Langenbeck's Archives of Surgery

, Volume 391, Issue 5, pp 499–510 | Cite as

Chronic inflammation and oxidative stress in the genesis and perpetuation of cancer: role of lipid peroxidation, DNA damage, and repair

New Surgical Horizons

Abstract

Background and aims

Chronic inflammation, induced by biological, chemical, and physical factors, was associated with increased risk of human cancer at various sites. Chronic inflammatory processes induce oxidative/nitrosative stress and lipid peroxidation (LPO), thereby generating excess reactive oxygen species (ROS), reactive nitrogen species (RNS), and DNA-reactive aldehydes. Miscoding etheno- and propano-modified DNA bases are generated inter alia by reaction of DNA with these major LPO products. Steady-state levels of LPO-derived (etheno-) DNA adducts in organs affected by persistent inflammatory processes were investigated as potential lead markers for assessing progression of inflammatory cancer-prone diseases.

Results

Using ultrasensitive and specific detection methods for the analysis of human tissues, cells, and urine, etheno-DNA adduct levels were found to be significantly elevated in the affected organs of subjects with chronic pancreatitis, ulcerative colitis, and Crohn’s disease. Patients with alcohol-related liver diseases showed excess hepatic DNA damage progressively increasing from hepatitis, fatty liver, to liver cirrhosis. Ethenodeoxyadenosine excreted after DNA repair in urine of hepatitis B virus-related chronic hepatitis and liver cirrhosis patients was increased up to 90-fold. Putative mechanisms that may control DNA damage in inflamed tissues including impaired or imbalanced DNA repair pathways are reviewed.

Conclusion

Persistent oxidative/nitrosative stress and excess LPO are induced by inflammatory processes in a self-perpetuating process and cause progressive accumulation of DNA damage in target organs. Together with deregulation of cell homeostasis, the resulting genetic changes act as driving force in chronic inflammation-associated human disease pathogenesis. Thus steady-state levels of DNA damage caused by ROS, RNS, and LPO end products provide promising molecular signatures for risk prediction and potential targets and biomarkers for preventive measures.

Keywords

Chronic inflammation Oxidative stress DNA damage Impaired DNA repair Human cancers 

