of delivery of the demethylating drugs, which currently is subcutaneous and intravenous.…”

Section: Figurementioning

confidence: 99%

Harnessing the potential of epigenetic therapy to target solid tumors

Ahuja¹,

Easwaran²,

Baylin³

2014

J. Clin. Invest.

135

103

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Epigenetic therapies may play a prominent role in the future management of solid tumors. This possibility is based on the clinical efficacy of existing drugs in treating defined hematopoietic neoplasms, paired with promising new data from preclinical and clinical studies that examined these agents in solid tumors. We suggest that current drugs may represent a targeted therapeutic approach for reprogramming solid tumor cells, a strategy that must be pursued in concert with the explosion in knowledge about the molecular underpinnings of normal and cancer epigenomes. We hypothesize that understanding targeted proteins in the context of their enzymatic and scaffolding functions and in terms of their interactions in complexes with proteins that are targets of new drugs under development defines the future of epigenetic therapies for cancer. IntroductionThe last decade has witnessed an explosion in our understanding of epigenetic modifications in cancer, including a growing appreciation of its complexity and plasticity (1-4). These developments have poised us for an exciting time to translate this knowledge into the concept of "epigenetic therapy" for cancer. To date, such therapies have gained traction largely within the sphere of hematopoietic malignancies; however, an improved understanding of the determinants of sensitivity to existing drugs, both in laboratory and early clinical trial paradigms, suggests true potential for solid tumors (5, 6). Moreover, recent studies may pave the way for newly emerging drugs and novel drug combinations in solid tumor treatment.

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S110, a 5-Aza-2′-Deoxycytidine–Containing Dinucleotide, Is an Effective DNA Methylation Inhibitor In vivo and Can Reduce Tumor Growth

Cited by 140 publications

References 27 publications

Epigenetic cancer therapy: rationales, targets and drugs

Epigenetic cancer therapy: rationales, targets and drugs

Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia

Harnessing the potential of epigenetic therapy to target solid tumors

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