Intermediate Biomarkers

  • Jerome W. KosmederII
  • John M. Pezzuto
Part of the Cancer Treatment and Research book series (CTAR, volume 106)


Carcinogenesis is generally recognized as a disease that progresses through several stages beginning with mutation of genomic DNA (initiation) followed by growth acceleration and further genetic damage (promotion) and, finally, development of malignant tumors (progression) [1]. With the latency period between stages ranging from years to decades, the science of cancer chemoprevention seeks to intervene using relatively nontoxic agents to prevent, delay or reverse one or more stages of carcinogenesis [2]. Intermediate biomarkers of cancer encompass the phenotypic, genotypic and molecular changes that characterize the multistage nature of carcinogenesis; their measurement is necessary for evaluating potential chemopreventive agents, elucidating mechanisms of action, selecting clinical trial cohorts and acting as surrogate endpoints for cancer incidence in human clinical trials. While the development of cancer biomarkers has advanced considerably in the past 25 years, researchers have yet to fully unravel the complex molecular, cellular, tissue, and epidemiological interactions that ultimately define the nature of carcinogenesis. Furthermore, indirect monitoring of carcinogenesis intervention is challenged by the proper identification, quantification, and validation of biomarkers, as well as establishment of relevance to clinical disease.


Proliferate Cell Nuclear Antigen Cervical Intraepithelial Neoplasia Transitional Cell Carcinoma Prostatic Intraepithelial Neoplasia Chemoprevention Trial 
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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  1. 1.
    Foulds L. 1969. Neoplastic Development. New York: Academic Press.Google Scholar
  2. 2.
    Morse MA, Stoner GD. 1993. Cancer chemoprevention. Principles and prospects. Carcinogenesis 14:1737–1746.PubMedCrossRefGoogle Scholar
  3. 3.
    Lippman SM, Lee JS, Lotan R, Hittelman W, Wargovich MJ, Hong WK. 1990. Biomarkers as intermediate endpoints in chemoprevention trials. J Natl Cancer Inst 82:555–560.PubMedCrossRefGoogle Scholar
  4. 4.
    Kelloff GJ, Sigman CC, Johnson KM, Boone CW, Greenwald P, Crowell JA, Hawk ET, Doody LA. 2000. Perspectives on surrogate end points in the development of drugs that reduce the risk of cancer. Cancer Epid Bio Prey 9:127–137.Google Scholar
  5. 5.
    Kelloff GJ, Boone CW, Crowell JA, Steele VE, Lubet R, Doody LA. 1994. Surrogate endpoint biomarkers for Phase II cancer chemopreventive trials. J Cell Biochem 19:1–9.CrossRefGoogle Scholar
  6. 6.
    Cancer Facts &Figures-2000. 2000. American Cancer Society,Atlanta, GA.Google Scholar
  7. 7.
    Bostwick DG. 1992. Prostatic intraepithelial neoplasia (PIN): current concepts. J Cell Biochem 16H:10–19.CrossRefGoogle Scholar
  8. 8.
    Yatani R, Kusano I, Shiraishi T, Hayashi T, Stemmermann GN. 1989. Latent prostatic carcinoma: Pathological and epidemiological aspects. Jpn J Clin Oncol, 19:319–326.PubMedGoogle Scholar
  9. 9.
    Ronnett BM, Carmichael MJ, Carter HB, Epstein JI. 1993. Does high grade prostatic intraepithelial neoplasia result in elevated serum prostate specific antigen levels? J Urol 150:386–389.PubMedGoogle Scholar
  10. 10.
    Alexander EE, Qian J, Wollan PC, Myers RP, Bostwick DG. 1996. Prostatic intraepithelial neoplasia does not appear to raise serum prostate-specific antigen concentration. Urology 47:693–698.PubMedCrossRefGoogle Scholar
  11. 11.
    Kelloff GJ. 1999. Perspectives on cancer chemoprevention research and drug development. Adv Cancer Res 78:199–334.CrossRefGoogle Scholar
  12. 12.
    Bostwick DG. 1999. Prostatic intraepithelial neoplasia is a risk factor for cancer. Semin Urol Oncol 17:187–198.PubMedGoogle Scholar
  13. 13.
    Qian J, Bostwick DG, Takahashi S, Borell TJ, Herath JF, Lieber MM, Jenkins RB. 1995. Chromosomal anomalies in prostatic intraepithelial neoplasia and carcinoma detected by fluorescencein situhybridization. Cancer Res 55:5508–5514.Google Scholar
  14. 14.
    Malins DC, Polissar NL, Gunselman SJ. 1995. Models of DNA structure achieve almost perfect discrimination between normal prostate, benign prostatic hyperplasia (BPH) and adenocarcinoma and have a high potential for predicting BPH and prostate cancer. Proc Natl Acad Sci USA 87:670–675.Google Scholar
  15. 15.
    Pirtskhalaishvili G, Nelson JB. 2000. Endothelium-derived factors as paracrine mediators of prostate cancer progression. Prostate 44:77–87.PubMedCrossRefGoogle Scholar
  16. 16.
    Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH, Pollak M. 1998. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279:563–566.PubMedCrossRefGoogle Scholar
  17. 17.
    Kelloff GJ, Lieberman R, Steele VE, Boone CW, Lubet RA, Kopelovitch L, Malone WA, Crowell JA, Sigman CC. 1999. Chemoprevention of prostate cancer: concepts and strategies. Eur Urol 35:342–350.PubMedCrossRefGoogle Scholar
  18. 18.
    Fabian CJ, Kimler BF, Elledge RM, Grizzle WE, Beenken SW, Ward JH. 1998. Models for early chemoprevention trials in breast cancer. Hematol Oncol Clin North Am, 12:993–1017.PubMedCrossRefGoogle Scholar
  19. 19.
    Haagensen CD. 1986. Lobular neoplasia (LCIS).InHaagensen, C. D. (ed): Diseases of the Breast, 3rdEd. Philadelphia, WB Saunders, 192–241.Google Scholar
  20. 20.
    Modan B, Lubin F, Alfandary E. et al. 1997. Breast cancer following benign breast disease-a nationwide study. Breast Cancer Res Treat 46:45.Google Scholar
  21. 21.
    Page DL, Dupont WD. 1990. Anatomic markers of human premalignancy and risk of breast cancer. Cancer 66:1326–1335.PubMedCrossRefGoogle Scholar
  22. 22.
    Tavassoli FA, Man Y. 1995. Morphofunctional features of intraductal hyperplasia, atypical intraductal hyperplasia and various grades of intraductal carcinoma. The Breast Journal 1:155–162.CrossRefGoogle Scholar
  23. 23.
    Swain SM. 1992. Ductal carcinomain situ.Cancer Invest 10:443–454.PubMedCrossRefGoogle Scholar
  24. 24.
    Posner MC, Wolmark N. 1992. Non-invasive breast carcinoma. Breast Cancer Res Treat 21:155–164.PubMedCrossRefGoogle Scholar
  25. 25.
    Tuccari G, Rizzo A, Muscara M, Giuffre G, Barresi G. 1993. PCNA/cyclin expression in breast carcinomas: its relationships with Ki-67, ER, PgR immunostainings and clinicopathologic aspects. Pathologica 85:47–55.PubMedGoogle Scholar
  26. 26.
    Khan SA. 1995. Estrogen and progesterone receptors in benign breast epithelium. The Breast Journal 1:251–261.CrossRefGoogle Scholar
  27. 27.
    Tsutsumi Y, Naber SP, DeLellis RA, Wolfe HJ, Marks PJ, McKenzie SJ, Yin S. 1990. neu-Oncogene protein and epidermal growth factor receptor are independently expressed in benign and malignant breast tissues. Hum Pathol 21:750–758.PubMedCrossRefGoogle Scholar
  28. 28.
    Pezzino V, Papa V, Milazzo G, Gliozzo B, Russo P, Scalia, PL. 1996. Insulin-like growth factor-I (IGF-I) receptors in breast cancer. Ann. N. Y. Acad. Sci., 784: 189–201PubMedCrossRefGoogle Scholar
  29. 29.
    Dickson RB, Lippman ME. 1996. Oncogenes and suppressor genes.InHarris JR, Lippman, ME, Morrow M. (eds): Diseases of the Breast, Philadelphia, JB Lippincott, 221–229.Google Scholar
  30. 30.
    Kalkhoven E, Roelen BA, de Winter JP, Mummery CL, van den Eijnden-van AJ, van der Saag PT, van der Burg B. 1995. Resistance to transforming growth factor beta and activin due to reduced receptor expression in human breast tumor cell lines. Cell Growth Differ 6:1151–1161.PubMedGoogle Scholar
  31. 31.
    Gasparini G, Toi M, Gion M, Verderio P, Dittadi R, Hanatani M, Matsubara I, Vinante O, Bonoldi E, Boracchi P, Gatti C, Suzuki H, Tominaga T. 1997. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst 89:139–147.PubMedCrossRefGoogle Scholar
  32. 32.
    Bertin N, Clezardin P, Kubiak R, Frappart L. 1997. Thrombospondin-I and -2 messenger RNA expression in normal, benign, and neoplastic human breast tissues: correlation with prognostic factors, tumor angiogenesis, and fibroblastic desmoplasia. Cancer Res 57:396–399.PubMedGoogle Scholar
  33. 33.
    Olsson H, Jernstrom H, Alm P, Kreipe H, Ingvar C, Jonsson PE, Ryden S. 1996. Proliferation of the breast epithelium in relation to menstrual cycle phase, hormonal use, and reproductive factors. Breast Cancer Res Treat 40:187–196.PubMedCrossRefGoogle Scholar
  34. 34.
    Potten CS, Watson RJ, Williams GT, Tickle S, Roberts SA, Harris M, Howell A. 1988. The effect of age and menstrual cycle upon proliferative activity of the normal human breast. Br J Cancer 58:163–170.PubMedCrossRefGoogle Scholar
  35. 35.
    Muto T, Bussey HJ, Morson BC. 1975. The evolution of cancer of the colon and rectum. Cancer 36:2251–2270.PubMedCrossRefGoogle Scholar
  36. 36.
    Winawer SJ, O’Brien MJ, Waye JD, Kronborg O, Bond J, Fruhmorgen P, Sobin LH, Burt R, Zauber A, Morson B. 1990. Risk and surveillance of individuals with colorectal polyps. WHO Collaborating Centre for the Prevention of Colorectal Cancer. Bull World Health Organ 68:789–795.PubMedGoogle Scholar
  37. 37.
    Hamilton SR. 1992. The adenoma-adenocarcinoma sequence in the large bowel: variations on a theme. J. Cell Biochem. (Suppl.), 16G:41–46.CrossRefGoogle Scholar
  38. 38.
    Hamilton SR. 1996. Pathology and biology of colorectal neoplasia. In: Young, G. P., Levin, B., and Rozen, P. (eds.), Prevention and Early Detection of Colorectal Cancer: Principles and Practice, London, England: W. B. Saunders, 3–21.Google Scholar
  39. 39.
    Muto T, Bussey HJR, Morson B. 1975. The evolution of cancer of the colon and rectum. Cancer 36:2251–2270.PubMedCrossRefGoogle Scholar
  40. 40.