References

  1. 1.
    Parkin DM (2006) The global health burden of infection-associated cancers in the year 2002. Int J Cancer 118:3030–3044PubMedCrossRefGoogle Scholar
  2. 2.
    Ohshima H, Bartsch H (1994) Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis. Mutat Res 3005:253–264Google Scholar
  3. 3.
    Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545PubMedCrossRefGoogle Scholar
  4. 4.
    Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867PubMedCrossRefGoogle Scholar
  5. 5.
    Hussain SP, Hofseth LJ, Harris CC (2003) Radical causes of cancer. Nat Rev Cancer 3:276–285PubMedCrossRefGoogle Scholar
  6. 6.
    Ohshima H, Tatemichi M, Sawa T (2003) Chemical basis of inflammation-induced carcinogenesis. Arch Biochem Biophys 417:3–11PubMedCrossRefGoogle Scholar
  7. 7.
    Sawa T, Ohshima H (2006) Nitrative DNA damage in inflammation and its possible role in carcinogenesis. Nitric Oxide 14:91–100PubMedCrossRefGoogle Scholar
  8. 8.
    Chung FL, Chen HJC, Nath RG (1996) Lipid peroxidation as a potential endogenous source for the formation of exocyclic DNA adducts. Carcinogenesis 17:2105–2111PubMedCrossRefGoogle Scholar
  9. 9.
    Chung FL, Nath RG, Ocando J, Nishikawa A, Zhang L (2000) Deoxyguanosine adducts of t-4-hydroxy-2-nonenal are endogenous DNA lesions in rodents and humans: detection and potential sources. Cancer Res 60:1507–1511PubMedGoogle Scholar
  10. 10.
    Bartsch H (1999) Exocyclic adducts as new risk markers for DNA damage in man. In: Singer B, Bartsch H (eds) Exocyclic DNA adducts in mutagenesis and carcinogenesis, no. 150. IARC, Lyon, pp 1–16Google Scholar
  11. 11.
    Marnett LJ (2002) Oxyradicals, lipid peroxidation and DNA damage. Toxicology 181–182:219–222PubMedCrossRefGoogle Scholar
  12. 12.
    Lee SH, Arora JA, Oe T, Blair IA (2005) 4-Hydroperoxy-2-nonenal-induced formation of 1,N 2-etheno-2′-deoxyguanosine adducts. Chem Res Toxicol 18:780–786PubMedCrossRefGoogle Scholar
  13. 13.
    West JD, Marnett LJ (2006) Endogenous reactive intermediates as modulators of cell signaling and cell death. Chem Res Toxicol 19:173–194PubMedCrossRefGoogle Scholar
  14. 14.
    Ohshima H (2003) Genetic and epigenetic damage induced by reactive nitrogen species: implications in carcinogenesis. Toxicol Lett 140–141:99–104PubMedCrossRefGoogle Scholar
  15. 15.
    West JD, Marnett LJ (2005) Alterations in gene expression induced by the lipid peroxidation product, 4-hydroxy-2-nonenal. Chem Res Toxicol 18:1642–1653PubMedCrossRefGoogle Scholar
  16. 16.
    Bartsch H, Nair J (2005) Accumulation of lipid peroxidation-derived DNA-lesions: potential lead markers for chemoprevention of inflammation-driven malignancies. Mutat Res 591:34–44PubMedGoogle Scholar
  17. 17.
    Wilson GL, Patton NJ, Ledoux SP (1997) Mitochondrial DNA in β-cells is a sensitive target for damage by nitric oxide. Diabetes 46:1291–1295PubMedCrossRefGoogle Scholar
  18. 18.
    Nair J, Barbin A, Guichard Y, Bartsch H (1995) 1,N 6-ethenodeoxyadenosine and 3,N 4-ethenodeoxycytidine in liver DNA from humans and untreated rodents detected by immunoaffinity/32P-postlabelling. Carcinogenesis 16:513–517CrossRefGoogle Scholar
  19. 19.
    Nair J (1999) Lipid peroxidation-induced etheno-DNA adducts in humans. In: Singer B, Bartsch H (eds) Exocyclic DNA adducts in mutagenesis and carcinogenesis, no. 150. IARC, Lyon, pp 55–62Google Scholar
  20. 20.
    Singer B, Bartsch H (eds) (1999) Exocyclic DNA adducts in mutagenesis and carcinogenesis, no. 150. IARC, Lyon, pp 55–62Google Scholar
  21. 21.
