Advanced Search

Journal Navigation

Journal Home

Subscriptions

Archive

Contact Us

Table of Contents

CiteULike is a free service for managing and discovering scholarly references - click here to get started.

Sign In to gain access to subscriptions and/or personal tools.
Toxicologic Pathology
This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Leblanc, B.
Right arrow Articles by Guillermo, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Leblanc, B.
Right arrow Articles by Guillermo, C.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Journal Article

Nucleolar Organizer Regions in Cardiac Lesions Induced by Doxorubicin

Bernard Leblanc

Laboratoires Pfizer, Centre de Recherche, BP159, 37401 Amboise, France

Paul R. Mompon

Laboratoires Pfizer, Centre de Recherche, BP159, 37401 Amboise, France

Odile Espérandieu

Laboratoires Pfizer, Centre de Recherche, BP159, 37401 Amboise, France

Brigitte Geffray

Laboratoires Pfizer, Centre de Recherche, BP159, 37401 Amboise, France

Christine Guillermo

Laboratoires Pfizer, Centre de Recherche, BP159, 37401 Amboise, France

The use of the argyrophilic (Ag) staining technique for nucleolar organizer regions (NORs) revealed nuclear changes in myocytes of the left atrium of 10 rats treated twice a week for 6 weeks with doxorubicin (1 mg/kg body weight) iv and sacrificed after 6 weeks without treatment. The changes were easily detected qualitatively and further assessed by quantification. Cardiac myocytes of doxorubicin-treated rats had larger nuclei and/or a larger quantity of AgNORs that were either dispersed in a number of small dots or clustered in rounded, rod-shaped, or tortuous large structures. AgNOR alterations may reflect a defect of nucleolar association leading to an impairment of protein synthesis that could be involved in doxorubicin cardiotoxicity.