    Fearon ER, Vogelstein B. 1990. A genetic model for colorectal tumorigenesis. Cell 61:759–767.PubMedCrossRefGoogle Scholar
  41. 41.
    Scalmati A, Lipkin M. 1992. Intermediate biomarkers of increased risk for colorectal cancer: comparison of different methods of analysis and modifications by chemopreventive interventions. J Cell Biochem, (Suppl) 166:65–71.CrossRefGoogle Scholar
  42. 42.
    Risio M, Candelaresi G, Rossini FP. 1993. Bromodeoxyuridine uptake and proliferating cell nuclear antigen expression throughout the colorectal tumor sequence. Cancer Epidemiol Biomarkers Prey 2:363–367.Google Scholar
  43. 43.
    Mingazzini PL, Scucchi L, Di Stefano D, Malchiodi Albedi F, Ciaralli F, Falchi M, Marinozzi V. 1991. Expression of interphasic nucleolar organizer regions in normal, dysplastic and neoplastic colorectal mucosa. Virchows Arch A Pathol Anat Histopathol 419:487–491.PubMedCrossRefGoogle Scholar
  44. 44.
    Einsphar J, Nixon L, Alberts D, Durbin D, Pennle K, Davidson J, McGee D, Garewal N. 1991. Comparison of [3H1-Thyd and BrDU labelling index (LI) in human colorectal mucosa. Gastroenterology 100:A359.Google Scholar
  45. 45.
    Lawson MJ, White LM, Coyle P, Butler RN, Roberts-Thomson IC, Conyers RA. 1989. An assessment of proliferative and enzyme activity in transitional mucosa adjacent to colonic cancer. Cancer 64:1061–1066.PubMedCrossRefGoogle Scholar
  46. 46.
    Paganelli GM, Saccoccio G, Brandi G, Bellentani S, Santucci R, Armocida C, Ponz de Leon M, Biasco G. 1991. Correlation between bromodeoxyuridine labelling and ornithine decarboxylase levels in normal rectal mucosa of patients with colorectal adenoma. Cancer Lett 59:221–224.PubMedCrossRefGoogle Scholar
  47. 47.
    Campo E, de la Calle-Martin 0, Miguel R, Palacin A, Romero M, Fabregat V, Vives J, Cardesa A, Yague J. 1991. Loss of heterozygosity of p53 gene and p53 protein expression in human colorectal carcinomas. Cancer Res 51:4436–4442.PubMedGoogle Scholar
  48. 48.
    Pignatelli M, Stamp GW, Kafiri G, Lane D, Bodmer WF. 1992. Over-expression of p53 nuclear oncoprotein in colorectal adenomas. Int J Cancer 50:683–688.PubMedCrossRefGoogle Scholar
  49. 49.
    Einspahr JG, Alberts DS, Gapstur SM, Bostick RM, Emerson SS, Gerner EW. 1997. Surrogate end-point biomarkers as measures of colon cancer risk and their use in cancer chemoprevention trials. Cancer Epidemiol Biomarkers Prey 6:37–48.Google Scholar
  50. 50.
    Sanders DS, Kerr MA. 1999. Lewis blood group and CEA related antigens; coexpressed cell-cell adhesion molecules with roles in the biological progression and dissemination of tumours. Mol Pathol 52:174–178.PubMedCrossRefGoogle Scholar
  51. 51.
    Krishnan K, Ruffin MT, Brenner DE. 1998. Clinical models of chemoprevention for colon cancer. Hematol Oncol Clin North Am 12:1079–1113, viii.PubMedCrossRefGoogle Scholar
  52. 52.
    Mulshine JL. 1999. Reducing lung cancer risk: early detection. Chest 116(6 Suppl):493S–496S.PubMedCrossRefGoogle Scholar
  53. 53.
    Auerbach 0, Gere JB, Forman JB, Petrick TG, Smolin HG, Muehsam GE, Kassouny DY, Stout AP. 1957.N Engl J Med 256:97–104.PubMedCrossRefGoogle Scholar
  54. 54.
    Auerbach 0, Stout AP, Hammond EC, Garfinkel L. 1962. N Engl J Med 267:111–125.PubMedCrossRefGoogle Scholar
  55. 55.
    Auerbach O. 1981. Pathogenesis of lung cancer. Compr Ther 7:11–21.PubMedGoogle Scholar
  56. 56.
    Saccomanno G, Archer VE, Auerbach 0, Saunders RP, Brennan LM. 1974. Development of carcinoma of the lung as reflected in exfoliated cells. Cancer 1974 33:256–270.PubMedCrossRefGoogle Scholar
  57. 57.
    Trump BF, McDowell EM, Glavin F, Barrett LA, Becci PJ, Schurch W, Kaiser HE, Harris CC. 1978. The respiratory epithelium. III. Histogenesis of epidermoid metaplasia and carcinomain situin the human. J Nati Cancer Inst 61:563–575.Google Scholar
  58. 58.
    McDowell EM, McLaughlin JS, Merenyl DK, Kieffer RF, Harris CC, Trump BF. 1978. The respiratory epithelium. V. Histogenesis of lung carcinomas in the human. J Natl Cancer Inst 61:587–606.PubMedGoogle Scholar
  59. 59.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC. 1991. p53 mutations in human cancers. Science 253:49–53.PubMedCrossRefGoogle Scholar
  60. 60.
    Bennett WP, Colby TV, Travis WD, Borkowski A, Jones RT, Lane DP, Metcalf RA, Samet JM, Takeshima Y, Gu JR, Vahakangas KH, Soini Y, Paakko P, Welsh JA, Trump BF, Harris CC. 1991. p53 protein accumulates frequently in early bronchial neoplasia. Cancer Res 153:4817–4822.Google Scholar
  61. 61.
    Shaulsky G, Ben-Ze’ev A, Rotter V. 1990. Subcellular distribution of the p53 protein during the cell cycle of Balb/c 3T3 cells. Oncogene 5:1707–1711.PubMedGoogle Scholar
  62. 62.
    Husgafvel-Pursiainen K, Boffetta P, Kannio A, Nyberg F, Pershagen G, Mukeria A, Constantinescu V, Fortes C, Benhamou S. 2000. p53 mutations and exposure to environmental tobacco smoke in a multicenter study on lung cancer. Cancer Res 60:2906–2911.PubMedGoogle Scholar
  63. 63.
    Minamoto T, Mai M, Ronai Z. 2000. K-ras mutation: early detection in molecular diagnosis and risk assessment of colorectal, pancreas, and lung cancers--a review. Cancer Detect Prey 24:1–12.Google Scholar
  64. 64.
    Kanazawa H, Ebina M, Ino-Oka N, Shimizukawa M, Takahashi T, Fujimura S, Imai T, Nukiwa T. 2000. Transition from squamous cell carcinoma to adenocarcinoma in adenosquamous carcinoma of the lung. Am J Pathol 156:1289–1298.PubMedCrossRefGoogle Scholar
  65. 65.
    Wright GS, Gruidl ME. 2000. Early detection and prevention of lung cancer. Curr Opin Oncol 2000 12:143–148.PubMedCrossRefGoogle Scholar
  66. 66.
    Martinet N, Alla F, Farre G, Labib T, Drouot H, Vidili R, Picard E, Gaube MP, Le Faou D, Siat J, Borelly J, Vermylen P, Bazarbachi T, Vignaud JM, Martinet Y. 2000. Retinoic acid receptor and retinoid X receptor alterations in lung cancer precursor lesions. Cancer Res 60:2869–2875.PubMedGoogle Scholar
  67. 67.
    Kozulic M, Chen XQ, Bonilla F, Silva J. 2000. Loss of heterozygosity at the ACTBP2 locus in lung cancer detected on Elchrom precast Spreadex gels. Ann N Y Acad Sci 906:83–86.PubMedCrossRefGoogle Scholar
  68. 68.
    Bruhn N, Beinert T, Oehm C, Jandrig B, Petersen I, Chen XQ, Possinger K, Fleischhacker M. 2000. Detection of microsatellite alterations in the DNA isolated from tumor cells and from plasma DNA of patients with lung cancer. Ann N Y Acad Sci 906:72–82.PubMedCrossRefGoogle Scholar
  69. 69.
    Ahrendt SA, Decker PA, Doffek K, Wang B, Xu L, Demeure MJ, Jen J, Sidransky D. 2000. Microsatellite instability at selected tetranucleotide repeats is associated with p53 mutations in non-small cell lung cancer. Cancer Res 60:2488–2491.PubMedGoogle Scholar
  70. 70.
    Chang JW, Chen YC, Chen CY, Chen JT, Chen SK, Wang YC. 2000. Correlation of genetic instability with mismatch repair protein expression and p53 mutations in non-small cell lung cancer. Clin Cancer Res 6:1639–1646.PubMedGoogle Scholar
  71. 71.
    Zhou X, Kemp BL, Khuri FR, Liu D, Lee JJ, Wu W, Hong WK, Mao L. 2000. Prognostic implication of microsatellite alteration profiles in early-stage non-small cell lung cancer. Clin Cancer Res 6:559–565.PubMedGoogle Scholar
  72. 72.
    Wistuba II, Behrens C, Virmani AK, Mele G, Milchgrub S, Girard L, Fondon JW 3rd, Garner HR, McKay B, Latif F, Lerman MI, Lam S, Gazdar AF, Minna JD. 2000. High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints. Cancer Res 60:1949–1960.PubMedGoogle Scholar
  73. 73.
    Mariatos G, Gorgoulis VG, Zacharatos P, Kotsinas A, Vogiatzi T, Rassidakis G, Foukas P, Liloglou T, Tiniakos D, Angelou N, Manolis EN, Veslemes M, Field JK, Kittas C. 2000. Expression of p16(INK4A) and alterations of the 9p21–23 chromosome region in nonsmall-cell lung carcinomas: relationship with tumor growth parameters and ploidy status. Int J Cancer 89:133–141.PubMedCrossRefGoogle Scholar
  74. 74.
    Gorgoulis VG, Mariatosl G, Manolis EN, Zacharatos P, Kotsinas A, Liloglou T, Vogiatzi T, Tsagkaraki A, Kokotas S, Tsoli E, Alchanatis M, Sfikakis PP, Asimacopoulos PJ, Field JK, Kittas C. 2000. Allelic imbalance at the 5q14 locus is associated with decreased apoptotic rate in non-small cell lung carcinomas (NSCLCs). Possible synergistic effect with p53 gene alterations on apoptosis. Lung Cancer 28:211–224.PubMedCrossRefGoogle Scholar
  75. 75.
    Geradts J, Fong KM, Zimmerman PV, Minna JD. 2000. Loss of FHIT expression in nonsmall-cell lung cancer: correlation with molecular genetic abnormalities and clinicopathological features. Br J Cancer 82:1191–1197.PubMedCrossRefGoogle Scholar
  76. 76.
    Thiberville L, Payne P, Vielkinds J, LeRiche J, Horsman D, Nouvet G, Palcic B, Lam S. 1995. Evidence of cumulative gene losses with progression of premalignant epithelial esions to carcinoma of the bronchus. Cancer Res 55:5133–5139.PubMedGoogle Scholar
  77. 77.
