Cancer Chemotherapy and Pharmacology

, Volume 22, Issue 2, pp 153–162 | Cite as

The hepatotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in rats

Ultrastructural evidence of a delayed microtubular toxicity
  • T. Ducastelle
  • G. Raguenez-Viotte
  • H. Fouin-Fortunet
  • M. Matysiak
  • J. Hemet
  • J. P. Fillastre
Original Articles Hepatotoxicity, CCNU
Received:
Accepted:

Summary

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.

Keywords

Cholestasis Single Oral Dose Portal Tract Liver Involvement Intrahepatic Cholestasis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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References

  1. 1.
    Ahmed AE, Grissom M, El-Azhary R, Haque A, Boor PJ, Costanzi J (1987) Studies on the mechanism of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)-induced hepatotoxicity: II. Biochemical and morphological characterization of the injury and its prevention by phenobarbital. Cancer Chemother Pharmacol 19:103Google Scholar
  2. 2.
    Babson JR, Reed DJ (1978) Inactivation of glutathione reductase by 2-chloroethyl nitrosourea derived isocyanates. Biochem Biophys Res Commun 83:754Google Scholar
  3. 3.
    Babson JR, Reed DJ, Sinkey MA (1977) Active site specific inactivation of chymotrypsin by cyclohexyl isocyanate formed during degradation of the carcinostatic 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. Biochemistry 16:1584Google Scholar
  4. 4.
    Becker BA, Plaa GL (1965) Hepatotoxicity of α-naphtylisothiocyanate congeners with particular emphasis on phenylisothiocyanate. Toxicol Appl Pharmacol 7:804Google Scholar
  5. 5.
    Bessey OA, Lowry OH, Brock MJ (1946) A method for the rapid determination of alkaline phosphatase with five cubic millimeters of serum. J Biol Chem 164:321Google Scholar
  6. 6.
    Brodie AE, Babson JR, Reed DJ (1980) Inhibition of tubulin polymerization by nitrosourea derived isocyanates. Biochem Pharmacol 29:652Google Scholar
  7. 7.
    Carter SK, Newmann JW (1968) Nitrosoureas: 1,3-bis (2-chloroethyl)-1-nitrosourea (NSC 409962, BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (NSC 79037, CCNU). Cancer Chemother Rep Part 3 1:115Google Scholar
  8. 8.
    Cheng CJ, Fujimura S, Grundberger D, Weinstein B (1972) Interaction of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (NSC 79037) with nucleic acids and proteins “in vivo” and “in vitro”. Cancer Res 32:22Google Scholar
  9. 9.
    Connors TA, Hare JR (1974) The binding of 14C labelled 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) to macromolecules of sensitive and resistant tumours. Br J Cancer 30:477Google Scholar
  10. 10.
    De Labarthe B, Chahinian P, Gosselin M, Goasguen J, Ferrand B, Danrigal A, Israel L (1975) Atteinte hepatique au cours d'un traitement par le CCNU. Sem Hop Paris Ther 51: 309Google Scholar
  11. 11.
    De Vita VT, Carbone PP, Owens AH, Gold GL, Krant MJ, Edmonson J (1965) Clinical trials with 1,3-bis (2-chloroethyl)-1-nitrosourea, NSC 409 962. Cancer Res 25:1876Google Scholar
  12. 12.
    Drewinko B, Loo TL, Gottlieb JA (1976) A comparison of the lethal effects of three nitrosourea derivatives on cultured human lymphoma cells. Cancer Res 36:511Google Scholar
  13. 13.
    Dubin M, Maurice M, Feldman G, Erlinger S (1980) Influence of colchicine and phalloidin on bile secretion and hepatic ultrastructure in the rat: possible interaction between microtubules and microfilament. Gastroenterology 79:646Google Scholar
  14. 14.
    El-Azhary R, Ahmed AE, Reynolds ES (1983) Protection by phenobarbital (PB) against bile ductular injury caused by CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea). Fed Proc 42:514Google Scholar
  15. 15.
    Forrest GL, Klevecz RR (1972) Synthesis and degradation of microtubule protein in synchronized Chinese hamster cells. J Biol Chem 247:3147Google Scholar
  16. 16.
    Gratzl M, Schwab D (1976) The effect of microtubular inhibitors on secretion from liver into blood plasma and bile. Cytobiologie Z Exp Zellforsch 13:199Google Scholar
  17. 17.
    Gregory DH, Vlahcevic ZR, Prughl MF, Swell L (1978) Mechanism of secretion of biliary lipids: role of microtubular system in hepatocellular transport of biliary lipids in the rat. Gastroenterology 74:93Google Scholar
  18. 18.
    Herzig GP, Philips GL, Herzig RH, Fay JW, Weiner RL, Wolff SN, Lazarus HM (1981) High dose nitrosourea (BCNU) and autologous bone marrow transplantation: a phase I study. In: Nitrosoureas: current status and new developments. Academic Press, New York, p 155Google Scholar
  19. 19.
    Hill DL, Kirk MC, Struck RF (1975) Microsomal metabolism of nitrosoureas. Cancer Res 35:296Google Scholar