    Collins AR, Dusinska M, Gedik CM, Stetina R (1996) Oxidative damage to DNA: do we have a reliable biomarker? Environ Health Perspect 104:465–469PubMedCrossRefGoogle Scholar
  22. 22.
    Zarkovic N (2003) 4-Hydroxynonenal as a bioactive marker of pathophysiological processes. Mol Aspects Med 24:281–291PubMedCrossRefGoogle Scholar
  23. 23.
    Wacker M, Schuler D, Wanek P, Eder E (2000) Development of a (32)P-postlabeling method for the detection of 1,N(2)-propanodeoxyguanosine adducts of trans-4-hydroxy-2-nonenal in vivo. Chem Res Toxicol 13:1165–1173PubMedCrossRefGoogle Scholar
  24. 24.
    Frank A, Seitz HK, Bartsch H, Frank N, Nair J (2004) Immunohistochemical detection of 1,N 6-ethenodeoxadenosine in nuclei of human liver affected by diseases predisposing to hepato-carcinogenesis. Carcinogenesis 25:1027–1031PubMedCrossRefGoogle Scholar
  25. 25.
    Yang Y, Nair J, Barbin A, Bartsch H (2000) Immunohistochemical detection of promutagenic 1,N 6-ethenodeoxyadenosine DNA adducts in liver of rats exposed to vinyl chloride or an iron overload. Carcinogenesis 21:777–781PubMedCrossRefGoogle Scholar
  26. 26.
    Hanaoka T, Nair J, Takahashi Y, Sasaki S, Bartsch H, Tsugane S (2002) Urinary level of 1,N6-etheno-deoxyadenosine, a marker of oxidative stress, is associated with salt excretion and ω6-polyunsaturated fatty acid intake in postmenopausal Japanese women. Int J Cancer 100:71–75PubMedCrossRefGoogle Scholar
  27. 27.
    Sun X, Karlsson A, Bartsch H, Nair J (2006) A new ultrasensitive 32P-postlabeling method for the analysis of 3,N 4-etheno-2′-deoxycytidine in human urine. Biomarkers (in press)Google Scholar
  28. 28.
    Chen HJ, Chang CM (2004) Quantification of urinary excretion of 1,N6-ethenoadenine, a potential biomarker of lipid peroxidation, in humans by stable isotope dilution liquid chromatography–electrospray ionization-tandem mass spectrometry: comparison with gas chromatography-mass spectrometry. Chem Res Toxicol 17:963–971PubMedCrossRefGoogle Scholar
  29. 29.
    Chen HJ, Wu CF, Hong CL, Chang CM (2004) Urinary excretion of 3,N4-etheno-2′-deoxycytidine in humans as a biomarker of oxidative stress: association with cigarette smoking. Chem Res Toxicol 17:896–903PubMedCrossRefGoogle Scholar
  30. 30.
    Hillestrom PR, Hoberg AM, Weimann A, Poulsen HE (2004) Quantification of 1,N 6-etheno-2′-deoxyadenosine in human urine by column-switching LC/APCI-MS/MS. Free Radic Biol Med 36:1383–1392PubMedCrossRefGoogle Scholar
  31. 31.
    Hillestrom PR, Weimann A, Poulsen HE (2006) Quantification of urinary etheno-DNA adducts by column-switching LC/APCI-MS/MS. J Am Soc Mass Spectrom 17:605–610PubMedCrossRefGoogle Scholar
  32. 32.
    Leuratti C, Watson MA, Deag EJ, Welch A, Singh R, Gottschald E, Marnett LJ, Atkin W, Day NE, Shuker DE, Bingham SA (2002) Detection of malondialdehyde DNA adducts in human colorectal mucosa: relationship with diet and the presence of adenomas. Cancer Epidemiol Biomarkers Prev 11:267–273PubMedGoogle Scholar
  33. 33.
    Hoberg AM, Otteneder M, Marnett LJ, PouIsen HE (2004) Measurement of the malondialdehyde-2′-deoxyguanosine adduct in human urine by immuno-extraction and liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry. J Mass Spectrom 39:38–42PubMedCrossRefGoogle Scholar
  34. 34.
    Sun X, Nair J, Bartsch H (2004) A modified immuno-enriched 32P-postlabeling method for analyzing the MDA-deoxyguanosine adduct, 3-(2-deoxy-β-D-erythro-pentofuranosyl)pyrimido[1,2-α]purin-10(3H)-one in human tissue samples. Chem Res Toxicol 17:268–272PubMedCrossRefGoogle Scholar
  35. 35.