    Kishimoto Y, Sugio K, Flung JY, Virmani AK, McIntire DD, Minna JD, Gazdar AF. 1995. Allele-specific loss in chromosome 9p loci in preneoplastic lesions accompanying non-small-cell lung cancers. J Natl Cancer Inst 87:1224–1229.PubMedCrossRefGoogle Scholar
  78. 78.
    Zhou J, Mulshine JL, Unsworth EJ, Scott FM, Avis IM, Vos MD, Treston AM. 1996. Purification and characterization of a protein that permits early detection of lung cancer. Identification of heterogeneous nuclear ribonucleoprotein-A2/B1 as the antigen for monoclonal antibody 703D4. J Biol Chem 271:10760–10766.PubMedCrossRefGoogle Scholar
  79. 79.
    Tockman MS, Mulshine JL, Piantadosi S, Erozan YS, Gupta PK, Ruckdeschel JC, Taylor PR, Zhukov T, Zhou WH, Qiao YL, Yao SX. 1997. Prospective detection of preclinical lung cancer: results from two studies of heterogeneous nuclear ribonucleoprotein A2/B1 overexpression. Clin Cancer Res 3(12 Pt 1):2237–2246.PubMedGoogle Scholar
  80. 80.
    Zhou J, Mulshine JL, Ro JY, Avis I, Yu R, Lee JJ, Morice R, Lippman SM, Lee JS. 1998. Expression of heterogeneous nuclear ribonucleoprotein A2/B1 in bronchial epithelium of chronic smokers. Clin Cancer Res 4:1631–1640.PubMedGoogle Scholar
  81. 81.
    Fielding P, Turnbull L, Prime W, Walshaw M, Field JK. 1999. Heterogeneous nuclear ribonucleoprotein A2/B1 up-regulation in bronchial lavage specimens: a clinical marker of early lung cancer detection. Clin Cancer Res 5:4048–4052.PubMedGoogle Scholar
  82. 82.
    Montuenga LM, Zhou J, Avis I, Vos M, Martinez A, Cuttitta F, Treston AM, Sunday M, Mulshine JL. 1998. Expression of heterogeneous nuclear ribonucleoprotein A2/B1 changes with critical stages of mammalian lung development. Am J Respir Cell Mol Biol 19:554–562.PubMedGoogle Scholar
  83. 83.
    Rizvi N, Hayes DF. 1999. A “breathalyser” for lung cancer? Lancet 353:1897–1898.PubMedCrossRefGoogle Scholar
  84. 84.
    Phillips M, Gleeson K, Hughes JM, Greenberg J, Cataneo RN, Baker L, McVay WP. 1999. Volatile organic compounds in breath as markers of lung cancer: a cross-sectional study. Lancet 353:1930–1933.PubMedCrossRefGoogle Scholar
  85. 85.
    Benner SE, Hong WK, Lippman SM, Lee JS, Hittelman WM. 1992. Intermediate biomarkers in upper aerodigestive tract and lung chemoprevention trials. J Cell Biochem 16G:33–38.CrossRefGoogle Scholar
  86. 86.
    Papadimitrakopoulou VA, Shin DM, Hong WK. 1996. Molecular and cellular biomarkers for field cancerization and multistep process in head and neck tumorigenesis. Cancer Metastasis Rev 15:53–76.PubMedCrossRefGoogle Scholar
  87. 87.
    Stich HF. 1987. Micronucleated exfoliated cells as indicators for genotoxic damage and as markers in chemoprevention trials. J. Nutr Growth Cancer 4:9–18.Google Scholar
  88. 88.
    Rosin MP, Dunn BP, Stich HF. 1987. Use of intermediate endpoints in quantitating the response of precancerous lesions to chemopreventive agents. Can J Physiol Pharmacol 65:483–487.PubMedCrossRefGoogle Scholar
  89. 89.
    Stich HF, Dunn BP. 1988. DNA adducts, micronuclei and leukoplakias as intermediate endpoints in intervention trials. IARC Sci Publ 89:137–145.PubMedGoogle Scholar
  90. 90.
    Lippman SM, Peters EJ, Wargovich MJ, Dixon DO, Dekmezian RH, Cunningham JE, Loewy JW, Morice RC, Hong WK. 1990. The evaluation of micronuclei as an intermediate endpoint of bronchial carcinogenesis. Prog Clin Biol Res 339:165–177.PubMedGoogle Scholar
  91. 91.
    Lippman SM, Peters EJ, Wargovich MJ, Stadnyk AN, Dixon DO, Dekmezian RH, Loewy JW, Morice RC, Cunningham JE, Hong WK. 1990. Bronchial micronuclei as a marker of an early stage of carcinogenesis in the human tracheobronchial epithelium. Int J Cancer 45:811–815.PubMedCrossRefGoogle Scholar
  92. 92.
    Jin Y, Mertens F, Mandahl N, Heim S, Olegard C, Wennerberg J, Biorklund A, Mitelman F. 1993. Chromosome abnormalities in eighty-three head and neck squamous cell carcinomas: influence of culture conditions on karyotypic pattern. Cancer Res 53:2140–2146.PubMedGoogle Scholar
  93. 93.
    Carey TE, Van Dyke DL, Worsham MJ. 1993. Nonrandom chromosome aberrations and clonal populations in head and neck cancer. Anticancer Res 13(6B):2561–2567.PubMedGoogle Scholar
  94. 94.
    Carey TE, Worsham MJ, Van Dyke DL. 1993. Chromosomal bioniarkers in the clonal evolution of head and neck squamous neoplasia. J Cell Biochem Suppl 17F:213–222.PubMedCrossRefGoogle Scholar
  95. 95.
    Van Dyke DL, Worsham MJ, Benninger MS, Krause CJ, Baker SR, Wolf GT, Drumheller T, Tilley BC, Carey TE. 1994. Recurrent cytogenetic abnormalities in squamous cell carcinomas of the head and neck region. Genes Chromosomes Cancer 9:192–206.PubMedCrossRefGoogle Scholar
  96. 96.
    Cowan JM, Beckett MA, Weichselbaum RR. 1993. Chromosome changes characterizing in vitro response to radiation in human squamous cell carcinoma lines. Cancer Res 53:5542–5547.PubMedGoogle Scholar
  97. 97.
    Califano J, van der Riet P, Westra W, Nawroz H, Clayman G, Piantadosi S, Corio R, Lee D, Greenberg B, Koch W, Sidransky D. 1996. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res 56:2488–2492.PubMedGoogle Scholar
  98. 98.
    Thiberville L, Payne P, Vielkinds J, LeRiche J, Horsman D, Nouvet G, Palcic B, Lam S. 1995. Evidence of cumulative gene losses with progression of premalignant epithelial lesions to carcinoma of the bronchus. Cancer Res 55:5133–5139.PubMedGoogle Scholar
  99. 99.
    Cloos J, Spitz MR, Schantz SP, Hsu TC, Zhang ZF, Tobi H, Braakhuis BJ, Snow GB. 1996. Genetic susceptibility to head and neck squamous cell carcinoma. J Nat] Cancer Inst 88:530–535.CrossRefGoogle Scholar
  100. 100.
    Bockmuhl U, Wolf G, Schmidt S, Schwendel A, Jahnke V, Dietel M, Petersen 1. 1998. Genomic alterations associated with malignancy in head and neck cancer. Head Neck 1998 20:145–151.PubMedCrossRefGoogle Scholar
  101. 101.
    Benner SE, Lippman SM, Wargovich MJ, Velasco M, Peters EJ, Morice RC, Hong WK. 1992. Micronuclei in bronchial biopsy specimens from heavy smokers: characterization of an intermediate marker of lung carcinogenesis. Int J Cancer 52:44–47.PubMedCrossRefGoogle Scholar
  102. 102.
    Benner SE, Lippman SM, Wargovich MJ, Lee.1.1, Velasco M, Martin JW, Toth BB, Hong WK. 1994. Micronuclei, a biomarker for chemoprevention trials: results of a randomized study in oral pre-malignancy. Int J Cancer 59:457–459.Google Scholar
  103. 103.
    Voravud N, Shin DM, Ro JY, Lee JS, Hong WK, Hittelman WN. 1993. Increased polysomies of chromosomes 7 and 17 during head and neck multistage tumorigenesis. Cancer Res 53:2874–2883.PubMedGoogle Scholar
  104. 104.
    Hittelman WN, Voravud N, Shin DM, Lee JS, Ro JY, Hong WK. 1993. Early genetic changes during upper aerodigestive tract tumorigenesis. J Cell Biochem (Suppl) 17F:233–236.CrossRefGoogle Scholar
  105. 105.
    Lee JJ, Hong WK, Hittelman WN, Mao L, Lotan R, Shin DM, Benner SE, Xu XC, Lee JS, Papadimitrakopoulou VM, Geyer C, Perez C, Martin JW, El-Naggar AK, Lippman SM. 2000. Predicting cancer development in oral leukoplakia: ten years of translational research. Clin Cancer Res 6:1702–1710.PubMedGoogle Scholar
  106. 106.
    Furth ME, Davis LJ, Fleurdelys B. Scolnick EM. 1982. Monoclonal antibodies to the p21 products of the transforming gene of Harvey murine sarcoma virus and of the cellular ras gene family. J Virol 43:294–304.PubMedGoogle Scholar
  107. 107.
    Sheng ZM, Barrois M, Klijanienko J, Micheau C, Richard JM, Riou G. 1990. Analysis of the c-Ha-ras-1 gene for deletion, mutation, amplification and expression in lymph node metastases of human head and neck carcinomas. Br J Cancer 62:398–404PubMedCrossRefGoogle Scholar
  108. 108.
    Rumsby G, Carter RL, Gusterson BA. 1990. Low incidence of ras oncogene activation in human squamous cell carcinomas. Br J Cancer 61:365–368.PubMedCrossRefGoogle Scholar
  109. 109.
    Saranath D, Chang SE, Bhoite LT, Panchal RG, Kerr IB, Mehta AR, Johnson NW, Deo MG. 1991. High frequency mutation in codons 12 and 61 of H-ras oncogene in chewing tobacco-related human oral carcinoma in India. Br J Cancer 63:573–578.PubMedCrossRefGoogle Scholar
  110. 110.
    Kuo MY, Chang HH, Hahn Li, Wang JT, Chiang CP. 1995. Elevated ras p21 expression in oral premalignant lesions and squamous cell carcinoma in Taiwan. J Oral Pathol Med 24:255–260.PubMedCrossRefGoogle Scholar
  111. 111.
    Brachman DG, Graves D, Vokes E, Beckett M, Haraf D, Montag A, Dunphy E, Mick R, Yandell D, Weichselbaum RR. 1992. Occurrence of p53 gene deletions and human papilloma virus infection in human head and neck cancer. Cancer Res 52:4832–4836.PubMedGoogle Scholar
  112. 112.
    Gusterson BA, Anbazhagan R, Warren W, Midgely C, Lane DP, O’Hare M, Stamps A, Carter R, Jayatilake H. 1991. Expression of p53 in premalignant and malignant squamous epithelium. Oncogene 6:1785–1789.PubMedGoogle Scholar
  113. 113.
    Field JK, Spandidos DA, Malliri A, Gosney JR, Yiagnisis M, Steil PM. 1991. Elevated P53 expression correlates with a history of heavy smoking in squamous cell carcinoma of the head and neck. Br J Cancer 64:573–577.PubMedCrossRefGoogle Scholar
  114. 114.