  20. 20.
    Hoogstraten B, Gottlieb JA, Caoili E, Tucker WG, Talley RW, Haut A (1973) CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, NSC 79037) in treatment of cancer. Phase II study. Cancer 32:38Google Scholar
  21. 21.
    Hoogstraten B, Haas CD, Haut A, Talley RW, Rivkin S, Isaacs BL (1975) CCNU and bleomycin in the treatment of cancer: a Southwest Oncology Group study. Med Pediatr Oncol 1:95Google Scholar
  22. 22.
    Kretschmer NW, Boor PJ, El-Azhary RA, Ahmed AE, Reynolds ES (1987) Studies on the mechanism of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)-induced hepatotoxicity: III. Ultrastructural characterization of bile duct injury. Cancer Chemother Pharmacol 19:109Google Scholar
  23. 23.
    Lee FYP, Workman P, Roberts JT, Bleehen NM (1985) Clinical pharmacokinetics of oral CCNU (Lomustine). Cancer Chemother Pharmacol 14:125Google Scholar
  24. 24.
    Lokich JJ, Drum DE, Kaplan W (1974) Hepatic toxicity of nitrosourea analogues. Clin Pharmacol Ther 16:363Google Scholar
  25. 25.
    Marantz R, Ventilla M, Shelanski ML (1969) Vinblastine induced precipitations of microtubule proteins. Science 165: 498Google Scholar
  26. 26.
    May HE, Boose R, Reed DJ (1974) Hydroxylation of the carcinostatic 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) by rat liver microsomes. Biochem Biophys Res Commun 57:426Google Scholar
  27. 27.
    Moertel CG, Reitemeier RJ, Hahn RG (1986) Therapy of advanced gastro-intestinal cancer with 1-3-bis (2-chloroethyl)-1-nitrosourea (BCNU). Clin Pharmacol Ther 9:652Google Scholar
  28. 28.
    Moertel CG, Schutt AJ, Reitemeier RJ, Hahn RG (1972) A phase II study of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (NSC 9037) in the palliative management of advanced gastro-intestinal cancer. Cancer Res 32:1278Google Scholar
  29. 29.
    Montgomery JA, James R, McCaleb GS, Johnston TP (1967) The mode of decomposition of 1,3-bis (2-chloroethyl)-1-nitrosourea and related compounds. J Med Chem 10:668Google Scholar
  30. 30.
    Oliviero VT (1976) Pharmacology of the nitrosoureas: an overview. Cancer Treat Rep 60:703Google Scholar
  31. 31.
    Oliviero VT, Vietzke WM, Williams MK, Adamson RH (1970) The absorption, distribution, excretion and biotrans-formation of the carcinostatic 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea in animals. Cancer Res 30:1330Google Scholar
  32. 32.
    Oshio C, Miyairi M, Smith CR, Phillips MJ (1985) Colchicine effect on bile canalicular motility. Long term study using isolated cultured hepatocytes and time-lapse cinephotomicrography. Liver 5:101Google Scholar
  33. 33.
    Phillips MJ, Poucell S, Oda M (1986) Mechanism of cholestasis. Lab Invest 54:593Google Scholar
  34. 34.
    Reed DJ, May HE (1975) Alkylation and carbamoylation intermediates from the carcinostatic 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). Life Sci 16:1263Google Scholar
  35. 35.
    Reed DJ, May HE, Boose RB, Gregory KM, Beilstein MA (1975) 2-chloroethanol formation as evidence from a 2-chloroethyl alkylating intermediate during chemical degradation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea. Cancer Res 35:568Google Scholar
  36. 36.
    Stein O, Sanger L, Stein Y (1974) Colchicine-induced inhibition of lipoproteins and protein secretion into the serum and lack of interference with secretion of biliary phospholipids and cholesterol by rat liver in vivo. J Cell Biol 62:90Google Scholar
  37. 37.
    Takvorian T, Hochberg F, Canellos G, Parker L, Zerves N, Frei E (1981) The toxicity of high-dose BCNU with autologous narrow supports. In: Nitrosoureas: current status and new developments. Academic Press, New York, p 155Google Scholar
  38. 38.
    Thompson GR, Larson RE (1969) The hepatotoxicity of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) in rats. J Pharmacol Exp Ther 166:105Google Scholar
  39. 39.
    Weiss RB, Issell BF (1982) The nitrosoureas carmustine (BCNU) and lomustine (CCNU). Cancer Treat Rep 9:313Google Scholar

Copyright information

© Springer-Verlag 1988

Authors and Affiliations

  • T. Ducastelle
    • 1
  • G. Raguenez-Viotte
    • 2
  • H. Fouin-Fortunet
    • 3
  • M. Matysiak
    • 1
  • J. Hemet
    • 1
  • J. P. Fillastre
    • 2
  1. 1.Laboratoire d'Anatomie et de Cytologie PathologiquesHôpital Charles NicolleRouenFrance
  2. 2.INSERM, Unité 295, U.E.R. Médecine-PharmacieUniversité de RouenRouenFrance
  3. 3.Groupe de Biochimie et de Physiopathologie digestive et nutritionnelle, U.E.R. Médecine-PharmacieUniversité de RouenRouenFrance

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