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Long-term epigenetic therapy with oral zebularine has minimal side effects and prevents intestinal tumors in mice.

ABSTRACT: Recent successes in the application of epigenetic drugs for the treatment of myelodysplastic syndrome have raised questions on the safety of long-term administration of DNA methylation inhibitors. We treated preweaned cancer prone Apc(Min/+) (Min) mice continuously with the DNA methylation inhibitor zebularine in their drinking water to determine the effects of the drug on normal mouse development as well as cancer prevention. Zebularine caused a tissue-specific reduction in DNA methylation at B1 short interspersed nucleotide elements in the small and large intestines of female Min mice but not in other organs examined after chronic oral treatment. No significant difference in the average weights of mice was observed during the treatment. In addition, analysis of global gene expression of colonic epithelial cells from the females indicated that only 3% to 6% of the genes were affected in their expression. We did not detect toxicity and abnormalities from the histopathologic analysis of liver and intestinal tissues. Lastly, we tested whether prevention of tumorigenesis can be achieved with chronic oral administration of zebularine in Min mice. The average number of polyps in Min females decreased from 58 to 1, whereas the average polyp number remained unaffected in Min males possibly due to differential activity of aldehyde oxidase. Taken together, our results show for the first time that long-term oral administration of zebularine causes a gender-specific abrogation of intestinal tumors while causing a tissue-specific DNA demethylation. Importantly, prolonged treatment of mice with epigenetic drugs resulted in only minor developmental and histologic changes.

SUBMITTER: Yoo CB

PROVIDER: S-EPMC6959547 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Long-term epigenetic therapy with oral zebularine has minimal side effects and prevents intestinal tumors in mice.

Yoo Christine B CB Chuang Jody C JC Byun Hyang-Min HM Egger Gerda G Yang Allen S AS Dubeau Louis L Long Tiffany T Laird Peter W PW Marquez Victor E VE Jones Peter A PA

Cancer prevention research (Philadelphia, Pa.) 20080319 4

Recent successes in the application of epigenetic drugs for the treatment of myelodysplastic syndrome have raised questions on the safety of long-term administration of DNA methylation inhibitors. We treated preweaned cancer prone Apc(Min/+) (Min) mice continuously with the DNA methylation inhibitor zebularine in their drinking water to determine the effects of the drug on normal mouse development as well as cancer prevention. Zebularine caused a tissue-specific reduction in DNA methylation at B ...[more]

PMID: 19138966

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Project description:How genetic and phenotypic variation are maintained has long been one of the fundamental questions in population and quantitative genetics. A variety of factors have been implicated to explain the maintenance of genetic variation in some contexts (e.g. balancing selection), but the potential role of epigenetic regulation to influence population dynamics has been understudied. It is well recognized that epigenetic regulation, including histone methylation, small RNA expression, and DNA methylation, helps to define differences between cell types and facilitate phenotypic plasticity. In recent years, empirical studies have shown the potential for epigenetic regulation to also be heritable for at least a few generations without selection, raising the possibility that differences in epigenetic regulation can act alongside genetic variation to shape evolutionary trajectories. Heritable differences in epigenetic regulation that arise spontaneously are termed "epimutations." Epimutations differ from genetic mutations in 2 key ways-they occur at a higher rate and the loci at which they occur often revert back to their original state within a few generations. Here, we present an extension of the standard population genetic model with selection to incorporate epigenetic variation arising via epimutation. Our model assumes a diploid, sexually reproducing population with random mating. In addition to spontaneous genetic mutation, we included parameters for spontaneous epimutation and back-epimutation, allowing for 4 potential epialleles at a single locus (2 genetic alleles, each with 2 epigenetic states), each of which affect fitness. We then analyzed the conditions under which stable epialleles were maintained. Our results show that highly reversible epialleles can be maintained in long-term equilibrium under neutral conditions in a manner that depends on the epimutation and back-epimutation rates, which we term epimutation-back-epimutation equilibrium. On the other hand, epialleles that compensate for deleterious mutations cause deviations from the expectations of mutation-selection balance by a simple factor that depends on the epimutation and back-epimutation rates. We also numerically analyze several sets of fitness parameters for which large deviations from mutation-selection balance occur. Together, these results demonstrate that transient epigenetic regulation may be an important factor in the maintenance of both epigenetic and genetic variation in populations.

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Long-term epigenetic therapy with oral zebularine has minimal side effects and prevents intestinal tumors in mice.

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Long-term epigenetic therapy with oral zebularine has minimal side effects and prevents intestinal tumors in mice.

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