Key Words: AgNOR • doxorubicin • heart • rat

  • 1. Adnet JJ (1989). Les organisateurs nucláolaires: In-teret en anatomie pathologique et en cytologie clinique. Ann. Pathol. 9: 3–6.[Web of Science][Medline] [Order article via Infotrieve]
  • 2. Anonymous (1987). NORs. A new method for the pathologist. Lancet 1: 1413–1414.[Medline] [Order article via Infotrieve]
  • 3. Arena E, Biondo F, D'Alessandro N, Dusonchet L, Gebbia N, Gerbasi F, Rausa L, and Sanguedolce R (1974). DNA, RNA and protein synthesis in heart, liver and brain of mice treated with daunomycin or adriamycin. IRCS Med. Sci. 2: 1053–1061.
  • 4. Arena E, D'Alessandro N, Dusonchet L, Rausa L, and Sanguedolce R (1975). Adriamycin and daunomycin-induced cardiotoxicity: Effects on DNA, RNA and proteins synthesis in mouse heart after strophanthin pretreatment. IRCS Med. Sci. 3: 190.
  • 5. Aversano RC and Boor PJ (1983). Histochemical alterations of acute and chronic doxorubicin cardiotoxicity. J. Mol. Cell Cardiol. 15: 543–553.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 6. Bachur N, Gordon SL, and Gee MV (1978). A general mechanism for microsomal activation of quinone anticancer agents to free radicals. Cancer Res. 38: 1745–1750.[Abstract/Free Full Text]
  • 7. Balazs T (1981). Cardiotoxicity of antineoplastic drugs. In: Cardiac Toxicology, Vol. 2, T Balazs (ed). CRC Press, Boca Raton, Florida, pp. 165–186.
  • 8. Bertazzoli C, Bellini O, Magrini U, and Tosana MG (1979). Quantitative experimental evaluation of adriamycin cardiotoxicity in the mouse. Cancer Treat. Rep. 63: 1877–1883.[Web of Science][Medline] [Order article via Infotrieve]
  • 9. Billingham ME, Mason JW, Bristow MR, and Daniels JR (1978). Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treat. Rep. 62: 865–872.[Web of Science][Medline] [Order article via Infotrieve]
  • 10. Billingham ME (1979). Some recent advances in cardiac pathology. Hum. Pathol. 10: 367–386.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 11. Bouteille M and Hernandez-Verdun D (1979). Localization of a gene: The nucleolar organizer. Bio-mádecine 30: 282–287.
  • 12. Bristow RM, Scott SW, Scott HR, Billingham ME, Bowden RE, Kernoff RS, Snidow GH, and Daniels JR (1980). Acute and chronic cardiovascular pharmacology of drug-induced histamine release. J. Cardiovasc. Pharmacol. 2: 487–515.[Web of Science][Medline] [Order article via Infotrieve]
  • 13. Buja LM, Ferrans VJ, Mayer RJ, Roberts WC, and Henderson ES (1973). Cardiac ultrastructural changes induced by daunorubicin therapy. Cancer 32: 771–788.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 14. Buja LM, Ferrans VJ, and Rabson AS (1974). Unusual nuclear alterations. Lancet 1: 402–403.[Web of Science][Medline] [Order article via Infotrieve]
  • 15. Caulfield JB and Bittner V (1988). Cardiac matrix alterations induced by adriamycin. Am. J. Pathol. 133: 298–305.[Abstract]
  • 16. Crocker J and Nar P (1987). Nucleolar organizer regions in lymphomas. J. Pathol. 151: 111–118.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 17. Crocker J, Boldy DAR, and Egan MJ (1989). How should we count AgNORs? Proposals for a standardized approach. J. Pathol. 158: 185–188.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 18. Crocker J (1990). Nucleolar organizer regions. In: Current Topics in Pathology, Pathology of the Nucleus, JCE Underwood (ed). Springer-Verlag, London, pp. 91–143.
  • 19. Delahunt B, Mostofi FK, Sesterhenn IA, Ribas JL, and Avallone FA (1990). Nucleolar organizer regions in seminoma and intratubular malignant germ cells. Modern Pathol. 3: 141–145.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 20. Denine EP and Schmidt LH (1975). Adriamycin-induced myopathies in the rhesus monkey with emphasis on cardiomyopathy (Abstract). Toxicol. Appl. Pharmacol. 33: 162.
  • 21. Derenzini M, Romagnoli T, Mingazzini P, and Marinozzi V (1988). Interphasic nucleolar organizer region distribution as a diagnostic parameter to differentiate benign from malignant epithelial tumors of human intestine. Virchows Archiv. B Cell Pathol. 54: 334–340.[CrossRef]
  • 22. Derenzini M, Pession A, Farabegoli F, Trerè D, Badiali M, and Dehan P (1989). Relationship between interphasic nucleolar organizer regions and growth rate in two neuroblastoma cell lines. Am. J. Pathol. 134: 925–932.[Abstract]
  • 23. Doroshow JH, Tallent C, and Schechter JE (1985). Ultrastructural features of adriamycin-induced skeletal and cardiac muscle toxicity. Am. J. Pathol. 118: 288–297.[Abstract]
  • 24. Eckenhoff RG and Somlyo AP (1989). Cardiac mitochondrial calcium content during fatal doxorubicin toxicity. Toxicol. Appl. Pharmacol. 97: 167–172.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 25. Egan MJ, Raafat F, Crocker J, and Smith K (1987). Nucleolar organizer regions in small cell tumours of childhood. J. Pathol. 153: 275–280.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 26. Egan MJ and Crocker J (1988). Nucleolar organizer regions in cutaneous tumours. J. Pathol. 154: 247–253.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 27. Ferrero ME, Ferrero E, Gaja G, and Bernelli-Zazzera A (1976). Adriamycin: Energy metabolism and mitochondrial oxidation in the heart of treated rabbits. Biochem. Pharmacol. 25: 125.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 28. Gebbia N, Leto G, Gagliano M, Tumminello FM, and Rausa L (1985). Lysosomal alterations in heart and liver of mice treated with doxorubicin. Cancer Chemother. Pharmacol. 15: 26–30.[Web of Science][Medline] [Order article via Infotrieve]
