• 1. Moore AS, London CA, Wood CA, et al. Lomustine (CCNU) for the treatment of resistant lymphoma in dogs. J Vet Intern Med 1999;13:395398.

    • Search Google Scholar
    • Export Citation
  • 2. Rassnick KM, Moore AS, Williams LE, et al. Treatment of canine mast cell tumors with CCNU (lomustine). J Vet Intern Med 1999;13:601605.

    • Search Google Scholar
    • Export Citation
  • 3. Skorupski KA, Clifford CA, Paoloni MC, et al. CCNU for the treatment of dogs with histiocytic sarcoma. J Vet Intern Med 2007;21:121126.

    • Search Google Scholar
    • Export Citation
  • 4. Van Meervenne S, Verhoeven PS, de Vos J, et al. Comparison between symptomatic treatment and lomustine supplementation in 71 dogs with intracranial, space-occupying lesions. Vet Comp Oncol 2014;12:6777.

    • Search Google Scholar
    • Export Citation
  • 5. Williams LE, Rassnick KM, Power HT, et al. CCNU in the treatment of canine epitheliotropic lymphoma. J Vet Intern Med 2006;20:136143.

  • 6. Schabel FM Jr, Johnston TP, McCaleb GS, et al. Experimental evaluation of potential anticancer agents VIII. Effects of certain nitrosoureas on intracerebral L1210 leukemia. Cancer Res 1963;23:725733.

    • Search Google Scholar
    • Export Citation
  • 7. Leukemias and plasma cell tumors. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg's cancer: principles and practice of oncology. 10th ed. Philadelphia: Wolters Kluwer Health, 2015;16021719.

    • Search Google Scholar
    • Export Citation
  • 8. Gustafson DL, Bailey DB. Cancer chemotherapy. In: Withrow SJ, Vail DM, Page RL, eds. Withrow and MacEwen's small animal clinical oncology. 6th ed. St Louis: Elsevier Saunders, 2019;182208.

    • Search Google Scholar
    • Export Citation
  • 9. Hosoya K, Lord LK, Lara-Garcia A, et al. Prevalence of elevated alanine transaminase activity in dogs treated with CCNU (lomustine). Vet Comp Oncol 2009;7:244255.

    • Search Google Scholar
    • Export Citation
  • 10. Carter SK, Newman JW. Nitrosoureas: 1,3-bis(2-chloroethyl)-1-nitrosourea (NSC-409962;BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (NSC-79037; CCNU)—clinical brochure. Cancer Chemother Rep 3 1968;1:115151.

    • Search Google Scholar
    • Export Citation
  • 11. Henry MC, Davis RD, Schein PS. Hepatotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. (CCNU) in dogs: the use of serial percutaneous liver biopsies. Toxicol Appl Pharmacol 1973;25:410417.

    • Search Google Scholar
    • Export Citation
  • 12. Heading KL, Brockley LK, Bennett PF. CCNU (lomustine) toxicity in dogs: a retrospective study (2002–07). Aust Vet J 2011;89:109116.

    • Search Google Scholar
    • Export Citation
  • 13. Skorupski KA, Hammond GM, Irish AM, et al. Prospective randomized clinical trial assessing the efficacy of Denamarin for prevention of CCNU-induced hepatopathy in tumor-bearing dogs. J Vet Intern Med 2011;25:838845.

    • Search Google Scholar
    • Export Citation
  • 14. Center SA, Slater MR, Manwarren T, et al. Diagnostic efficacy of serum alkaline phosphatase and γ-glutamyltransferase in dogs with histologically confirmed hepatobiliary disease: 270 cases (1980–1990). J Am Vet Med Assoc 1992;201:12581264.

    • Search Google Scholar
    • Export Citation
  • 15. Vail DM, von Euler H, Rusk AW, et al. A randomized trial investigating the efficacy and safety of water soluble micellar paclitaxel (Paccal Vet) for treatment of nonresectable grade 2 or 3 mast cell tumors in dogs. J Vet Intern Med 2012;26:598607.

    • Search Google Scholar
    • Export Citation
  • 16. Kristal O, Rassnick KM, Gliatto JM, et al. Hepatotoxicity associated with CCNU (lomustine) chemotherapy in dogs. J Vet Intern Med 2004;18:7580.

    • Search Google Scholar
    • Export Citation
  • 17. Hosoya K, Kisseberth WC, Alvarez FJ, et al. Adjuvant CCNU (lomustine) and prednisone chemotherapy for dogs with incompletely excised grade 2 mast cell tumors. J Am Anim Hosp Assoc 2009;45:1418.

