Decitabine triphosphate levels in peripheral blood mononuclear cells from patients receiving prolonged low-dose decitabine administration: a pilot study

Jansen, Robert S.; Rosing, Hilde; Wijermans, Pierre W.; Keizer, Ron J.; Schellens, Jan H.M.; Beijnen, Jos H.

doi:10.1007/s00280-012-1850-x

Cited by 19 publications

(38 citation statements)

References 51 publications

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“…5). It would be interesting to determine the kinetics and duration of conversion of DAC to DAC triphosphate in cells treated with DAC solution vs. those treated with DAC nanogel to complement the DNMT1 depletion data [31]. The data from such studies may provide further insight in correlating DAC cellular levels with the agent’s antiproliferative effect and in understanding the mechanism of efficacy in overcoming drug resistance in drug- and DAC-resistant cell lines.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of decitabine-loaded nanogels in overcoming cancer drug resistance is mediated via sustained DNA methyltransferase 1 (DNMT1) depletion

Vijayaraghavalu

Labhasetwar

2013

Cancer Letters

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DNA Methyltransferase 1 (DNMT1) promotes DNA methylation to maintain cancer drug resistance. The epigenetic drug, decitabine (DAC) is a potent hypomethylating agent, but its effect is transient because of its instability. We tested the efficacy of DAC-loaded nanogels in doxorubicin-resistant breast cancer cells, DAC-resistant melanoma cells, and leukemia cells. DAC in nanogel sustained DNMT1 depletion, prolonged cell arrest in the G2/M cell-cycle phase, and significantly enhanced antiproliferative effect of DAC. The efficacy of DAC-loaded nanogels was more significant in resistant than sensitive cells. Our data suggest that effective delivery of DAC and prolonged DNMT1 depletion are critical to overcoming drug resistance.

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Section: Discussionmentioning

confidence: 99%

Efficacy of decitabine-loaded nanogels in overcoming cancer drug resistance is mediated via sustained DNA methyltransferase 1 (DNMT1) depletion

Vijayaraghavalu

Labhasetwar

2013

Cancer Letters

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“…Two reports, one in seven, and the other in three patients, have found higher DAC-TP levels in responders. 44,45 DNA methylation Despite their description as 'hypomethylating agents', it has proven difficult to consistently demonstrate correlations between response to azacitidine or decitabine and pre-or post-treatment DNA methylation status. The proclivity of different authors to analyze different genes complicates such attempts.…”

Section: Biologic Predictors Of Response To Epigenetic Therapymentioning

confidence: 99%

Epigenetics in clinical practice: the examples of azacitidine and decitabine in myelodysplasia and acute myeloid leukemia

Estey

2013

Leukemia

118

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Randomized trials have clearly demonstrated that the hypomethylating agents azacitidine and decitabine are more effective than 'best supportive care'(BSC) in reducing transfusion frequency in 'low-risk' myelodysplasia (MDS) and in prolonging survival compared with BSC or low-dose ara-C in 'high-risk' MDS or acute myeloid leukemia (AML) with 21-30% blasts. They also appear equivalent to conventional induction chemotherapy in AML with >20% blasts and as conditioning regimens before allogeneic transplant (hematopoietic cell transplant, HCT) in MDS. Although azacitidine or decitabine are thus the standard to which newer therapies should be compared, here we discuss whether the improvement they afford in overall survival is sufficient to warrant a designation as a standard in treating individual patients. We also discuss pre- and post-treatment covariates, including assays of methylation to predict response, different schedules of administration, combinations with other active agents and use in settings other than active disease, in particular post HCT. We note that rational development of this class of drugs awaits delineation of how much of their undoubted effect in fact results from hypomethylation and reactivation of gene expression.