    Boyle JO, Hakim J, Koch W, van der Riet P, Hruban RH, Roa RA, Correo R, Eby YJ, Ruppert JM, Sidransky D. 1993.Cancer Res 53:4477–4780.PubMedGoogle Scholar
  115. 115.
    Brennan JA, Boyle JO, Koch WM, Goodman SN, Hruban RH, Eby YJ, Couch MJ, Forastiere AA, Sidransky D. 1995. Association between cigarette smoking and mutation of the p53 gene in squamous-cell carcinoma of the head and neck. N Engl J Med 332:712–717.PubMedCrossRefGoogle Scholar
  116. 116.
    Shin DM, Kim J, Ro JY, Hittelman J, Roth JA, Hong WK, Hittelman WN. 1995. Activation of p53 gene expression in premalignant lesions during head and neck tumorigenesis. Cancer Res 54:321–326.Google Scholar
  117. 117.
    Williams ME, Gaffey MJ, Weiss LM, Wilczynski SP, Schuuring E, Levine PA. 1993. Chromosome 11Q13 amplification in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 119:1238–1243.PubMedCrossRefGoogle Scholar
  118. 118.
    Callender T, el-Naggar AK, Lee MS, Frankenthaler R, Luna MA, Batsakis JG. 1994. PRAD-1 (CCNDI)/cyclin DI oncogene amplification in primary head and neck squamous cell carcinoma. Cancer 74:152–158.PubMedCrossRefGoogle Scholar
  119. 119.
    Zhang SY, Klein-Szanto AJ, Sauter ER, Shafarenko M, Mitsunaga S, Nobori T, Carson DA, Ridge JA, Goodrow TL. 1994. Higher frequency of alterations in the p16/CDKN2 gene in squamous cell carcinoma cell lines than in primary tumors of the head and neck. Cancer Res 54:5050–5053.PubMedGoogle Scholar
  120. 120.
    Lydiatt WM, Murty VV, Davidson BJ, Xu L, Dyomina K, Sacks PG, Schantz SP, Chaganti RS. 1995. Homozygous deletions and loss of expression of the CDKN2 gene occur frequently in head and neck squamous cell carcinoma cell lines but infrequently in primary tumors. Genes Chromosomes Cancer 13:94–98.PubMedCrossRefGoogle Scholar
  121. 121.
    Spruck CH 3rd, Gonzalez-Zulueta M, Shibata A, Simoneau AR, Lin MF, Gonzales F, Tsai YC, Jones PA. 1994. p16 gene in uncultured tumours. Nature 370:183–184.PubMedCrossRefGoogle Scholar
  122. 122.
    Shin DM, Voravud N, Ro JY, Lee JS, Hong WK, Hittelman WN. 1993. Sequential increases in proliferating cell nuclear antigen expression in head and neck tumorigenesis: a potential biomarker. J Natl Cancer Inst 85:971–978.PubMedCrossRefGoogle Scholar
  123. 123.
    Huang WY, Coltrera M, Schubert M, Morton T, Truelove E. 1994. Histopathologic evaluation of proliferating cell nuclear antigen (PC10) in oral epithelial hyperplasias and premalignant lesions. Oral Surg Oral Med Oral Pathol 78:748–754.PubMedCrossRefGoogle Scholar
  124. 124.
    Liu SC, Klein-Szanto AJ. 2000. Markers of proliferation in normal and leukoplakic oral epithelia. Oral Oncol 36:145–151.PubMedCrossRefGoogle Scholar
  125. 125.
    Sittel C, Ruiz S, Volling P, Kvasnicka HM, Jungehulsing M, Eckel HE. 2000. Prognostic significance of Ki-67 (MIB1), PCNA and p53 in cancer of the oropharynx and oral cavity. Oral Oncol 35:583–589.CrossRefGoogle Scholar
  126. 126.
    Eisbruch A, Buick M, Lee JS, Sacks PG, Gutterman J. 1987. Analysis of the epidermal growth factor receptor gene in fresh human head and neck tumors. Cancer Res 47:3603–3605.PubMedGoogle Scholar
  127. 127.
    Todd R, Donoff BR, Gertz R, Chang AL, Chow P, Matossian K, McBride J, Chiang T, Gallagher GT, Wong DT. 1989. TGF-alpha and EGF-receptor mRNAs in human oral cancers. Carcinogenesis 10:1553–1556.PubMedCrossRefGoogle Scholar
  128. 128.
    Maxwell SA, Sacks PG, Gutterman JU, Gallick GE. 1989. Epidermal growth factor receptor protein-tyrosine kinase activity in human cell lines established from squamous carcinomas of the head and neck. Cancer Res 49:1130–1137.PubMedGoogle Scholar
  129. 129.
    Santini J, Formento JL, Francoual M, Milano G, Schneider M, Dassonville O, Demard F. 1991. Characterization, quantification, and potential clinical value of the epidermal growth factor receptor in head and neck squamous cell carcinomas. Head Neck 13:132–139.PubMedCrossRefGoogle Scholar
  130. 130.
    Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. 1982. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 31:11–24.PubMedCrossRefGoogle Scholar
  131. 131.
    Thacher SM. 1989. Purification of keratinocyte transglutaminase and its expression during squamous differentiation. J Invest Dermatol 92:578–584.PubMedGoogle Scholar
  132. 132.
    Said JW, Nash G, Sassoon AF, Shintaku IP, Banks-Schlegel S. 1983. Involucrin in lung tumors. A specific marker for squamous differentiation. Lab Invest 49:563–568.PubMedGoogle Scholar
  133. 133.
    Michalides R, van Veelen N, Hart A, Loftus B, Wientjens E, Balm A. 1995. Overexpression of cyclin DI correlates with recurrence in a group of forty-seven operable squamous cell carcinomas of the head and neck. Cancer Res 55:975–978.PubMedGoogle Scholar
  134. 134.
    Cairns P, Mao L, Merlo A, Lee DJ, Schwab D, Eby Y, Tokino K, van der Riet P, Blaugrund JE, Sidransky D. 1994. Rates of p16 (MTS1) mutations in primary tumors with 9p loss. Science 265:415–417.PubMedCrossRefGoogle Scholar
  135. 135.
    Lindberg K, Rheinwald JG. 1989. Suprabasal 40 kd keratin (K19) expression as an immunohistologic marker of premalignancy in oral epithelium. Am J Pathol 134:89–98.PubMedGoogle Scholar
  136. 136.
    Shin DM, Gimenez IB, Lee JS, Nishioka K, Wargovich MJ, Thacher S, Lotan R, Slaga TJ, Hong WK. 1990. Expression of epidermal growth factor receptor, polyamine levels, ornithine decarboxylase activity, micronuclei, and transglutaminase I in a 7,12- dimethylbenz(a)anthracene-induced hamster buccal pouch carcinogenesis model. Cancer Res 50:2505–2510.PubMedGoogle Scholar
  137. 137.
    Silverman DT, Hartge P, Morrison AS, Devesa SS. 1992. Epidemiology of bladder cancer. Hematol Oncol Clin North Am 6:1–30.PubMedGoogle Scholar
  138. 138.
    Harris AL, Neal DE. 1992. Bladder cancer-field versus clonal origin. N Engl J Med 326:759–761.PubMedCrossRefGoogle Scholar
  139. 139.
    Herr HW, Jakse G, Sheinfeld J. 1990. The T1 bladder tumor. Semin Urol 8:254–261.PubMedGoogle Scholar
  140. 140.
    Farrow GM, Barlebo H, Enjoji M, Chisholm G, Friedell GH, Jackse G, Kakizoe T, Koss LG, Kotake T, Vahlensieck W. 1986. Transitional cell carcinomain situ.Prog Clin Biol Res 221:85–96.PubMedGoogle Scholar
  141. 141.
    Allard P, Fradet Y, Tetu B, Bernard P. 1995. Tumor-associated antigens as prognostic factors for recurrence in 382 patients with primary transitional cell carcinoma of the bladder. Clin Cancer Res 1:1195–1202.PubMedGoogle Scholar
  142. 142.
    Lee E, Schwaibold H, Fradet Y, Huland E, Huland H. 1997. Tumor-associated antigens in normal mucosa of patients with superficial transitional cell carcinoma of the bladder. J Urol 157:1070–1073.PubMedCrossRefGoogle Scholar
  143. 143.
    Joseph JV, Messing M. 1997. Chemoprevention of bladder and prostate carcinoma. Cancer Control 4:136–141.PubMedGoogle Scholar
  144. 144.
    Mian C, Pycha A, Wiener H, Haitel A, Lodde M, Marberger M. 1999. Immunocyt: a new tool for detecting transitional cell cancer of the urinary tract. J Urol 161:1486–1489.PubMedCrossRefGoogle Scholar
  145. 145.
    Sidransky D, Messing E. 1992. Molecular genetics and biochemical mechanisms in bladder cancer. Oncogenes, tumor suppressor genes, and growth factors. Urol Clin North Am 19:629–639.PubMedGoogle Scholar
  146. 146.
    Mao L, Schoenberg MP, Scicchitano M, Erozan YS, Merlo A, Schwab D, Sidransky D. 1996. Molecular detection of primary bladder cancer by microsatellite analysis. Science 271:659–662.PubMedCrossRefGoogle Scholar
  147. 147.
    Cordon-Cardo C. 1998. Molecular alterations in bladder cancer. Cancer Sury 32:115–131.Google Scholar
  148. 148.
    de Vere White RW, Stapp E. 1998. Predicting prognosis in patients with superficial bladder cancer. Oncology (Huntingt) 112:1717–23; discussion 1724–6.Google Scholar
  149. 149.
    deVere White RW, Deitch AD. 1992. Evaluation of DNA flow cytometry as a screening test for bladder cancer. J Cell Biochem (Suppl) 161:80–84.CrossRefGoogle Scholar
  150. 150.
    Sandberg AA. 1992. Chromosome changes in early bladder neoplasms. J Cell Biochem Suppl 161:76–79.CrossRefGoogle Scholar
  151. 151.
    Benedict WF. 1992. Altered RB expression is a prognostic clinical marker involved in human bladder tumorigenesis. J Cell Biochem Suppl 161:69–71.CrossRefGoogle Scholar
  152. 152.
    Rabbani F, Cordon-Cardo C. 2000. Mutation of cell cycle regulators and their impact on superficial bladder cancer. Urol Clin North Am 27:83–102, ix.PubMedCrossRefGoogle Scholar
  153. 153.
    Bruno S, Torrisi R, Costantini M, Baglietto L, Fontana V, Gatteschi B, Melioli G, Nicolo G, Curotto A, Malcangi B, Bruttini GP, Varaldo M, Bruzzi P, Decensi A. 1999. Assessment of DNA flow cytometry as a surrogate end point biomarker in a bladder cancer chemoprevention trial. J Cell Biochem 76:311–321.PubMedCrossRefGoogle Scholar
  154. 154.
    Desgrippes A, Izadifar V, Assailly J, Fontaine E, Beurton D. 2000. Diagnosis and prediction of recurrence and progression in superficial bladder cancers with DNA image cytometry and urinary cytology. BJU Int 85:434–436.PubMedCrossRefGoogle Scholar
  155. 155.
    deVere White RW, Deitch AD, Daneshmand S, Blumenstein B, Lowe BA, Sagalowsky AI, Smith JA Jr, Schellhammer PF, Stanisic TH, Grossman HB, Messing E, Crissman JD, Crawford ED. 2000. Eur Urol 37:595–600.PubMedCrossRefGoogle Scholar
  156. 156.
