PMID: 18202788Jan 19, 2008Paper

DNA methylation and sensitivity to antimetabolites in cancer cell lines

Oncology Reports
Shin SasakiHirokazu Nagawa

Abstract

The prediction of the cellular direction of metabolic pathways toward either DNA synthesis or DNA methylation is crucial for determining the susceptibility of cancers to anti-metabolites such as fluorouracil (5-FU). We genotyped the methylenetetrahydrofolate reductase (MTHFR) gene in NCI-60 cancer cell lines, and identified the methylation status of 24 tumor suppressor genes using methylation-specific multiplex ligation-dependent probe amplification. The susceptibility of the cancer cell lines to seven antimetabolites was then determined. Cells homozygous for CC at MTHFR-A1298C were significantly more sensitive to cyclocytidine, cytarabine (AraC) and floxuridine than those with AA or AC (p=0.0215, p=0.0166, and p=0.0323, respectively), and carried more methylated tumor suppressor genes (p=0.0313). Among the 12 tumor suppressor genes which were methylated in >25% of cancer cell lines, the methylation status of TIMP3, APC and IGSF4 significantly correlated with sensitivity to pyrimidine synthesis inhibitors. In particular, cells with methylated TIMP3 had reduced mRNA levels and were significantly more sensitive to aphidicolin-glycinate, AraC and 5-FU than cells with unmethylated TIMP3. We speculate that MTHFR-A1298C homozygous CC...Continue Reading

Citations

Feb 10, 2016·Frontiers in Pharmacology·Neha S BhiseJatinder K Lamba
May 25, 2013·Journal of Cellular Physiology·Chiara MolinariWainer Zoli
Mar 23, 2011·Seminars in Oncology·Federico InnocentiM Eileen Dolan

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