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“…The experience of the subject with hypercellular relapse, in whom an increasing frequency of drug administration salvaged the response, illustrates this point. Continuous infusion of decitabine causes accumulation of decitabine triphosphate in normal cells up to levels that are cytotoxic (66), hence, the use of intermittent s.c. administration in the present trial.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes

Saunthararajah¹,

Sekeres²,

Advani³

et al. 2015

J. Clin. Invest.

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IntroductionAlthough conventional cytotoxic treatments for myeloid cancers can have differing proximal actions, e.g., topoisomerase inhibition (daunorubicin) or termination of DNA chain synthesis (cytarabine), a final common pathway converges onto p53 (TP53), a master regulator of apoptosis (cytotoxicity) (reviewed in ref. 1). As such, TP53 mutation or deletion is associated with resistance to cytotoxic treatments in vitro (2, 3) and in vivo: TP53-mutated acute myeloid leukemia (AML) treated with daunorubicin and/ or cytarabine had a response rate of 33% compared with 81% for TP53 WT AML, while TP53-mutated myelodysplastic syndromes (MDS) had a response rate of 8% versus 60% for MDS with WT TP53 (4). The poorest-risk MDS and AML subtypes, e.g., MDS and AML with complex cytogenetic abnormalities, have the highest rate of TP53 mutations, exceeding 70% in some series (5). Even if TP53 itself is not mutated, alterations in other key p53-system BACKGROUND. Mutational inactivation in cancer of key apoptotic pathway components, such as TP53/p53, undermines cytotoxic therapies that aim to increase apoptosis. Accordingly, TP53 mutations are reproducibly associated with poor treatment outcomes. Moreover, cytotoxic treatments destroy normal stem cells with intact p53 systems, a problem especially for myeloid neoplasms, as these cells reverse the low blood counts that cause morbidity and death. Preclinical studies suggest that noncytotoxic concentrations of the DNA methyltransferase 1 (DNMT1) inhibitor decitabine produce p53-independent cellcycle exits by reversing aberrant epigenetic repression of proliferation-terminating (MYC-antagonizing) differentiation genes in cancer cells. METHODS.In this clinical trial, patients with myelodysplastic syndrome (n = 25) received reduced decitabine dosages (0.1-0.2 mg/kg/day compared with the FDA-approved 20-45 mg/m 2 /day dosage, a 75%-90% reduction) to avoid cytotoxicity. These well-tolerated doses were frequently administered 1-3 days per week, instead of pulse cycled for 3 to 5 days over a 4-to 6-week period, to increase the probability that cancer S-phase entries would coincide with drug exposure, which is required for S-phase-dependent DNMT1 depletion. RESULTS.The median subject age was 73 years (range, 46-85 years), 9 subjects had relapsed disease or were refractory to 5-azacytidine and/or lenalidomide, and 3 had received intensive chemoradiation to treat other cancers. Adverse events were related to neutropenia present at baseline: neutropenic fever (13 of 25 subjects) and septic death (1 of 25 subjects). Blood count improvements meeting the International Working Group criteria for response occurred in 11 of 25 (44%) subjects and were highly durable. Treatment-induced freedom from transfusion lasted a median of 1,025 days (range, 186-1,152 days; 3 ongoing), and 20% of subjects were treated for more than 3 years. Mutations and/or deletions of key apoptosis genes were frequent (present in 55% of responders and in 36% of nonresponders). Noncytotoxic DNMT1 depletion was confirmed b...

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Decitabine triphosphate levels in peripheral blood mononuclear cells from patients receiving prolonged low-dose decitabine administration: a pilot study

Cited by 19 publications

References 51 publications

Efficacy of decitabine-loaded nanogels in overcoming cancer drug resistance is mediated via sustained DNA methyltransferase 1 (DNMT1) depletion

Efficacy of decitabine-loaded nanogels in overcoming cancer drug resistance is mediated via sustained DNA methyltransferase 1 (DNMT1) depletion

Epigenetics in clinical practice: the examples of azacitidine and decitabine in myelodysplasia and acute myeloid leukemia

Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes

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