Display options
Share it on

Cancer Chemother Pharmacol. 1988;22(2):153-62. doi: 10.1007/BF00257314.

The hepatotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in rats. Ultrastructural evidence of a delayed microtubular toxicity.

Cancer chemotherapy and pharmacology

T Ducastelle, G Raguenez-Viotte, H Fouin-Fortunet, M Matysiak, J Hemet, J P Fillastre

Affiliations

  1. Laboratoire d'Anatomie et de Cytologie Pathologiques, Hôpital Charles Nicolle, Rouen, France.

PMID: 3409447 DOI: 10.1007/BF00257314

Abstract

A few cases of liver involvement have been reported in patients receiving treatment with the antineoplastic nitrosourea CCNU. A single oral dose of 20 or 50 mg/kg CCNU in female Wistar rats induced an important increase in transaminases between day 2 and day 6, followed by a second, moderate increase between day 21 and day 28. Alkaline phosphatases and conjugated hyperbilirubinemia (threefold-increase) were noted for the two doses and were greater for the highest dose. Histological and ultrastructural studies disclosed hepatic lesions of two types: during the first phase of transaminase increase, inflammation of the portal tracts; during the second phase marked dilation of bile canaliculi and numerous filamentous bundles distributed at random throughout the liver cell cytoplasm like normal microtubules. Thus, CCNU induced pericholangitis and intrahepatic cholestasis with microtubular abnormalities. The long-term evolution of hepatic alterations revealed that in the 3rd month after a single oral dose of 20 mg/kg CCNU, lesions were persistent but stable; no reversibility was observed in the 3rd month after 50 mg/kg CCNU, and evolution towards cholangiolysis and biliary cirrhosis was noted. We suggest that CCNU causes a bimodal hepatotoxicity in rats: an early and prolonged ductal injury and a delayed anti-liver cell microtubule toxicity.

Cited by

References

  1. Biochem Biophys Res Commun. 1974 Mar 25;57(2):426-33 - PubMed
  2. Clin Pharmacol Ther. 1968 Sep-Oct;9(5):652-6 - PubMed
  3. Cancer Treat Rep. 1976 Jun;60(6):703-7 - PubMed
  4. Gastroenterology. 1978 Jan;74(1):93-100 - PubMed
  5. Cancer Chemother Pharmacol. 1987;19(2):103-8 - PubMed
  6. Gastroenterology. 1980 Oct;79(4):646-54 - PubMed
  7. Cancer Res. 1975 Feb;35(2):296-301 - PubMed
  8. Cancer Res. 1972 Jun;32(6):1278-9 - PubMed
  9. Biochem Biophys Res Commun. 1978 Jul 28;83(2):754-62 - PubMed
  10. Science. 1969 Aug 1;165(3892):498-9 - PubMed
  11. Life Sci. 1975 Apr 15;16(8):1263-70 - PubMed
  12. Sem Hop Ther. 1975 May-Jun;51(5-6):309-14 - PubMed
  13. Biochemistry. 1977 Apr 19;16(8):1584-9 - PubMed
  14. Cancer Res. 1972 Jan;32(1):22-7 - PubMed
  15. Cancer Chemother Pharmacol. 1987;19(2):109-17 - PubMed
  16. Biochem Pharmacol. 1980 Feb 15;29(4):652-4 - PubMed
  17. Lab Invest. 1986 Jun;54(6):593-608 - PubMed
  18. Liver. 1985 Apr;5(2):101-7 - PubMed
  19. Cancer Chemother Pharmacol. 1985;14(2):125-31 - PubMed
  20. J Pharmacol Exp Ther. 1969 Mar;166(1):104-12 - PubMed
  21. Cancer Res. 1975 Mar;35(3):568-76 - PubMed
  22. Cancer Treat Rev. 1982 Dec;9(4):313-30 - PubMed
  23. J Med Chem. 1967 Jul;10(4):668-74 - PubMed
  24. Toxicol Appl Pharmacol. 1965 Nov;7(6):804-11 - PubMed
  25. Cancer Res. 1976 Feb;36(2 Pt 1):511-5 - PubMed
  26. Cancer Res. 1965 Dec;25(11):1876-81 - PubMed
  27. Br J Cancer. 1974 Nov;30(5):477-80 - PubMed
  28. Clin Pharmacol Ther. 1974 Aug;16(2):363-7 - PubMed
  29. Cancer Res. 1970 May;30(5):1330-7 - PubMed
  30. J Biol Chem. 1972 May 25;247(10):3147-52 - PubMed
  31. Cancer. 1973 Jul;32(1):38-43 - PubMed
  32. J Cell Biol. 1974 Jul;62(1):90-103 - PubMed
  33. J Biol Chem. 1946 Jul;164:321-9 - PubMed
  34. Med Pediatr Oncol. 1975;1(2):95-106 - PubMed
  35. Cancer Chemother Rep 3. 1968 Dec;1(1):115-51 - PubMed

Substances

MeSH terms

Publication Types