  • 29. Haidle CW and McKinney SH (1986). Adriamycin-mediated introduction of a limited number of single-strand breaks into supercoiled DNA. Cancer Biochem. Biophys. 8: 327–335.[Web of Science][Medline] [Order article via Infotrieve]
  • 30. Hansen AB and Ostergard B (1990). Nucleolar organizer regions in hyperplastic and neoplastic prostatic tissue. Virchows Archiv. A Pathol. Anat. 417: 9–13.[CrossRef]
  • 31. Harada H, Cusack BJ, Olson RD, Stroo W, Azuma J, Hamaguchi T, and Schaffer SW (1990). Taurine deficiency and doxorubicin interaction with the cardiac sarcolemmal calcium pump. Biochem. Pharmacol. 39: 745–751.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 32. Harris RN and Doroshow JH (1985). Effect of doxorubicin-enhanced hydrogen peroxide and hydroxyl radical formation on calcium sequestration by cardiac sarcoplasmic reticulum. Biochem. Biophys. Res. Commun. 130: 739–745.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 33. Hemandez-Verdun D (1983). The nucleolar organizer regions. Biol. Cell 49: 191–202.[Web of Science][Medline] [Order article via Infotrieve]
  • 34. Howat AJ, Giri DD, Wright WL, and Underwood JC (1988). Silver-stained nucleoli and nucleolar organizer region counts are of no prognostic value in thick cutaneous malignant melanoma. J. Pathol. 156: 227–232.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 35. Jackson JA, Reeves JP, Muntz KH, Kruk D, Prough RA, Willerson JT, and Buja LM (1984). Evaluation of free radical effects and catecholamine alterations in adriamycin cardiotoxicity. Am. J. Pathol. 117: 140–153.[Abstract]
  • 36. Jordan J (1987). At the heart of the nucleolus. Nature 329: 489–490.[CrossRef][Medline] [Order article via Infotrieve]
  • 37. Kehoe R, Singer DH, Trapani A, Billingham M, Levandowski R, and Elson J (1978). Adriamycin-induced cardiac dysrhythmias in an experimental dog model. Cancer Treat. Rep. 62: 936–978.
  • 38. Klugmann FB, Decorti G, Candussio L, Grill V, Mal-lardi F, and Baldini L (1986). Inhibitors of adriamycin-induced histamine release in vitro limit adriamycin cardiotoxicity in vivo. Br. J. Cancer 54: 743–748.[Web of Science][Medline] [Order article via Infotrieve]
  • 39. Lambertenghi-Deliliers G, Zanon PL, Pozzoli EF, and Bellini O (1976). Myocardial injury induced by a single dose of adriamycin: An electron microscopic study. Tumori 62: 517–528.[Web of Science][Medline] [Order article via Infotrieve]
  • 40. Lenaz L and Page JA (1976). Cardiotoxicity of adriamycin and related anthracyclines. Cancer Treat. Rev. 3: 111–120.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 41. Lomholt BE and Toft JM (1987). The effect of pH on silver staining of nucleolus organizer regions. Stain Technol. 62: 101–104.[Web of Science][Medline] [Order article via Infotrieve]
  • 42. McMeekin W, Kennedy A, and McNicol AM (1989). Combined immunocytochemistry and nucleolar organizer region staining: Some technical aspects. Med. Lab. Sci. 46: 11–15.[Web of Science][Medline] [Order article via Infotrieve]
  • 43. Merski JA, Daskal I, and Busch H (1976). Effects of adriamycin on ultrastructure of nucleoli in the heart and liver cells of the rat. Cancer Res. 36: 1580–1584.[Abstract/Free Full Text]
  • 44. Merski J, Daskal Y, and Busch H (1978). Comparison of adriamycin-induced nucleolar segregation in skeletal muscle, cardiac muscle, and liver cells. Cancer Treat. Rep. 62: 771–778.[Web of Science][Medline] [Order article via Infotrieve]
  • 45. Mettler FP, Young DM, and Ward JM (1977). Adriamycin-induced cardiotoxicity (cardiomyopathy and congestive heart failure) in rats. Cancer Res. 37: 2705–2713.[Abstract/Free Full Text]
  • 46. Olson HM and Capen CC (1978). Chronic cardiotoxicity of doxorubicin (adriamycin) in the rat: Morphological and biomedical investigations. Toxicol. Appl. Pharmacol. 44: 605–616.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 47. Ooms ECM and Veldhuizen RW (1989). Argyrophilic proteins of the nucleolar organizer region in bladder tumours. Virchows Archiv. [A] Pathol. Anat. 414: 365–369.[CrossRef]
  • 48. Papoian W and Lewis W (1990). Adriamycin cardiotoxicity in vivo. Am. J. Pathol. 136: 1201–1207.[Abstract]
  • 49. Paulus GP, Masson MT, and Mompon P (1988). Cardiotoxicity of doxorubicin: A histochemical and morphometric approach. Arch. Toxicol. suppl. 12: 410–412.
  • 50. Peebles SE and McNicol AM (1989). AgNOR numbers in rat pituitary corticotrophs following adrenalectomy or corticotrophin releasing factor administration. Virchows Archiv. [B] Pathol. Anat. 57: 209–212.