    Ioakim-Liossi A, Pantazopoulos D, Karakitsos P, Athanassiadou P, Aroni K, Chourdakis N, Giachnaki A, Athanassiades P. 2000.Cytopathology 11:96–103.PubMedCrossRefGoogle Scholar
  157. 157.
    Zhao J, Richter J, Wagner U, Roth B, Schraml P, Zellweger T, Ackermann D, Schmid U, Moch H, Mihatsch MJ, Gasser TC, Sauter G. 1999. Chromosomal imbalances in noninvasive papillary bladder neoplasms (pTa). Cancer Res 59:4658–4661.PubMedGoogle Scholar
  158. 158.
    Toma V, Hauri D, Schmid U, Ackermann D, Maurer R, Alund G, Knonagel H, Rist M, Gasser TC, Sauter G, Roth J. 1999. Focal loss of CD44 variant protein expression is related to recurrence in superficial bladder carcinoma. Am J Pathol 155:1427–1432.PubMedCrossRefGoogle Scholar
  159. 159.
    Baffa R, Gomella LG, Vecchione A, Bassi P, Mimori K, Sedor J, Calviello CM, Gardiman M, Minimo C, Strup SE, McCue PA, Kovatich AJ, Pagano F, Huebner K, Croce CM. 2000. Loss of FHIT expression in transitional cell carcinoma of the urinary bladder. Am J Pathol 156:419–424.PubMedCrossRefGoogle Scholar
  160. 160.
    Friedrich MG, Erbersdobler A, Schwaibold H, Conrad S, Huland E, Huland H. 2000. Detection of loss of heterozygosity in the p53 tumor-suppressor gene with PCR in the urine of patients with bladder cancer. J Urol 163:1039–1042.PubMedCrossRefGoogle Scholar
  161. 161.
    Czerniak B, Li L, Chaturvedi V, Ro JY, Johnston DA, Hodges S, Benedict WF. 2000. Genetic modeling of human urinary bladder carcinogenesis. Genes Chromosomes Cancer 27:392–402.PubMedCrossRefGoogle Scholar
  162. 162.
    Bohm M, Kleine-Besten R, Wieland I. 2000. Loss of heterozygosity analysis on chromosome 5p defines 5p13–12 as the critical region involved in tumor progression of bladder carcinomas. Int J Cancer 89:194–197.PubMedCrossRefGoogle Scholar
  163. 163.
    Choi C, Kim MH, Juhng SW, Oh BR. 2000. Loss of heterozygosity at chromosome segments 8p22 and 8p11.2–21.1 in transitional-cell carcinoma of the urinary bladder. Int J Cancer 86:501–505.PubMedCrossRefGoogle Scholar
  164. 164.
    Hartmann A, Rosner U, Schlake G, Dietmaier W, Zaak D, Hofstaedter F, Knuechel R. 2000. Clonality and genetic divergence in multifocal low-grade superficial urothelial carcinoma as determined by chromosome 9 and p53 deletion analysis. Lab Invest 2000 May;80:709–718.CrossRefGoogle Scholar
  165. 165.
    Grossman HB, Liebert M, Antelo M, Dinney CP, Hu SX, Palmer JL, Benedict WF. 1998 p53 and RB expression predict progression in T1 bladder cancer. Clin Cancer Res 4:829–834.PubMedGoogle Scholar
  166. 166.
    Cote RJ, Dunn MD, Chatterjee SJ, Stein JP, Shi SR, Tran QC, Hu SX, Xu HJ, Groshen S, Taylor CR, Skinner DG, Benedict WF. 1998. Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53. Cancer Res 58:1090–1094.PubMedGoogle Scholar
  167. 167.
    Wada T, Louhelainen J, Hemminki K, Adolfsson I, Wijkstrom H, Norming U, Borgstrom E, Hansson J, Sandstedt B, Steineck G. 2000. Bladder cancer: allelic deletions at and around the retinoblastoma tumor suppressor gene in relation to stage and grade. Clin Cancer Res 6:610–615.PubMedGoogle Scholar
  168. 168.
    Niehans GA, Kratzke RA, Froberg MK, Aeppli DM, Nguyen PL, Geradts J. 1999. GI checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder. Br J Cancer 80:1175–1184.PubMedCrossRefGoogle Scholar
  169. 169.
    Benedict WF, Lerner SP, Zhou J, Shen X, Tokunaga H, Czemiak B. 1999. Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer. Oncogene I8:1197–1203.CrossRefGoogle Scholar
  170. 170.
    Chow NH, Liu HS, Lee EI, Chang CJ, Chan SH, Cheng HL, Tzai TS, Lin JS. 1997. Significance of urinary epidermal growth factor and its receptor expression in human bladder cancer. Anticancer Res 17:1293–1296.PubMedGoogle Scholar
  171. 171.
    Turkeri LN, Erton ML, Cevik I, Akdas A. 1998. Impact of the expression of epidermal growth factor, transforming growth factor alpha, and epidermal growth factor receptor on the prognosis of superficial bladder cancer. Urology 51:645–649.PubMedCrossRefGoogle Scholar
  172. 172.
    Thogersen VB, Jorgensen PE, Sorensen BS, Bross P, Orntoft T, Wolf H, Nexo E. 1999. Expression of transforming growth factor alpha and epidermal growth factor receptor in human bladder cancer. Scand J Clin Lab Invest 59:267–277.PubMedCrossRefGoogle Scholar
  173. 173.
    Sriplakich S, Jahnson S, Karlsson MG. 1999. Epidermal growth factor receptor expression: predictive value for the outcome after cystectomy for bladder cancer? BJU Int 83:498–503.PubMedCrossRefGoogle Scholar
  174. 174.
    Liukkonen T, Rajala P, Raitanen M, Rintala E, Kaasinen E, Lipponen P. 1999. Prognostic value of MIB-1 score, p53, EGFr, mitotic index and papillary status in primary superficial(Stage pTa/T1) bladder cancer: a prospective comparative study. The Finnbladder Group. Eur Urol 36:393–400.PubMedCrossRefGoogle Scholar
  175. 175.
    Juhl BR. 1994. Blood group antigens in transitional cell tumours of the urinary bladder. An immunohistochemical study. Dan Med Bull 141:1–11.Google Scholar
  176. 176.
    Loy TS, Alexander CJ, Calaluce RD. 1995. Lewis X antigen immunostaining in the diagnosis of transitional cell carcinoma. Mod Pathol 8:587–590.PubMedGoogle Scholar
  177. 177.
    Konety BR, Ballou B, Jaffe R, Singh J, Reiland J, Hakala TR. 1997. Expression of SSEA1 (Lewis(x)) on transitional cell carcinoma of the bladder. Urol Int 58:69–74.PubMedCrossRefGoogle Scholar
  178. 178.
    Planz B, Striepecke E, Jakse G, Bocking A. 1998. Use of Lewis X antigen and deoxyribonucleic acid image cytometry to increase sensitivity of urinary cytology in transitional cell carcinoma of the bladder. J Urol 159:384–387; discussion 387–388.PubMedCrossRefGoogle Scholar
  179. 179.
    Pode D, Golijanin D, Sherman Y, Lebensart P, Shapiro A. 1998. Immunostaining of Lewis X in cells from voided urine, cytopathology and ultrasound for noninvasive detection of bladder tumors. J Urol 159:389–392; discussion 393.PubMedCrossRefGoogle Scholar
  180. 180.
    Kirollos MM, McDermott S, Bradbrook RA. 1998. Bladder tumor markers: need, nature and application. 2. Tumor and tumor-associated antigens. Int Urogynecol J Pelvic Floor Dysfunct 9:228–235.PubMedCrossRefGoogle Scholar
  181. 181.
    Cohen MB, Griebling TL, Ahaghotu CA, Rokhlin OW, Ross IS. 1997. Cellular adhesion molecules in urologic malignancies. Am J Clin Pathol 107:56–63.PubMedGoogle Scholar
  182. 182.
    Imo T, Koshida K, Endo Y, Uchibayashi T, Sasaki T, Namiki M. 1999. Dominant role of E-cadherin in the progression of bladder cancer. J Urol 161:692–698.CrossRefGoogle Scholar
  183. 183.
    Syrigos KN, Harrington KJ, Pignatelli M. 1999. Role of adhesion molecules in bladder cancer: an important part of the jigsaw. Urology 53:428–434.PubMedCrossRefGoogle Scholar
  184. 184.
    Grossman HB, Lee C, Bromberg J, Liebert M. 2000. Expression of the alpha6beta4 integrin provides prognostic information in bladder cancer. Oncol Rep 7:13–16.PubMedGoogle Scholar
  185. 185.
    Rao JY, Bonner RB, Hurst RE, Liang YY, Reznikoff CA, Hemstreet GP 3rd. 1997. Quantitative changes in cytoskeletal and nuclear actins during cellular transformation. Int J Cancer 70:423–429.PubMedCrossRefGoogle Scholar
  186. 186.
    Honda K, Yamada T, Endo R, Ino Y, Gotoh M, Tsuda H, Yamada Y, Chiba H, Hirohashi S. 1998. Actinin-4, a novel actin-bundling protein associated with cell motility and cancer invasion. J Cell Biol 140:1383–1393, erratum 143(1):following 276.PubMedCrossRefGoogle Scholar
  187. 187.
    Hemstreet GP 3rd, Rao J, Hurst RE, Bonner RB, Mellott JE, Rooker GM. 1999. Biomarkers in monitoring for efficacy of immunotherapy and chemoprevention of bladder cancer with dimethylsulfoxide. Cancer Detect Prey 23:163–171.CrossRefGoogle Scholar
  188. 188.
    Beer DG, Stoner GD. 1998. Clinical models of chemoprevention for the esophagus. Hematol Oncol Clin North Am 12:1055–1077.PubMedCrossRefGoogle Scholar
  189. 189.
    Heath EI, Limburg PJ, Hawk ET, Forastiere AA. 2000. Adenocarcinoma of the esophagus: risk factors and prevention. Oncology 14:507–514; discussion 518–520, 522–523.Google Scholar
  190. 190.
    Bosetti C, La Vecchia C, Talamini R, Simonato L, Zambon P, Negri E, Trichopoulos D, Lagiou P, Bardini R, Franceschi S. 2000. Food groups and risk of squamous cell esophageal cancer in Northern Italy. Int J Cancer 87:289–294.PubMedCrossRefGoogle Scholar
  191. 191.
    Roth MJ, Guo-Qing W, Lewin KJ, Ning L, Dawsey SM, Wesley MN, Giffen C, YongQiang X, Maher MM, Taylor PR. 1998. Histopathologic changes seen in esophagectomy specimens from the high-risk region of Linxian, China: potential clues to an etiologic exposure? Hum Pathol 29:1294–1298.PubMedCrossRefGoogle Scholar
  192. 192.
    Reynolds JC, Waronker M, Pacquing MS, Yassin RR. 1999. Barrett’s esophagus. Reducing the risk of progression to adenocarcinoma. Gastroenterol Clin North Am 28:917–945.PubMedCrossRefGoogle Scholar
  193. 193.
