Pharmacokinetic and pharmacodynamic analysis of 5-aza-2’-deoxycytidine decitabine in the design of its dose-schedule for cancer therapyReport as inadecuate




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Clinical Epigenetics

, 5:3

First Online: 01 February 2013Received: 01 October 2012Accepted: 04 January 2013

Abstract

5-Aza-2′-deoxycytidine 5-AZA-CdR, decitabine, an epigenetic drug that inhibits DNA methylation, is currently used to treat myelodysplastic syndrome MDS, and is under investigation for treating acute myeloid leukemia AML and other malignancies. 5-AZA-CdR can reactivate tumor suppressor genes silenced by aberrant DNA methylation, a frequent event in all types of cancer. Because this epigenetic change is reversible, it is a good target for 5-AZA-CdR therapy. We have reviewed the preclinical data of 5-AZA-CdR to analyze the concentrations and exposure times required to eradicate cancer stem cells. We analyzed the dose-schedules used in animal models that show potent antineoplastic activity of 5-AZA-CdR. We attempted to correlate the preclinical data with the responses obtained in clinical trials of 5-AZA-CdR in patients with cancer. The pharmacokinetics and drug distribution of 5-AZA-CdR are key parameters because adequate therapeutic drug levels are required to eliminate cancer stem cells in all anatomic compartments. The plasma half-life of 5-AZA-CdR in humans is approximately 20 minutes due to the high levels in the liver of cytidine deaminase, the enzyme that inactivates this analogue. This provides a rationale to use an inhibitor of cytidine deaminase in combination with 5-AZA-CdR. Low-dose 5-AZA-CdR is effective for MDS and AML and can induce complete remissions CR. However, maintenance of CR with low-dose 5-AZA-CdR is difficult. Based on analyses of preclinical and clinical data, low dose 5-AZA-CdR has the potential to be an effective form of therapy in some patients with cancer. For patients who do not respond to low dose therapy we recommend dose-intensive treatment with 5-AZA-CdR. Patients who are candidates for intensive dose 5-AZA-CdR should have a good bone marrow status so as to permit adequate recovery from myelosuppression, the major toxicity of 5-AZA-CdR. Solid tumors are also interesting targets for therapy with 5-AZA-CdR. Both low dose and intensive therapy with 5-AZA-CdR can reduce the proliferative potential of tumor stem cells in animal models. We propose novel dose schedules of 5-AZA-CdR for investigation in patients with cancer. The full chemotherapeutic potential of 5-AZA-CdR to treat cancer merits further clinical investigation and can only be realized when its optimal dose-schedule is determined.

KeywordsDecitabine 5-aza-2’-deoxycytidine Epigenetics AML MDS DNA methylation Pharmacokinetics Pharmacodynamics Abbreviations5-AZA-CdR5-Aza-2′-deoxycytidine

ALLAcute lymphocytic leukemia

AMLAcute myeloid leukemia

ARA-CCytosine arabinoside

BSCBest supportive care

CFU-SColony forming unit in spleen

CMLChronic myeloid leukemia

CMMLChronic myelomonocytic leukemia

CpGCytosine-phosphate-guanine

CRComplete remission

CSFCerebrospinal fluid

D5050% decomposition rates

DGUN′-β-d-2-deoxyribofuranosyl-3-guanylurea

DNMTDNA methyltransferase

FDAUS Food and Drug Administration

G-CSFGranulocyte colony stimulating factor

HDACHistone deacetylase

HPLCHigh performance liquid chromatography

HPLC-MSHigh performance liquid chromatography-mass spectrometry

IC50Half maximal inhibitory concentration

i.pIntraperitoneal

MDSMyelodysplastic syndrome

MTDMaximally tolerated dose

NFDUN-formylamidino-N′-β-d-2-deoxyribofuranosylurea

NSCLCNon-small cell lung cancer

OSOverall survival

s.cSubcutaneous.

Electronic supplementary materialThe online version of this article doi:10.1186-1868-7083-5-3 contains supplementary material, which is available to authorized users.

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Author: Metin Karahoca - Richard L Momparler

Source: https://link.springer.com/







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