5-Azacytidine: Microbiological Assay in Mouse Blood

Pittillo, Robert F.; Woolley, Carolyn

doi:10.1128/am.18.2.284-286.1969

Cited by 6 publications

(3 citation statements)

References 5 publications

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“…5 Pseudourea, for example, was one of the earliest examples of anthracene-based drugs tested in clinical trials, 6 and anthracene itself was reported to be effective against specific skin ailments. 7 The planar, linear, three-ring system of the anthracene nucleus has potential for significant overlap with the DNA base pairs, and it is expected to facilitate intercalation of the probe into the DNA helix (Chart 1). 8 The versatile chemistry of anthracene nucleus provides a convenient route to prepare a number of closely related derivatives.…”

Section: Introductionmentioning

confidence: 99%

“…Several anthracene derivatives are known to have significant biological activities against specific types of cancers . Pseudourea, for example, was one of the earliest examples of anthracene-based drugs tested in clinical trials, and anthracene itself was reported to be effective against specific skin ailments . The planar, linear, three-ring system of the anthracene nucleus has potential for significant overlap with the DNA base pairs, and it is expected to facilitate intercalation of the probe into the DNA helix (Chart ) .…”

Section: Introductionmentioning

confidence: 99%

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Contributions of Hydroxyethyl Groups to the DNA Binding Affinities of Anthracene Probes

et al. 2006

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Contributions of hydroxyethyl functions to the DNA binding affinities of substituted anthracenes are evaluated by calorimetry and spectroscopy. Isothermal titration calorimetry indicated that binding of the ligands to calf thymus DNA (5 mM Tris buffer, 50 mM NaCl, pH 7.2, 25 degrees C) is exothermic. The binding constants increased from 1.5 x 10(4) to 1.7 x 10(6) M(-1) as a function of increase in the number of hydroxyethyl functions (0-4). DNA binding was accompanied by red-shifted absorption (approximately 630 cm(-1)), strong hypochromism (>65%), positive induced-circular dichroism bands, and negative linear dichroism signals. DNA binding, in general, increased the helix stabilities to a significant extent (DeltaT(m) approximately 7 degrees C, DeltaDeltaH approximately 3 kcal/mol, DeltaDeltaS approximately 6-20 cal/K.mol). The binding constants showed a strong correlation with the number of hydroxyethyl groups present on the anthracene ring system. Analysis of the binding data using the hydrophobicity parameter (Log P) showed a poor correlation between the binding affinity and hydrophobicity. This observation was also supported by a comparison of the affinities of probes carrying N-ethyl (Kb = 0.8 x 10(5) M(-1)) versus N-hydroxyethyl side chains (Kb = 5.5 x 10(5) M(-1)). These are the very first examples of a strong quantitative correlation between the DNA binding affinity of a probe and the number of hydroxyethyl groups present on the probe. These quantitative findings are useful in the rational design of new ligands for high-affinity binding to DNA.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Contributions of Hydroxyethyl Groups to the DNA Binding Affinities of Anthracene Probes

et al. 2006

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“…The earliest methods for quantitating DNMTis in plasma utilized microbiologic assays. 86 These assays were limited by both instability of the parent drug and lack of specificity due to degradation products having residual cytostatic properties. These limitations ultimately led to a shift to chromatography‐based methods.…”

Section: Exposure–response Relationshipsmentioning

confidence: 99%

DNA methyltransferase inhibitor exposure–response: Challenges and opportunities

Kagan

Garrison

Anders

et al. 2023

Clinical Translational Sci

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Although DNA methyltransferase inhibitors (DNMTis), such as azacitidine and decitabine, are used extensively in the treatment of myelodysplastic syndromes and acute myeloid leukemia, there remain unanswered questions about DNMTi's mechanism of action and predictors of clinical response. Because patients often remain on single‐agent DNMTis or DNMTi‐containing regimens for several months before knowing whether clinical benefit can be achieved, the development and clinical validation of response‐predictive biomarkers represents an important unmet need in oncology. In this review, we will summarize the clinical studies that led to the approval of azacitidine and decitabine, as well as the real‐world experience with these drugs. We will then focus on biomarker development for DNMTis—specifically, efforts at determining exposure–response relationships and challenges that remain impacting the broader clinical translation of these methods. We will highlight recent progress in liquid‐chromatography tandem mass spectrometry technology that has allowed for the simultaneous measurement of decitabine genomic incorporation and global DNA methylation, which has significant potential as a mechanism‐of‐action based biomarker in patients on DNMTis. Last, we will cover important research questions that need to be addressed in order to optimize this potential biomarker for clinical use.

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Quantification of 5-azacytidine in plasma by electrospray tandem mass spectrometry coupled with high-performance liquid chromatography

Zhao

Rudek

et al. 2004

Journal of Chromatography B

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5-Azacytidine: Microbiological Assay in Mouse Blood

Abstract: A 6-chloropurine-resistant strain of Escherichia coli has been used to develop a microbiological assay for the estimation of 5-azacytidine distribution in mouse tissues.

Cited by 6 publications

References 5 publications

Contributions of Hydroxyethyl Groups to the DNA Binding Affinities of Anthracene Probes

Contributions of Hydroxyethyl Groups to the DNA Binding Affinities of Anthracene Probes

DNA methyltransferase inhibitor exposure–response: Challenges and opportunities

Quantification of 5-azacytidine in plasma by electrospray tandem mass spectrometry coupled with high-performance liquid chromatography

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