    Koop H. 2000. Reflux disease and Barrett’s esophagus. Endoscopy 32:101–107.Google Scholar
  194. 194.
    Li SD, Mobarhan S. 2000. Association between body mass index and adenocarcinoma of the esophagus and gastric cardia. Nutr Rev 58(2 Pt 1):54–56.PubMedGoogle Scholar
  195. 195.
    Chow WH, Blot WJ, Vaughan TL, Risch HA, Gammon MD, Stanford JL, Dubrow R, Schoenberg JB, Mayne ST, Farrow DC, Ahsan H, West AB, Rotterdam H, Niwa S, Fraumeni JF Jr. 1998. Body mass index and risk of adenocarcinomas of the esophagus and gastric cardia. J Natl Cancer Inst 90:150–155.PubMedCrossRefGoogle Scholar
  196. 196.
    Blot WJ, McLaughlin JK. 1999. The changing epidemiology of esophageal cancer. Semin Oncol 26(5 Suppl 15):2–8.PubMedGoogle Scholar
  197. 197.
    Werner M, Mueller J, Watch A, Holler H. 1999. The molecular pathology of Barrett’s esophagus. Histol Histopathol 14:553–559.PubMedGoogle Scholar
  198. 198.
    Polkowski W, Baak JP, van Lanschot JJ, Meijer GA, Schuurmans LT, Ten Kate FJ, Obertop H, Offerhaus GJ. 1998. Clinical decision making in Barrett’s oesophagus can be supported by computerized immunoquantitation and morphometry of features associated with proliferation and differentiation. J Pathol 184:161–168.PubMedCrossRefGoogle Scholar
  199. 199.
    Lindholm J, Rubio CA, Kato Y, Hata J. 1989. A morphometric method to discriminate normal from dysplastic/carcinoma in situ squamous epithelium in the human esophagus. Pathol Res Pract 184:297–305.PubMedCrossRefGoogle Scholar
  200. 200.
    Boone CW, Bacus JW, Bacus JV, Steele VE, Kelloff GJ. 1997. Properties of intraepithelial neoplasia relevant to cancer chemoprevention and to the development of surrogate end points for clinical trials. Proc Soc Exp Biol Med 216:151–165.PubMedGoogle Scholar
  201. 201.
    Younes M, Lechago J, Chakraborty S, Ostrowski M, Bridges M, Meriano F, Solcher D, Barroso A, Whitman D, Schwartz J, Johnson C, Schmulen AC, Verm R, Balsaver A, Carlson N, Ertant A. 2000. Relationship between dysplasia, p53 protein accumulation, DNA ploidy, and Glutl overexpression in Barrett metaplasia. Scand J Gastroenterol 35:131–137.PubMedCrossRefGoogle Scholar
  202. 202.
    Gimenez A, Minguela A, de Haro LM, Parrilla P, Bermejo J, Perez D, Garcia AM, Ortiz MA, Molina J, Alvarez R. 2000. DNA ploidy status and proliferative activity as markers of malignant potential in Barrett’s esophagus: flow cytometric study using routinely paraffin-embedded tissue. World J Surg 24:72–77.PubMedCrossRefGoogle Scholar
  203. 203.
    Mueller J, Werner M, Siewert JR. 2000. Malignant progression in Barrett’s esophagus: pathology and molecular biology. Recent Results Cancer Res 155:29–41.PubMedCrossRefGoogle Scholar
  204. 204.
    al-Kasspooles M, Moore JH, Orringer MB, Beer DG. 1993. Amplification and over-expression of the EGFR and erbB-2 genes in human esophageal adenocarcinomas. Int J Cancer 54:213–219.PubMedCrossRefGoogle Scholar
  205. 205.
    Yacoub L, Goldman H, Odze RD. 1997. Transforming growth factor-alpha, epidermal growth factor receptor, and MiB-1 expression in Barrett’s-associated neoplasia: correlation with prognosis. Mod Pathol 10:105–112.PubMedGoogle Scholar
  206. 206.
    Ouatu-Lascar R, Fitzgerald RC, Triadafilopoulos G. 1999. Differentiation and proliferation in Barrett’s esophagus and the effects of acid suppression. Gastroenterology 117:327–335.PubMedCrossRefGoogle Scholar
  207. 207.
    Ferrando I, Ferrando J, Reig G, Navarro P, Llombart A, Minguez M, Mora F, Benages A. 1998. Barrett’s esophagus, markers to distinguish risk groups. Rev Esp Enferm Dig 90:431–440.PubMedGoogle Scholar
  208. 208.
    Kim R, Clarke MR, Melhem MF, Young MA, Vanbibber MM, Safatle-Ribeiro AV, Ribeiro U Jr, Reynolds JC. 1997. Expression of p53, PCNA, and C-erbB-2 in Barrett’s metaplasia and adenocarcinoma. Dig Dis Sci 42:2453–2462.PubMedCrossRefGoogle Scholar
  209. 209.
    Younes M, Lechago J, Ertan A, Finnie D, Younes A. 2000. Decreased expression of Fas (CD95/APOI) associated with goblet cell metaplasia in Barrett’s esophagus. Hum Pathol 31:434–438.PubMedCrossRefGoogle Scholar
  210. 210.
    Canavan TP, Doshi NR. 2000. Cervical cancer. Am Fam Physician 261:1369–1376.Google Scholar
  211. 211.
    zur Hausen H. 1999. Papillomaviruses in human cancers. Proc Assoc Am Physicians 111:581–587.PubMedCrossRefGoogle Scholar
  212. 212.
    Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Munoz N. 1999. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189:12–19.PubMedCrossRefGoogle Scholar
  213. 213.
    Schoell WM, Janicek MF, Mirhashemi R. 1999. Epidemiology and biology of cervical cancer. Semin Surg Oncol 16:203–211.PubMedCrossRefGoogle Scholar
  214. 214.
    Haverkos H, Rohrer M, Pickworth W. 2000. The cause of invasive cervical cancer could be multifactorial. Biomed Pharmacother 54:54–59.PubMedCrossRefGoogle Scholar
  215. 215.
    Mitchell MF, Hittelman WK, Lotan R, Nishioka K, Tortolero-Luna G, Richards-Kortum R, Wharton JT, Hong WK. 1995. Chemoprevention trials and surrogate end point biomarkers in the cervix. Cancer 76(10 Suppl):1956–1977.PubMedCrossRefGoogle Scholar
  216. 216.
    zur Hausen H. 2000. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 92:690–698.PubMedCrossRefGoogle Scholar
  217. 217.
    zur Hausen H. 1996. Papillomavirus infections--a major cause of human cancers. Biochim Biophys Acta 1288:F55–78.PubMedGoogle Scholar
  218. 218.
    Busmanis I. 1998. Biomarkers in carcinoma of the cervix: emphasis on tissue-related factors and their potential prognostic factors. Ann Acad Med Singapore 27:671–675.PubMedGoogle Scholar
  219. 219.
    Heatley MK. 1998. What is the value of proliferation markers in the normal and neoplastic cervix? Histol Histopathol 13:249–254.PubMedGoogle Scholar
  220. 220.
    Poulin N, Boiko I, MacAulay C, Boone C, Nishioka K, Hittelman W, Mitchell MF. 1999. Nuclear morphometry as an intermediate endpoint biomarker in chemoprevention of cervical carcinoma using alpha-difluoromethylornithine. Cytometry 38:214–223.PubMedCrossRefGoogle Scholar
  221. 221.
    Magtibay PM, Perrone JF, Stanhope CR, Katzmann JA, Keeney GL, Li H. 1999. Flow cytometric DNA analysis of early stage adenocarcinoma of the cervix. Gynecol Oncol 75:242–247.PubMedCrossRefGoogle Scholar
  222. 222.
    Lazo PA. 1999. The molecular genetics of cervical carcinoma. Br J Cancer 1999 Aug;80:2008–2018.Google Scholar
  223. 223.
    Hu W, Mitchell MF, Boiko IV, Linares A, Kim HG, Malpica A, Tortolero-Luna G, Hittelman WN. 1997. Progressive dysregulation of proliferation during cervical carcinogenesis as measured by MPM-2 antibody staining. Cancer Epidemiol Biomarkers Prey 6:711–718.Google Scholar
  224. 224.
    Smela M, Chosia M, Domagala W. 1996. Proliferation cell nuclear antigen (PCNA) expression in cervical intraepithelial neoplasia (CIN). An immunohistochemical study. Pol J Pathol 47:171–174.PubMedGoogle Scholar
  225. 225.
    Lohr F, Wenz F, Haas S, Flentje M. 1995. Comparison of proliferating cell nuclear antigen (PCNA) staining and BrdUrd-labelling index under different proliferative conditions in vitro by flow cytometry. Cell Prolif 28:93–104.PubMedCrossRefGoogle Scholar
  226. 226.
    Raju GC. 1994. Expression of the proliferating cell nuclear antigen in cervical neoplasia. Int J Gynecol Pathol 13:337–341.PubMedCrossRefGoogle Scholar
  227. 227.
    Mittal K. 1999. Utility of proliferation-associated marker MIB-1 in evaluating lesions of the uterine cervix. Adv Mat Pathol 6:177–185.CrossRefGoogle Scholar
  228. 228.
    Boiko IV, Mitchell MF, Hu W, Pandey DK, Mathevet P, Malpica A, Hittelman WN. 1998. Epidermal growth factor receptor expression in cervical intraepithelial neoplasia and its modulation during an alpha-difluoromethylomithine chemoprevention trial. Clin Cancer Res 4:1383–1391.PubMedGoogle Scholar
  229. 229.
    Maddox P, Sasieni P, Szarewski A, Anderson M, Hanby A. 1999. Differential expression of keratins 10, 17, and 19 in normal cervical epithelium, cervical intraepithelial neoplasia, and cervical carcinoma. J Clin Pathol 52:41–46.PubMedCrossRefGoogle Scholar
  230. 230.
    Dimitrakakis C, Kymionis G, Diakomanolis E, Papaspyrou I, Rodolakis A, Arzimanoglou I, Leandros E, Michalas S. 2000. The possible role of p53 and bcl-2 expression in cervical carcinomas and their premalignant lesions. Gynecol Oncol 77:129–136.PubMedCrossRefGoogle Scholar
  231. 231.
    Ferrandina G, Mozzetti S, Marone M, Fagotti A, Macchia G, Mancuso S, Scambia G. 2000. Bcl-2, bax, bcl-x(L) and bcl-x(S) expression in neoplastic and normal cervical tissue. Cancer Lett 155:19–27.PubMedCrossRefGoogle Scholar
  232. 232.
    Ngan HY, Liu SS, Yu H, Liu KL, Cheung AN. 1999. Proto-oncogenes and p53 protein expression in normal cervical stratified squamous epithelium and cervical intra-epithelial neoplasia. Eur 1 Cancer 35:1546–1550.CrossRefGoogle Scholar
  233. 233.
    Xu XC, Mitchell MF, Silva E, Jetten A, Lotan R. 1999. Decreased expression of retinoic acid receptors, transforming growth factor beta, involucrin, and comifin in cervical intraepithelial neoplasia. Clin Cancer Res 5:1503–1508.PubMedGoogle Scholar
  234. 234.