  • 51. Pelikan PCD, Weisfeldt ML, Jacobus WE, Miceli MV, Bulkley BH, and Gerstenblith G (1986). Acute doxorubicin cardiotoxicity: Functional, metabolic, and morphologic alterations in the isolated, perfused rat heart. J. Cardiovasc. Pharmacol. 8: 1058–1066.[Web of Science][Medline] [Order article via Infotrieve]
  • 52. Ploton D, Menager M, and Adnet JJ (1984). Simultaneous high resolution localization of Ag-NOR proteins and nucleoproteins in interphasic and mitotic nuclei. Histochem. J. 16: 897–906.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 53. Ploton D, Menager M, Jeannesson P, Himber G, Pigeon F, and Adnet JJ (1986). Improvement in the staining and in the visualization of the argyrophilic proteins of the nucleolar organizer region at the optical level. Histochem. J. 18: 5–14.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 54. Ploton D, Menager M, Lechki CH, Jeannesson P, Visseaux B, and Adnet JJ (1988). Coloration des organisateurs nucláolaires (NORs) par l'argent. Application à l'átude de la structure du nucláole et intárets en pathologic Ann. Pathol. 8: 248–252.[Web of Science][Medline] [Order article via Infotrieve]
  • 55. Rosenoff SH, Brooks E, Bostick F, and Young RC (1975). Alterations in DNA synthesis in cardiac tissue induced by adriamycin in vivo—Relationship to fatal toxicity. Biochem. Pharmacol. 24: 1898–1901.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 56. Rüschoff J, Plate K, Contractor H, and Thomas C (1990). Silver-stained structures (AgNORs), their dependence on tissue fixation and absence of prognostic relevance in rectal adenocarcinoma (Letter). J. Pathol. 161: 89–90.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 57. Singal PK, Deally CRM, and Weinberg L (1987). Sub-cellular effects of adriamycin in the heart: A concise review. J. Mol Cell Cardiol. 19: 827–828.
  • 58. Smith R and Crocker J (1988). Evaluation of nucleolar organizer region-associated proteins in breast malignancy. Histopathology 12: 113–125.[Web of Science][Medline] [Order article via Infotrieve]
  • 59. Smith PJ, Skilbeck N, Harrison A, and Crocker J (1988). The effect of a series of fixatives on the AgNOR technique. J. Pathol. 155: 109–112.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 60. Solcia E, Ballerini L, Bellini O, Magrini U, Bertazzoli C, Tosana G, Sala L, Balconi F, and Rallo F (1981). Cardiomyopathy of doxorubicin in experimental animals. Factors affecting the severity, distribution and evolution of myocardial lesions. Tumori 67: 461–472.[Web of Science][Medline] [Order article via Infotrieve]
  • 61. Suresh UR, Chawner L, Buckley CH, and Fox H (1990). Do AgNOR counts reflect cellular ploidy or cellular proliferation? A study of throphoblastic tissue. J. Pathol. 160: 213–215.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 62. Takeuchi T, Tanaka T, Ohno T, Yamamoto N, Kobayashi S, Kuriyama M, Kawada Y, and Mori H (1990). Nucleolar organizer regions in rat urinary bladder tumors induced by N-butyI-N-(4-hydroxy-butyl)nitrosamine. Virchows Archiv. [B] Cell Pathol. 58: 383–387.
  • 63. Tanaka T, Takeuchi T, Nishikawa A, Takami T, and Mori H (1989). Nucleolar organizer regions in hepatocarcinogenesis induced by N-2-fluorenylacetamide in rats: Comparison with bromodeoxyuridine immunohistochemistry. Jpn. J. Cancer Res. 80: 1047–1051.[CrossRef][Web of Science]
  • 64. Taylor AL and Bulkley BH (1982). Acute adriamycin cardiotoxicity. Morphologic alterations in isolated perfused rabbit heart. Lab. Invest. 47: 459–464.[Web of Science][Medline] [Order article via Infotrieve]
  • 65. Trerè D, Pession A, and Derenzini M (1989). The silver-stained proteins of interphasic nucleolar organizer regions as a parameter of cell duplication rate. Exp. Cell. Res. 184: 131–137.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 66. Underwood JCE and Giri DD (1988). Nucleolar organizer regions as diagnostic discriminants for malignancy. J. Pathol. 155: 95–96.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 67. Unverferth DV, Magorien RD, Unverferth BP, Talley RL, Balcerzak SP, and Baba N (1981). Human myocardial morphologic and functional changes in the first 24 hours after doxorubicin administration. Cancer Treat. Rep. 65: 1093–1097.[Web of Science][Medline] [Order article via Infotrieve]
  • 68. Van Vleet JF and Ferrans VJ (1986). Myocardial diseases of animals. Am. J. Pathol. 124: 98–177.[Abstract]
  • 69. Walker RA (1988). The histopathological evaluation of nucleolar organizer region proteins (Commentary). Histopathology 12: 221–223.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Toxicologic Pathology, Vol. 19, No. 2, 176-183 (1991)
DOI: 10.1177/019262339101900213
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?



This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Leblanc, B.
Right arrow Articles by Guillermo, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Leblanc, B.
Right arrow Articles by Guillermo, C.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?