    • Search Google Scholar
    • Export Citation
  • 18. Hall AP, Elcombe CR, Foster JR, et al. Liver hypertrophy: a review of adaptive (adverse and non-adverse) changes—conclusions from the 3rd International ESTP Expert Workshop. Toxicol Pathol 2012;40:971994.

    • Search Google Scholar
    • Export Citation
  • 19. Henry MC, Marlow M. Serum enzymes in hepatotoxicity induced by chloroethylcyclohexyl nitrosourea and arabinofuranosyl-6-mercaptopurine. Toxicol Appl Pharmacol 1973;24:250255.

    • Search Google Scholar
    • Export Citation
  • 20. Borel AG, Abbott FS. Identification of carbamoylated thiol conjugates as metabolites of the antineoplastic 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, in rats and humans. Drug Metab Dispos 1993;21:889901.

    • Search Google Scholar
    • Export Citation
  • 21. Center SA, Warner KL, Erb HN. Liver glutathione concentrations in dogs and cats with naturally occurring liver disease. Am J Vet Res 2002;63:11871197.

    • Search Google Scholar
    • Export Citation
  • 22. Mitchell JR, Jollow DJ, Potter WZ, et al. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther 1973;187:211217.

    • Search Google Scholar
    • Export Citation
  • 23. Chapman SE, Hostutler RA. A laboratory diagnostic approach to hepatobiliary disease in small animals. Vet Clin North Am Small Anim Pract 2013;43:12091225.

    • Search Google Scholar
    • Export Citation
  • 24. VCOG. Veterinary Cooperative Oncology Group—common terminology criteria for adverse events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.1. Vet Comp Oncol 2016;14:417446.

    • Search Google Scholar
    • Export Citation
  • 25. World Small Animal Veterinary Association Liver Standardization Group. WSAVA standards for clinical and histological diagnosis of canine and feline liver diseases. Philadelphia: Saunders Elsevier, 2006.

    • Search Google Scholar
    • Export Citation
  • 26. Barry-Heffernan C, Ekena J, Dowling S, et al. Biomarkers of oxidative stress as an assessment of the redox status of the liver in dogs. J Vet Intern Med 2019;33:611617.

    • Search Google Scholar
    • Export Citation
  • 27. Anadón A, Martínez-Larrañaga MR, Ares I, et al. Biomarkers of drug toxicity and safety evaluation. In: Gupta RC, ed. Biomarkers in toxicology. 2nd ed. San Diego: Academic Press, 2019;655691.

    • Search Google Scholar
    • Export Citation
  • 28. Brown PM, Tzannes S, Nguyen S, et al. LOPP chemotherapy as a first-line treatment for dogs with T-cell lymphoma. Vet Comp Oncol 2018;16:108113.

    • Search Google Scholar
    • Export Citation
  • 29. Tennant BC, Center SA. Hepatic function. In: Kaneko JJ, Harvey JW, Bruss ML, eds. Clinical biochemistry of domestic animals. 6th ed. San Diego: Academic Press, 2008;379412.

    • Search Google Scholar
    • Export Citation
  • 30. Center SA, Baldwin BH, Erb HN, et al. Bile acid concentrations in the diagnosis of hepatobiliary disease in the dog. J Am Vet Med Assoc 1985;187:935940.

    • Search Google Scholar
    • Export Citation
  • 31. Kramer RA. Cytochrome P-450-dependent formation of alkylating metabolites of the 2-chloroethylnitrosoureas MeCCNU and CCNU. Biochem Pharmacol 1989;38:31853192.

    • Search Google Scholar
    • Export Citation
  • 32. Chakkath T, Lavergne SN, Fan TM, et al. Preliminary metabolism of lomustine in dogs and comparative cytotoxicity of lomustine and its major metabolites in canine cells. Vet Sci 2014;1:159173.

    • Search Google Scholar
    • Export Citation
  • 33. Musser ML, Quinn HT, Chretin JD. Low apparent risk of CCNU (lomustine)-associated clinical hepatotoxicity in cats. J Feline Med Surg 2012;14:871875.

    • Search Google Scholar
    • Export Citation
  • 34. Gerson SL, Bulgar AD, Weeks LD, et al. Alkylating agents. Part A: classical alkylating agents. In: Chabner BA, Longo DL, eds. Cancer chemotherapy and biotherapy: principles and practice. 5th ed. Philadelphia: Wolters Kluwer-Lippincott Williams and Wilkins Health, 2011;267292.

    • Search Google Scholar
    • Export Citation
  • 35. Brakenhoff JP, Commandeur JN, Wormhoudt LW, et al. Molecular mechanisms of toxic effects of fotemustine in rat hepatocytes and subcellular rat liver fractions. Carcinogenesis 1996;17:715724.