    Nair J, Gal A, Tamir S, Tannenbaum SR, Wogan GN, Bartsch H (1998) Etheno adducts in spleen DNA of SJL mice stimulated to overproduce nitric oxide. Carcinogenesis 19:2081–2084PubMedCrossRefGoogle Scholar
  36. 36.
    Zha S, Yegnasubramanian V, Nelson WG, Isaacs WB, De Marzo AM (2004) Cyclooxygenases in cancer: progress and perspective. Cancer Lett 215:1–20PubMedCrossRefGoogle Scholar
  37. 37.
    Prescott SM, White RL (1996) Self-promotion? Intimate connections between APC and prostaglandin H synthase-2. Cell 87:783–786PubMedCrossRefGoogle Scholar
  38. 38.
    Schmid K, Nair J, Winde G, Velic I, Bartsch H (2000) Increased levels of promutagenic etheno-DNA adducts in colonic polyps of FAP patients. Int J Cancer 87:1–4PubMedCrossRefGoogle Scholar
  39. 39.
    Williams CS, Luongo C, Radhika A, Zhang T, Lamps LW, Nanney LB, Beauchamp RD, Du Bois RN (1996) Elevated cyclooxygenase-2 levels in Min mouse adenomas. Gastroenterology 4:1134–1140CrossRefGoogle Scholar
  40. 40.
    Williams MV, Lee SH, Pollack M, Blair IA (2006) Endogenous lipid hydroperoxide-mediated DNA-adduct formation in MIN mice. J Biol Chem 281(15):10127–10133PubMedCrossRefGoogle Scholar
  41. 41.
    Marks F, Müller-Decker K, Fürstenberger G (2000) A causal relationship between unscheduled eicosanoid signaling and tumor development: cancer chemoprevention by inhibitors of arachidonic acid metabolism. Toxicology 153:11–26PubMedCrossRefGoogle Scholar
  42. 42.
    Nair J, Fürstenberger G, Bürger F, Marks F, Bartsch H (2000) Promutagenic etheno-DNA adducts in multistage mouse skin carcinogenesis: correlation with lipoxygenase-catalyzed arachidonic acid metabolism. Chem Res Toxicol 13:703–709PubMedCrossRefGoogle Scholar
  43. 43.
    Loguercio C, Federico A (2003) Oxidative stress in viral and alcoholic hepatitis. Free Radic Biol Med 34:1–10PubMedCrossRefGoogle Scholar
  44. 44.
    Nair J, Srivatanakul P, Jedpiyawongse A, Bartsch H (2002) Urinary excretion of 1,N6-ethenodeoxyadenosine in patients diagnosed with chronic hepatitis, liver cirrhosis and hepatocellular carcinoma from Thailand. Proc AACR 42:2843Google Scholar
  45. 45.
    Smela ME, Currier SS, Bailey EA, Essigmann JM (2001) The chemistry and biology of aflatoxin B(1): from mutational spectrometry to carcinogenesis. Carcinogenesis 22:535–545PubMedCrossRefGoogle Scholar
  46. 46.
    Staib F, Hussain SP, Hofseth LJ, Wang XW, Harris CC (2003) TP53 and liver carcinogenesis. Hum Mutat 21:201–216PubMedCrossRefGoogle Scholar
  47. 47.
    Denissenko MF, Koudriakova TB, Smith L, O’Connor TR, Riggs AD, Pfeifer GP (1998) The p53 codon 249 mutational hotspot in hepatocellular carcinoma is not related to selective formation or persistence of aflatoxin B1 adducts. Oncogene 17:3007–3014PubMedCrossRefGoogle Scholar
  48. 48.
    Hussain SP, Raja K, Amstad PA, Sawyer M, Trudel LJ, Wogan GN, Hofseth LJ, Shields PG, Billiar TR, Trautwein C, Hohler T, Galle PR, Phillips DH, Markin R, Marrogi AJ, Harris CC (2000) Increased p53 mutation load in nontumorous human liver of Wilson disease and hemochromatosis: oxyradical overload diseases. Proc Natl Acad Sci USA 97:12770–12775PubMedCrossRefGoogle Scholar
  49. 49.
    Hu W, Feng Z, Eveleigh J, Lyer G, Pan J, Amin S, Chung FT, Tang MS (2002) The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma. Carcinogenesis 23:1781–1789PubMedCrossRefGoogle Scholar
  50. 50.
    Feng Z, Hu W, Amin S, Tang MS (2003) Mutational spectrum and genotoxicity of the major lipid peroxidation product, trans-4-hydroxy-2-nonenal, induced DNA adducts in nucleotide excision repair-proficient and -deficient human cells. Biochemistry 42:7848–7854PubMedCrossRefGoogle Scholar
  51. 51.