    Glogau RG. 2000. The risk of progression to invasive disease. J Am Acad Dermatol 42(1 Pt 2):23–24.PubMedCrossRefGoogle Scholar
  235. 235.
    Leffell DJ. 2000. The scientific basis of skin cancer. J Am Acad Dermatol 42(1 Pt 2):18–22.PubMedCrossRefGoogle Scholar
  236. 236.
    Cohn BA. 2000. From sunlight to actinic keratosis to squamous cell carcinoma. J Am Acad Dermatol 42(1 Pt 1):143–144.PubMedCrossRefGoogle Scholar
  237. 237.
    Greene MH. 1999. The genetics of hereditary melanoma and nevi. 1998 update. Cancer 86(11 Suppl):2464–2477.PubMedCrossRefGoogle Scholar
  238. 238.
    Moon TE, Levine N, Cartmel B, Bangert J, Rodney S, Schreiber M, Peng YM, Ritenbaugh C, Meyskens F, Alberts D. 1995. Design and recruitment for retinoid skin cancer prevention (SKICAP) trials. The Southwest Skin Cancer Prevention Study Group. Cancer Epidemiol Biomarkers Prey 4:661–669.Google Scholar
  239. 239.
    Moon TE, Levine N, Cartmel B, Bangert IL. 1995. Retinoids in prevention of skin cancer. Cancer Lett 114:203–205.CrossRefGoogle Scholar
  240. 240.
    Stam-Posthuma JJ, Vink J, le Cessie S, Bruijn IA, Bergman W, Pavel S. 1998. Effect of topical tretinoin under occlusion on atypical naevi. Melanoma Res 8:539–548.PubMedCrossRefGoogle Scholar
  241. 241.
    Modiano MR, Dalton WS, Lippman SM, Joffe L, Booth AR, Meyskens FL Jr. 1990. Phase II study of fenretinide (N-[4-hydroxyphenyl]retinamide) in advanced breast cancer and melanoma. Invest New Drugs 8:317–319.PubMedCrossRefGoogle Scholar
  242. 242.
    Meyskens FL Jr, Liu PY, Tuthill RJ, Sondak VK, Fletcher WS, Jewell WR, Samlowski W, Balcerzak SP, Rector DJ, Noyes RD, et al. 1994. Randomized trial of vitamin A versus observation as adjuvant therapy in high-risk primary malignant melanoma: a Southwest Oncology Group study. J Clin Oncol 12:2060–2065.PubMedGoogle Scholar
  243. 243.
    Einspahr J, Alberts DS, Aickin M, Welch K, Bozzo P, Grogan T, Nelson M. 1997. Expression of p53 protein in actinic keratosis, adjacent, normal-appearing, and non-sunexposed human skin. Cancer Epidemiol Biomarkers Prey 6:583–587.Google Scholar
  244. 244.
    Brash DE, Ziegler A, Jonason AS, Simon JA, Kunala S, Leffell DJ. 1996. Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion. J Investig Dermatol Symp Proc 1:136–142.PubMedGoogle Scholar
  245. 245.
    Nelson MA, Einspahr JG, Alberts DS, Balfour CA, Wymer JA, Welch KL, Salasche SJ, Bangert JL, Grogan TM, Bozzo PO. 1994. Analysis of the p53 gene in human precancerous actinic keratosis lesions and squamous cell cancers. Cancer Lett 85:23–29.PubMedCrossRefGoogle Scholar
  246. 246.
    Lu S, Tiekso J, Hietanen S, Syrjanen K, Havu VK, Syrjanen S. 1999. Expression of cell-cycle proteins p53, p21 (WAF-1), PCNA and Ki-67 in benign, premalignant and malignant skin lesions with implicated HPV involvement. Acta Derm Venereol 79:268–273.PubMedCrossRefGoogle Scholar
  247. 247.
    Kawahira K. 1999. Immunohistochemical staining of proliferating cell nuclear antigen (PCNA) in malignant and nonmalignant skin diseases. Arch Dermatol Res 291:413–418.PubMedCrossRefGoogle Scholar
  248. 248.
    Tsuji T, Kitajima S, Koashi Y. 1998. Expression of proliferating cell nuclear antigen (PCNA) and apoptosis related antigen (LeY) in epithelial skin tumors. Am J Dermatopathol 20:164–169.PubMedCrossRefGoogle Scholar
  249. 249.
    Barrett TL, Smith KJ, Hodge JJ, Butler R, Hall FW, Skelton FIG. 1997. Immunohistochemical nuclear staining for p53, PCNA, and Ki-67 in different histologic variants of basal cell carcinoma. J Am Acad Dermatol 37(3 Pt 1):430–437.PubMedCrossRefGoogle Scholar
  250. 250.
    Yuspa SH. 1998. The pathogenesis of squamous cell cancer: lessons learned from studies of skin carcinogenesis. J Dermatol Sci 17:1–7.PubMedCrossRefGoogle Scholar
  251. 251.
    Gold LI, Jussila T, Fusenig NE, Stenback F. 2000. TGF-beta isoforms are differentially expressed in increasing malignant grades of HaCaT keratinocytes, suggesting separate roles in skin carcinogenesis. J Pathol 190:579–588.PubMedCrossRefGoogle Scholar
  252. 252.
    Akhurst RJ, Balmain A. 1999. Genetic events and the role of TGF beta in epithelial tumour progression. J Pathol 187:82–90.PubMedCrossRefGoogle Scholar
  253. 253.
    Hoon DS, Bostick P, Kuo C, Okamoto T, Wang HJ, Elashoff R, Morton DL. 2000. Molecular markers in blood as surrogate prognostic indicators of melanoma recurrence. Cancer Res 60:2253–2257.PubMedGoogle Scholar
  254. 254.
    Williams RA, Baak JP, Meijer GA, Charlton IG. 1999. DNA ploidy and nuclear morphometry for the classification of dysplastic nevi. Anal Quant Cytol Histol 21:437–444.PubMedGoogle Scholar
  255. 255.
    Happle R. 1999. Loss of heterozygosity in human skin. J Am Acad Dermatol 41(2 Pt 1):143–164.PubMedCrossRefGoogle Scholar
  256. 256.
    Rubben A, Babilas P, Baron JM, Hofheinz A, Neis M, Sels F, Sporkert M. 2000. Analysis of tumor cell evolution in a melanoma: evidence of mutational and selective pressure for loss of pl6ink4 and for microsatellite instability. J Invest Dermatol 114:14–20.PubMedCrossRefGoogle Scholar
  257. 257.
    Birindelli S, Tragni G, Bartoli C, Ranzani GN, Rilke F, Pierotti MA, Pilotti S. 2000. Detection of microsatellite alterations in the spectrum of melanocytic nevi in patients with or without individual or family history of melanoma. Int J Cancer 86:255–261.PubMedCrossRefGoogle Scholar
  258. 258.
    Radhi JM. 1999. Malignant melanoma arising from nevi, p53, p16, and Bcl-2: expression in benign versus malignant components. J Cutan Med Surg 3:293–297.PubMedGoogle Scholar
  259. 259.
    Kaleem Z, Lind AC, Humphrey PA, Sueper RH, Swanson PE, Ritter JH, Wick MR. 2000. Concurrent Ki-67 and p53 immunolabeling in cutaneous melanocytic neoplasms: an adjunct for recognition of the vertical growth phase in malignant melanomas? Mod Pathol 13:217–222.PubMedCrossRefGoogle Scholar
  260. 260.
    Straume O, Sviland L, Akslen LA. 2000. Loss of nuclear p16 protein expression correlates with increased tumor cell proliferation (Ki-67) and poor prognosis in patients with vertical growth phase melanoma. Clin Cancer Res 6:1845–1853.PubMedGoogle Scholar
  261. 261.
    Piepkorn M. 2000. Melanoma genetics: an update with focus on the CDKN2A(p16)/ARF tumor suppressors. J Am Acad Dermatol 42(5 Pt 1):705–722.PubMedCrossRefGoogle Scholar
  262. 262.
    Castellano M, Parmiani G. 1999. Genes involved in melanoma: an overview of INK4a and other loci. Melanoma Res 9:421–432.PubMedCrossRefGoogle Scholar
  263. 263.
    Greenwald P, Kelloff GJ. 1996. Principles of Chemoprevention, IARC Scientific Publication No. 139, Lyon, France: International Agency for Research on Cancer,. 13–23.Google Scholar
  264. 264.
    Yeh F-S, Shen K-N. 1986. Epidemiology and early diagnosis of primary liver cancer in China. Adv. Cancer Res. 47:297–329.CrossRefGoogle Scholar
  265. 265.
    Montesano R, Hainaut P, Wild CP. 1997. Hepatocellular carcinoma: from gene to public health. J Natl Cancer Inst 89:1844–1851.PubMedCrossRefGoogle Scholar
  266. 266.
    Robinson WS. 1994. Molecular events in the pathogenesis of hepadnavirus-associated hepatocellular carcinoma. Annu Rev Med 45:297–323.PubMedCrossRefGoogle Scholar
  267. 267.
    Idilman R, De Maria N, Colantoni A, Van Thiel DH. 1998. Pathogenesis of hepatitis B and C-induced hepatocellular carcinoma. J Viral Hepat 5:285–299.PubMedCrossRefGoogle Scholar
  268. 268.
    Chen CJ, Yu MW, Liaw YF. 1997. Epidemiological characteristics and risk factors of hepatocellular carcinoma. J Gastroenterol Hepatol 12:S294–308.PubMedCrossRefGoogle Scholar
  269. 269.
    Ross RK, Yuan JM, Yu MC, Wogan GN, Qian GS, Tu JT, Groopman JD, Gao YT, Henderson BE. 1992. Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. Lancet 339:943–946.PubMedCrossRefGoogle Scholar
  270. 270.
    Qian GS, Ross RK, Yu MC, Yuan JM, Gao YT, Henderson BE, Wogan GN, Groopman JD. 1994. A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People’s Republic of China. Cancer Epidemiol Biomarkers Prey 3:3–10.Google Scholar
  271. 271.
    Hussain SP, Harris CC. 2000. Molecular epidemiology and carcinogenesis: endogenous and exogenous carcinogens. Mutat Res 462:311–322.PubMedCrossRefGoogle Scholar
  272. 272.
    Su Q, Schroder CH, Otto G, Bannasch P. 2000. Overexpression of p53 protein is not directly related to hepatitis B x protein expression and is associated with neoplastic progression in hepatocellular carcinomas rather than hepatic preneoplasia. Mutat Res 2462:365–380.Google Scholar
  273. 273.
    Sato Y, Nakata K, Kato Y, Shima M, Ishii N, Koji T, Taketa K, Endo Y, Nagataki S. 1993. Early recognition of hepatocellular carcinoma based on altered profiles of alphafetoprotein. N Engl 1 Med 328:1802–1806.CrossRefGoogle Scholar
  274. 274.
    Taketa K, Endo Y, Sekiya C, Tanikawa K, Koji T, Taga H, Satomura S, Matsuura S, Kawai T, Hirai H. 1993. A collaborative study for the evaluation of lectin-reactive alphafetoproteins in early detection of hepatocellular carcinoma. Cancer Res 53:5419–5423.PubMedGoogle Scholar
  275. 275.