    • Search Google Scholar
    • Export Citation
  • 36. Vermeulen NP, Commandeur JN, Groot EJ, et al. Toxicity of fotemustine in rat hepatocytes and mechanism-based protection against it. Chem Biol Interact 1998;110:139158.

    • Search Google Scholar
    • Export Citation
  • 37. Robson CN, Lewis AD, Wolf CR, et al. Reduced levels of drug-induced DNA cross-linking in nitrogen mustard-resistant Chinese hamster ovary cells expressing elevated glutathione S-transferase activity. Cancer Res 1987;47:60226027.

    • Search Google Scholar
    • Export Citation
  • 38. Léveillé R, Partington BP, Biller DS, et al. Complications after ultrasound-guided biopsy of abdominal structures in dogs and cats: 246 cases (1984–1991). J Am Vet Med Assoc 1993;203:413415.

    • Search Google Scholar
    • Export Citation

Advertisement

Biochemical, functional, and histopathologic characterization of lomustine-induced liver injury in dogs

View More View Less
  • 1 1Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.
  • | 2 2Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.
  • | 3 3Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211
  • | 4 4Department of Statistics, College of Arts and Sciences, University of Missouri, Columbia, MO 65211.
  • | 5 5Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706.

Abstract

OBJECTIVE

To characterize the biochemical, functional, and histopathologic changes associated with lomustine-induced liver injury in dogs.

ANIMALS

I0 healthy purpose-bred sexually intact female hounds.

PROCEDURES

Dogs were randomly assigned to receive lomustine (approx 75 mg/m2, PO, q 21 d for 5 doses) alone (n = 5) or with prednisone (approx 1.5 mg/kg, PO, q 24 h for 12 weeks; 5). For each dog, a CBC, serum biochemical analysis, liver function testing, urinalysis, and ultrasonographic examination of the liver with acquisition of liver biopsy specimens were performed before and at predetermined times during and after lomustine administration. Results were compared between dogs that did and did not receive prednisone.

RESULTS

7 of the I0 dogs developed clinical signs of liver failure. For all dogs, serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities, bile acid concentrations, and liver histologic score increased and hepatic reduced glutathione content decreased over time. Peak serum ALT (r = 0.79) and ALP (r = 0.90) activities and bile acid concentration (r = 0.68) were positively correlated with the final histologic score. Prednisone did not appear to have a protective effect on histologic score.

CONCLUSIONS AND CLINICAL RELEVANCE

In dogs, liver enzyme activities, particularly ALT and ALP activities, should be closely monitored during lomustine treatment and acute increases in those activities may warrant discontinuation of lomustine to mitigate liver injury. Nonspecific ultrasonographic findings and abnormal increases in liver function tests were not detected until the onset of clinical liver failure. Glutathione depletion may have a role in lomustine-induced hepatopathy and warrants further investigation.

Abstract

OBJECTIVE

To characterize the biochemical, functional, and histopathologic changes associated with lomustine-induced liver injury in dogs.

ANIMALS

I0 healthy purpose-bred sexually intact female hounds.

PROCEDURES

Dogs were randomly assigned to receive lomustine (approx 75 mg/m2, PO, q 21 d for 5 doses) alone (n = 5) or with prednisone (approx 1.5 mg/kg, PO, q 24 h for 12 weeks; 5). For each dog, a CBC, serum biochemical analysis, liver function testing, urinalysis, and ultrasonographic examination of the liver with acquisition of liver biopsy specimens were performed before and at predetermined times during and after lomustine administration. Results were compared between dogs that did and did not receive prednisone.

RESULTS

7 of the I0 dogs developed clinical signs of liver failure. For all dogs, serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities, bile acid concentrations, and liver histologic score increased and hepatic reduced glutathione content decreased over time. Peak serum ALT (r = 0.79) and ALP (r = 0.90) activities and bile acid concentration (r = 0.68) were positively correlated with the final histologic score. Prednisone did not appear to have a protective effect on histologic score.

CONCLUSIONS AND CLINICAL RELEVANCE

In dogs, liver enzyme activities, particularly ALT and ALP activities, should be closely monitored during lomustine treatment and acute increases in those activities may warrant discontinuation of lomustine to mitigate liver injury. Nonspecific ultrasonographic findings and abnormal increases in liver function tests were not detected until the onset of clinical liver failure. Glutathione depletion may have a role in lomustine-induced hepatopathy and warrants further investigation.

Supplementary Materials

    • Supplementary Appendix S1 (PDF 185 kb)

Contributor Notes

Dr. Dedeaux's present address is the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996.

Dr. Reinhart's present address is the Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802.

Dr. Husnik's present address is the Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON NIG 2WI, Canada.

Address correspondence to Dr. Flesner (flesnerb@missouri.edu).