    Turner PC, Sylla A, Kuang SY, Marchant CL, Diallo MS, Hall AJ, Groopman JD, Wild CP (2005) Absence of TP53 codon 249 mutations in young Guinean children with high aflatoxin exposure. Cancer Epidemiol Biomarkers Prev 14:2053–2055PubMedCrossRefGoogle Scholar
  52. 52.
    Navasumrit P, Ward TH, O’Connor PJ, Nair J, Frank N, Bartsch H (2001) Ethanol enhances the formation of endogenously and exogenously derived adducts in rat hepatic DNA. Mutat Res 479:81–94PubMedGoogle Scholar
  53. 53.
    Nair J, Gansauge F, Beger H, Dolara P, Winde G, Bartsch H (2006) Increased etheno DNA adducts in affected tissues of patients suffering from Crohn’s disease, ulcerative colitis and chronic pancreatitis. Antioxid Redox Signal 8:1003–1010PubMedCrossRefGoogle Scholar
  54. 54.
    Seril DN, Liao J, Yang GY, Chung SY (2003) Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models. Carcinogenesis 24:353–362PubMedCrossRefGoogle Scholar
  55. 55.
    Fiocchi C (1998) Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 115:182–205PubMedCrossRefGoogle Scholar
  56. 56.
    Hussain SP, Amstad P, Raja K, Ambs S, Nagashima M, Bennett WP, Shields PG, Ham AJ, Swenberg JA, Marrogi AJ, Harris CC (2000) Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res 60:333–337Google Scholar
  57. 57.
    Hofseth LJ, Khan MA, Ambrose M, Nikolayeva O, Xu-Welliver M, Kartalou M, Hussain SP, Roth RB, Zhou X, Mechanic LE, Zurer I, Rotter V, Samson LD, Harris CC (2004) The adaptive imbalance in base excision-repair enzymes generates microsatellite instability in chronic inflammation. J Clin Invest 113:490CrossRefGoogle Scholar
  58. 58.
    Correa P (1995) Helicobacter pylori and gastric carcinogenesis. Am J Surg Pathol 19:37–43CrossRefGoogle Scholar
  59. 59.
    Iacopini F, Consolazio A, Bosco D, Marcheggiano A, Bella A, Pica R, Paoluzi OA, Crispino P, Rivera M, Mottolese M, Nardi F, Paoluzi P Oxidative damage of the gastric mucosa in Helicobacter pylori positive chronic atrophic and nonatrophic gastritis, before and after eradication. Helicobacter 8:503–512Google Scholar
  60. 60.
    Tsugane S, Tei Y, Takahashi T, Watanabe S, Sugano K (1994) Salty food intake and risk of Helicobacter pylori infection. Jpn J Cancer Res 85:474–478PubMedGoogle Scholar
  61. 61.
    Nair J, Strand S, Frank N, Knauft J, Wesch H, Galle PR, Bartsch H (2005) Apoptosis and age-dependant induction of nuclear and mitochondrial etheno-DNA adducts in Long–Evans cinnamon (LEC) rats: enhanced DNA damage by dietary curcumin upon copper accumulation. Carcinogenesis 26:1307–1315PubMedCrossRefGoogle Scholar
  62. 62.
    Wink DA, Vodovotz Y, Laval J, Laval F, Dewhirst MW, Mitchell JB (1998) The multifaceted roles of nitric oxide in cancer. Carcinogenesis 19:711–721PubMedCrossRefGoogle Scholar
  63. 63.
    Jaiswal M, LaRusso NF, Gores GJ (2001) Nitric oxide in gastrointestinal epithelial cell carcinogenesis: linking inflammation to oncogenesis. Am J Physiol Gastrointest Liver Physiol 281:626–634Google Scholar
  64. 64.
    Jaiswal M, LaRusso NF, Burgart LJ, Gores GJ (2000) Inflammatory cytokines induce DNA damage an inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res 60:184–190PubMedGoogle Scholar
  65. 65.
    Jaiswal M, LaRusso NF, Nishioka N, Nakabeppu Y, Gores GJ (2001) Human Ogg1, a protein involved in the repair of 8-oxoguanine, is inhibited by nitric oxide. Cancer Res 61:6399–6393Google Scholar
  66. 66.
    Choudhury S, Zhang R, Frenkel K, Kawamori T, Chung FL, Roy R (2003) Evidence of alterations in base excision repair of oxidative DNA damage during spontaneous hepatocarcinogenesis in Long Evans cinnamon rats. Cancer Res 63:7704–7707PubMedGoogle Scholar
