Carcinogenesis, Vol. 23, No. 1, 61-65,
January 2002
© 2002 Oxford University Press
CANCER BIOLOGY |
Studies of methionine cycle intermediates (SAM, SAH), DNA methylation and the impact of folate deficiency on tumor numbers in Min mice
1 Departments of Pediatrics and Human Genetics, McGill University-Montreal Children's Hospital Research Institute, 4060 Ste Catherine Street West, Montreal, Quebec H3Z 2Z3, Canada,
2 Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arizona, USA and
3 Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
Several epidemiological studies have suggested a modulatory effect of dietary folate intake on the risk of colorectal cancer. The molecular basis for this inverse association is not clearly understood, but may involve alterations in DNA methylation. In this study, we examined the levels of methylation intermediates [S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH)] and of global DNA methylation in the pre-neoplastic small intestine of Min (multiple intestinal neoplasia) mice. We also studied the effect of folate/choline deficiency on these parameters and on tumor multiplicity in this animal model. In folate-adequate Min mice, we identified positive linear correlations between SAM or SAH and tumor numbers (R2 = 0.38, P < 0.005; R2 = 0.26, P = 0.025, respectively). A positive correlation between global DNA hypomethylation and tumor multiplicity was also observed (R2 = 0.29, P = 0.014). These three biochemical determinants (SAM, SAH and DNA hypomethylation) may, therefore, serve as early markers of cell transformation. Folate/choline deficiency, however, did not produce a consistent effect on tumor numbers in three separate experiments. As an increase in tumor numbers was observed only in folate- and choline-deficient mice with low levels of SAM and DNA hypomethylation, the modulatory role of folate may be dependent on the transformation state of the cell.
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