Display options
Cite
Chakkath T, Lavergne S, Fan TM, et al. Alkylation and Carbamylation Effects of Lomustine and Its Major Metabolites and MGMT Expression in Canine Cells. Vet Sci. 2015;2(2):52-68doi: 10.3390/vetsci2020052.
Chakkath, T., Lavergne, S., Fan, T. M., Bunick, D., & Dirikolu, L. (2015). Alkylation and Carbamylation Effects of Lomustine and Its Major Metabolites and MGMT Expression in Canine Cells. Veterinary sciences, 2(2), 52-68. https://doi.org/10.3390/vetsci2020052
Chakkath, Thushara, et al. "Alkylation and Carbamylation Effects of Lomustine and Its Major Metabolites and MGMT Expression in Canine Cells." Veterinary sciences vol. 2,2 (2015): 52-68. doi: https://doi.org/10.3390/vetsci2020052
Chakkath T, Lavergne S, Fan TM, Bunick D, Dirikolu L. Alkylation and Carbamylation Effects of Lomustine and Its Major Metabolites and MGMT Expression in Canine Cells. Vet Sci. 2015 Apr 24;2(2):52-68. doi: 10.3390/vetsci2020052. PMID: 29061931; PMCID: PMC5644621.
Copy Download .nbib Format: NLM
Share it on

Vet Sci. 2015 Apr 24;2(2):52-68. doi: 10.3390/vetsci2020052.

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

Veterinary sciences

Thushara Chakkath, Sidonie Lavergne, Timothy M Fan, David Bunick, Levent Dirikolu

Affiliations

  1. Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802, USA. [email protected].
  2. Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802, USA. [email protected].
  3. Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802, USA. [email protected].
  4. Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802, USA. [email protected].
  5. Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802, USA. [email protected].

PMID: 29061931 PMCID: PMC5644621 DOI: 10.3390/vetsci2020052

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.

Keywords: MGMT; cis-4-hydroxylomustine; lomustine; lymphoma; trans-4-hydroxylomustine

References

  1. Carcinogenesis. 1996 Feb;17(2):219-24 - PubMed
  2. Clin Chem. 2011 Nov;57(11):1499-505 - PubMed
  3. J Neurooncol. 2009 Feb;91(3):257-64 - PubMed
  4. Cancer Immunol Immunother. 1987;24(3):197-201 - PubMed
  5. Oncogene. 1998 Aug 20;17(7):845-51 - PubMed
  6. Carcinogenesis. 2003 Apr;24(4):625-35 - PubMed
  7. Jpn J Cancer Res. 1987 Nov;78(11):1207-15 - PubMed
  8. Arch Toxicol. 2001 Jul;75(5):306-12 - PubMed
  9. Nucleic Acids Res. 2005 May 19;33(9):2859-67 - PubMed
  10. Xenobiotica. 1991 Jun;21(6):775-91 - PubMed
  11. Biochem Pharmacol. 1976 Mar 15;25(6):695-9 - PubMed
  12. Nat Rev Mol Cell Biol. 2004 Feb;5(2):148-57 - PubMed
  13. Cancer Res. 1974 Jan;34(1):194-200 - PubMed
  14. Chem Biol Interact. 1980 Aug;31(2):167-77 - PubMed
  15. Cancer Res. 1992 Oct 1;52(19):5257-63 - PubMed
  16. Environ Health Perspect. 1985 Oct;62:41-8 - PubMed
  17. Biochim Biophys Acta. 2011 Dec;1816(2):179-90 - PubMed
  18. J Clin Oncol. 2002 May 1;20(9):2388-99 - PubMed
  19. Biochem Pharmacol. 1977 Dec 15;26(24):2331-6 - PubMed
  20. J Med Chem. 1967 Jul;10(4):668-74 - PubMed
  21. Nucleic Acids Res. 2001 Jun 15;29(12):2558-66 - PubMed
  22. Mutat Res. 2009 Aug;678(2):76-94 - PubMed
  23. Carcinogenesis. 1995 Sep;16(9):2255-7 - PubMed
  24. Mutat Res. 1990 Jul;231(1):11-30 - PubMed
  25. Biochim Biophys Acta. 1995 Jan 25;1270(1):63-72 - PubMed
  26. Cytotechnology. 2006 Jun;51(2):51-6 - PubMed
  27. Cancer Res. 1978 Apr;38(4):1070-4 - PubMed
  28. Cancer Chemother Pharmacol. 1988;22(2):153-62 - PubMed
  29. J Vet Med Sci. 1996 May;58(5):469-71 - PubMed
  30. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):206-10 - PubMed
  31. Nature. 1980 Dec 25;288(5792):724-7 - PubMed
  32. DNA Repair (Amst). 2007 Aug 1;6(8):1079-99 - PubMed
  33. Adv Cancer Res. 1977;25:195-269 - PubMed
  34. Mutat Res. 1990 Nov-Dec;233(1-2):117-26 - PubMed
  35. Carcinogenesis. 1996 Nov;17(11):2329-36 - PubMed
  36. Biochem Pharmacol. 2003 Oct 15;66(8):1547-54 - PubMed
  37. Proc Natl Acad Sci U S A. 1990 Jan;87(2):686-90 - PubMed
  38. Cancer Res. 1975 Nov;35(11 Pt 1):2974-84 - PubMed
  39. Carcinogenesis. 1994 Apr;15(4):577-82 - PubMed

Publication Types