  67. 67.
    Nair J, Sone H, Nagao M, Barbin A, Bartsch H (1996) Copper-dependent formation of miscoding etheno-DNA adducts in the liver of Long Evans cinnamon (LEC) rats developing hereditary hepatitis and hepatocellular carcinoma. Cancer Res 56:1267–1271PubMedGoogle Scholar
  68. 68.
    Feng Z, Hu W, Tang MS (2004) Trans-4-hydroxy-2-nonenal inhibits nucleotic excision repair in human cells: a possible mechanism for lipid peroxidation-induced carcinogenesis. Proc Natl Acad Sci USA 101:8598–8602PubMedCrossRefGoogle Scholar
  69. 69.
    Guichard Y, El Ghissassi F, Nair J, Bartsch H, Barbin A (1996) Formation and accumulation of DNA ethenobases in adult Sprague–Dawley rats exposed to vinyl chloride. Carcinogenesis 17:1553–1559PubMedCrossRefGoogle Scholar
  70. 70.
    Nair J, Barbin A, Velic I, Barsch H (1999) Etheno DNA-base adducts from endogenous reactive species. Mutat Res 424:59–69PubMedGoogle Scholar
  71. 71.
    Barbin A, Ohgaki H, Nakamura J, Kurrer M, Kleihues P, Swenberg JA (2003) Endogenous deoxyribonucleic acid (DNA) damage in human tissues: a comparison of ethenobases with aldehydic DNA lesions. Cancer Epidemiol Biomarkers Prev 12:1241–1247PubMedGoogle Scholar
  72. 72.
    Gros L, Ishchenko AA, Saparbaev M (2003) Enzymology of repair of etheno-adducts. Mutat Res 531:219–229PubMedGoogle Scholar
  73. 73.
    Hang B, Chenna B, Rao S, Hang B, Chenna A, Rao S, Singer B (1996) 1,N6-ethenoadenine and 3,N4-ethenocytosine are excised by separate human DNA glycosylases. Carcinogenesis 17:155–157PubMedCrossRefGoogle Scholar
  74. 74.
    Saparbaev M, Kleibl K, Laval J (1995) Escherichia coli, Saccharomyces cerevisiae, rat and human 3-methyladenine DNA glycosylases repair 1,N 6-ethenoadenine when present in DNA. Nucleic Acids Res 23:3750–3755PubMedCrossRefGoogle Scholar
  75. 75.
    Mishina Y, Yang CG, He C (2005) Direct repair of the exocyclic DNA adduct 1,N6-ethenoadenine by the DNA repair AlkB proteins. J Am Chem Soc 127:14594–14595PubMedCrossRefGoogle Scholar
  76. 76.
    Delaney JC, Smeester L, Wong C, Frick LE, Taghizadeh K, Wishnok JS, Drennan CL, Samson LD, Essigmann JM (2005) AlkB reverses etheno DNA lesions caused by lipid oxidation in vitro and in vivo. Nat Struct Mol Biol 12:855–860PubMedCrossRefGoogle Scholar
  77. 77.
    Gros L, Maksimenko AV, Privezentzev CV, Laval J, Saparbaev MK (2004) Hijacking of the human alkyl-N-purine-DNA glycosylase by 3,N 4-ethenocytosine, a lipid peroxidation-induced DNA adduct. J Biol Chem 279:17723–17730PubMedCrossRefGoogle Scholar
  78. 78.
    Glassner BJ, Rasmussen LJ, Najarian MT, Posnick LM, Samson LD (1998) Generation of a strong mutator phenotype in yeast by imbalanced base excision repair. Proc Natl Acad Sci USA 95:9997–10002PubMedCrossRefGoogle Scholar
  79. 79.
    Ohshima H, Tazawa H, Sylla BS, Sawa T (2005) Prevention of human cancer by modulation of chronic inflammatory processes. Mutat Res 59:110–122Google Scholar
  80. 80.
    Hagenlocher T, Nair J, Becker N, Bartsch H (2001) Influence of dietary fatty acid, vegetable and vitamin intake on etheno-DNA adducts in white blood cells of healthy female volunteers: a pilot study. Cancer Epidemiol Biomarkers Prev 10:1187–1191PubMedGoogle Scholar
  81. 81.
    Singh R, Farmer PB (2006) Liquid chromatography-electrospray ionization-mass spectrometry: the future of DNA adduct detection. Carcinogenesis 27:178–196PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  1. 1.Division of Toxicology and Cancer Risk FactorsGerman Cancer Research Center (DKFZ)HeidelbergGermany

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