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Vet. Sci. 2015, 2(2), 52-68; doi:10.3390/vetsci2020052

Alkylation and Carbamylation Effects of Lomustine and Its Major Metabolites and MGMT Expression in Canine Cells

1
Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802, USA
2
Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Anthony Blikslager
Received: 16 December 2014 / Revised: 20 January 2015 / Accepted: 20 April 2015 / Published: 24 April 2015
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Abstract

DNA Alkylation is thought to be the reason for the efficacy of lomustine while carbamylation has been implicated as the cause for the side effects seen with lomustine treatment such as hepatotoxicity. In the alkylation study we show that lomustine and its metabolites form similar levels of the DNA adducts N7 hydroxyethylguanine and O6 hydroxyethyldeoxyguanosine. In terms of carbamylation, lomustine showed greater extent of carbamylation in the canine hepatocytes and lymphoma cell lines. The DNA repair enzyme O6 methylguanine DNA methyltransferase (MGMT) causes resistance of tumor cells to bifunctional nitrosourea, like lomustine. There is no data available regarding MGMT expression/activity in canine cells or tissues. Our study shows that there is low MGMT activity in the canine lymphoid cell line 17–71 while the GL-1 cells did not show any detectable enzyme activity or mRNA expression. The MGMT enzyme activity measured in canine hepatocytes is about 250–350 fmol/mg protein as compared to about 90 fmol/mg protein in 17–71 cells. We also show that MGMT mRNA expression in 17–71 cells and canine hepatocytes positively correlates with its enzyme activity in these cells. View Full-Text
Keywords: lomustine; trans-4-hydroxylomustine; cis-4-hydroxylomustine; lymphoma; MGMT lomustine; trans-4-hydroxylomustine; cis-4-hydroxylomustine; lymphoma; MGMT
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Chakkath, T.; Lavergne, S.; Fan, T.M.; Bunick, D.; Dirikolu, L. Alkylation and Carbamylation Effects of Lomustine and Its Major Metabolites and MGMT Expression in Canine Cells. Vet. Sci. 2015, 2, 52-68.

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