Expression of O(6)-methylguanine-DNA methyltransferase causes lomustine resistance in canine lymphoma cells.

Abstract

The DNA repair protein O (6)-methylguanine-DNA methyltransferase (MGMT) causes resistance to nitrosoureas in various human cancers. In this study, we analyzed the correlation between canine lymphomas and MGMT in vitro. Two of five canine lymphoma cell lines required higher concentrations of lomustine to inhibit cell growth by 50%, but their sensitivity to the drug increased when they were cultured with an MGMT inhibitor. Fluorometric oligonucleotide assay and real-time polymerase chain reaction of these cell lines revealed MGMT activity and high MGMT mRNA expression, respectively. We analyzed the methylation status of the CpG islands of the canine MGMT gene by the bisulfite-sequencing method. Unlike human cells, the canine lymphoma cell lines did not show significant correlation between methylation status and MGMT suppression levels. Our results suggest that in canine lymphoma MGMT activity may influence sensitivity to nitrosoureas; thus, inhibition of MGMT activity would benefit nitrosourea-resistant patients. Additional studies are necessary to elucidate the mechanism of regulation of MGMT expression.

• Authors: Satoshi Kambayashi, Kouji Minami, Yuka Ogawa, Takehiro Hamaji, Chung Chew Hwang, Masaya Igase, Hiroko Hiraoka, Takako Shimokawa Miyama, Shunsuke Noguchi, Kenji Baba, Takuya Mizuno, Masaru Okuda
• Journal: Canadian journal of veterinary research = Revue canadienne de recherche veterinaire (Can J Vet Res) Vol. 79 Issue 3 Pg. 201-9 (Jul 2015) ISSN: 1928-9022 [Electronic] Canada
• PMID: 26130852 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Lomustine
• DNA Modification Methylases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• CpG Islands
• DNA Modification Methylases (genetics, metabolism)
• Dog Diseases (enzymology, genetics, metabolism)
• Dogs
• Drug Resistance, Neoplasm (physiology)
• Gene Expression Regulation, Enzymologic (physiology)
• Gene Expression Regulation, Neoplastic (physiology)
• Lomustine (pharmacology)
• Lymphoma (enzymology, genetics, metabolism, veterinary)