    Shiraki K, Takase K, Tameda Y, Hamada M, Kosaka Y, Nakano T. 1995. A clinical study of lectin-reactive alpha-fetoprotein as an early indicator of hepatocellular carcinoma in the follow-up of cirrhotic patients. Hepatology 22:802–807.PubMedCrossRefGoogle Scholar
  276. 276.
    Yamashita F, Tanaka M, Satomura S, Tanikawa K. 1996. Prognostic significance of Lens culinaris agglutinin A-reactive alpha-fetoprotein in small hepatocellular carcinomas. Gastroenterology 111:996–1001.PubMedCrossRefGoogle Scholar
  277. 277.
    Moriwaki H, Yasuda I, Shiratori Y, Uematsu T, Okuno M, Muto Y. 1997. Deletion of serum lectin-reactive alpha-fetoprotein by acyclic retinoid: a potent biomarker in the chemoprevention of second primary hepatoma. Clin Cancer Res 3:727–731.PubMedGoogle Scholar
  278. 278.
    Wang JS, Shen X, He X, Zhu YR, Zhang BC, Wang JB, Qian GS, Kuang SY, Zarba A, Egner PA, Jacobson LP, Munoz A, Helzlsouer KJ, Groopman JD, Kensler TW. 1999. Protective alterations in phase 1 and 2 metabolism of aflatoxin B1 by oltipraz in residents of Qidong, People’s Republic of China. J Natl Cancer Inst 91:347–354.PubMedCrossRefGoogle Scholar
  279. 279.
    Jackson PE, Groopman JD. Aflatoxin and liver cancer. Baillieres Best Pract Res Clin Gastroenterology 13:545–555.Google Scholar
  280. 280.
    Zhang BC, Zhu YR, Wang JB, Wu Y, Zhang QN, Qian GS, Kuang SY, Li YF, Fang X, Yu LY, De Flora S, Jacobson LP, Zarba A, Egner PA, He X, Wang JS, Chen B, Enger CL, Davidson NE, Gordon GB, Gorman MB, Prochaska HJ, Groopman JD, Munoz A, Kensler TW. 1997. Oltipraz chemoprevention trial in Qidong, Jiangsu Province, People’s Republic of China. J Cell Biochem (Suppl) 28–29:166–173.CrossRefGoogle Scholar
  281. 281.
    Kensler TW, He X, Otieno M, Egner PA, Jacobson LP, Chen B, Wang JS, Zhu YR, Zhang BC, Wang JB, Wu Y, Zhang QN, Qian GS, Kuang SY, Fang X, Li YF, Yu LY, Prochaska HJ, Davidson NE, Gordon GB, Gorman MB, Zarba A, Enger C, Munoz A, Helzlsouer KJ, et al 1998. Oltipraz chemoprevention trial in Qidong, People’s Republic of China: modulation of serum aflatoxin albumin adduct biomarkers. Cancer Epidemiol Biomarkers Prey 7:127–134.Google Scholar
  282. 282.
    Jacobson LP, Zhang BC, Zhu YR, Wang JB, Wu Y, Zhang QN, Yu LY, Qian GS, Kuang SY, Li YF, Fang X, Zarba A, Chen B, Enger C, Davidson NE, Gorman MB, Gordon GB, Prochaska HJ, Egner PA, Groopman JD, Munoz A, Helzlsouer KJ, Kensler TW. 1997. Oltipraz chemoprevention trial in Qidong, People’s Republic of China: study design and clinical outcomes. Cancer Epidemiol Biomarkers Prey 6:257–265.Google Scholar
  283. 283.
    Kensler TW, Gange SJ, Egner PA, Dolan PM, Munoz A, Groopman JD, Rogers AE, Roebuck BD. 1997. Predictive value of molecular dosimetry: individual versus group effects of oltipraz on aflatoxin-albumin adducts and risk of liver cancer. Cancer Epidemiol Biomarkers Prey 6:603–610.Google Scholar
  284. 284.
    Kawai H, Suda T, Aoyagi Y, Isokawa O, Mita Y, Waguri N, Kuroiwa T, Igarashi M, Tsukada K, Mori S, Shimizu T, Suzuki Y, Abe Y, Takahashi T, Nomoto M, Asakura H. 2000. Quantitative evaluation of genomic instability as a possible predictor for development of hepatocellular carcinoma: comparison of loss of heterozygosity and replication error. Hepatology 31:1246–1250.PubMedCrossRefGoogle Scholar
  285. 285.
    Suzuki K, Hirooka Y, Tsujitani S, Yamane Y, Ikeguchi M, Kaibara N. 2000. Relationship between loss of heterozygosity at microsatellite loci and computerized nuclear morphometry in hepatocellular carcinoma. Anticancer Res 20:1257–1262.PubMedGoogle Scholar
  286. 286.
    Okabe H, Ikai I, Matsuo K, Satoh S, Momoi H, Kamikawa T, Katsura N, Nishitai R, Takeyama 0, Fukumoto M, Yamaoka Y. 2000. Comprehensive allelotype study of hepatocellular carcinoma: potential differences in pathways to hepatocellular carcinoma between hepatitis B virus-positive and -negative tumors. Hepatology 31:1073–1079.PubMedCrossRefGoogle Scholar
  287. 287.
    Macdonald GA, Greenson JK, Saito K, Cherian SP, Appelman HD, Boland CR. 1998. Microsatellite instability and loss of heterozygosity at DNA mismatch repair gene loci occurs during hepatic carcinogenesis. Hepatology 28:90–97.PubMedCrossRefGoogle Scholar
  288. 288.
    Wu X, Gu J, Patt Y, Hassan M, Spitz MR, Beasley RP, Hwang LY. 1998. Mutagen sensitivity as a susceptibility marker for human hepatocellular carcinoma. Cancer Epidemiol Biomarkers Prey 7:567–570.Google Scholar
  289. 289.
    Tiniakos DG, Brunt EM. 1999. Proliferating cell nuclear antigen and Ki-67 labeling in hepatocellular nodules: a comparative study. Liver 19:58–68.PubMedCrossRefGoogle Scholar
  290. 290.
    Wu PC, Lau VK, Fang JW, Lai VC, Lai CL, Lau JY. 1999. Imbalance between cell proliferation and cellular DNA fragmentation in hepatocellular carcinoma. Liver 19:444–451.PubMedCrossRefGoogle Scholar
  291. 291.
    Harada K, Shiota G, Kawasaki H. 1999. Transforming growth factor-alpha and epidermal growth factor receptor in chronic liver disease and hepatocellular carcinoma. Liver 19:318–325.PubMedCrossRefGoogle Scholar
  292. 292.
    Pezzuto JM. 1997. Plant-derived anticancer agents. Biochem Pharmacol 53:121–133.PubMedCrossRefGoogle Scholar
  293. 293.
    Pezzuto JM, Beecher CWW, Fong HHS, Farnsworth NR, Mehta RG, Moon RC, Hedayat S, Udeani GO, Moriarty RM, Kinghom AD. 1998. Discovery and characterization of natural product cancer chemopreventive agents. In: Atta-ur-Rahman and M. Iqbal (eds.), New Trends in Natural Product Chemistry, Harwood Academic Publishers: Chur, Switzerland, 95–107.Google Scholar
  294. 294.
    Pezzuto JM, Song LL, Lee SK, Shamon LA, Mata-Greenwood E, Jang J, Jeong HJ, Pisha E, Mehta RG, Kinghom AD. 1998. Bioassay methods useful for activity-guided isolation of natural product cancer chemopreventive agents. In: K Hostettmann, MP Gupta and A. Marston (eds.), Chemistry, Biological and Pharmacological Properties of Medicinal Plants from the Americas, Chur, Switzerland: Harwood Academic Publishers, 81–110.Google Scholar
  295. 295.
    Kinghom AD, Fong HHS, Farnsworth NR, Mehta RG, Moon RC, Moriarty RM, Pezzuto JM. 1998. Cancer chemopreventive agents discovered by activity-guided fractionation: a review. Curr Org Chem 2:597–612.Google Scholar
  296. 296.
    Shamon LA, Chen C, Mehta RG, Steele V, Moon RC, Pezzuto JM. 1994. A correlative approach for the identification of antimutagens that demonstrate chemopreventive activity. Anticancer Res 14:1775–1778.PubMedGoogle Scholar
  297. 297.
    Lee SK, Song L, Mata-Greenwood E, Kelloff GJ, Steele VE, Pezzuto JM. 1999. Modulation of in vitro biomarkers of the carcinogenic process by chemopreventive agents. Anticancer Res 19:35–44.PubMedGoogle Scholar
  298. 298.
    Gerhauser C, You M, Liu J, Moriarty RM, Hawthorne M, Mehta RG, Moon RC, Pezzuto JM. 1997. Cancer chemopreventive potential of sulforamate, a novel analogue of sulforaphane that induces phase 2 drug-metabolizing enzymes. Cancer Res 57:272–278.PubMedGoogle Scholar
  299. 299.
    Chang LC, Gerhauser C, Song L, Farnsworth NR, Pezzuto JM, Kinghorn AD. 1997. Activity-guided isolation of constituents of Tephrosia purpurea with the potential to induce the phase II enzyme, quinone reductase. J Nat Prod 60:869–873.PubMedCrossRefGoogle Scholar
  300. 300.
    Song LL, Kosmeder JW 2nd, Lee SK, Gerhauser C, Lantvit D, Moon RC, Moriarty RM, Pezzuto JM. 1999. Cancer chemopreventive activity mediated by 4’-bromoflavone, a potent inducer of phase II detoxification enzymes. Cancer Res 59:578–585.PubMedGoogle Scholar
  301. 301.
    Lee SK, Mbwambo ZH, Chung H, Luyengi L, Gamez EJ, Mehta RG, Kinghorn AD, Pezzuto JM. 1998. Evaluation of the antioxidant potential of natural products. Comb Chem High Throughput Screen 1:35–46.PubMedGoogle Scholar
  302. 302.
    Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218–220.Google Scholar
  303. 303.
    Subbaramaiah K, Chung WJ, Michaluart P, Telang N, Tanabe T, Inoue H, Jang M, Pezzuto JM, Dannenberg AL 1998. Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells. J Biol Chem 273:21875–21882.PubMedCrossRefGoogle Scholar
  304. 304.
    Gerhauser C, Mar W, Lee SK, Suh N, Luo Y, Kosmeder J, Luyengi L, Fong HH, Kinghorn AD, Moriarty RM, Mehta R, Constantinou A, Moon RC, Pezzuto JM. 1995. Rotenoids mediate potent cancer chemopreventive activity through transcriptional regulation of ornithine decarboxylase. Nature Med 1:260–266, erratum 1:598.Google Scholar
  305. 305.
    Lee SK, Pezzuto JM. 1999. Evaluation of the potential of cancer chemopreventive activity mediated by inhibition of 12–0-tetradecanoyl phorbol 13-acetate-induced ornithine decarboxylase activity. Arch Pharm Res 22:559–564.PubMedCrossRefGoogle Scholar
  306. 306.
    Pegg AE, Shantz LM, Coleman CS. 1995. Omithine decarboxylase as a target for chemoprevention. J Cell Biochem (Suppl) 22:132–138.CrossRefGoogle Scholar
  307. 307.
    Pisha E, Pezzuto JM. 1997. Cell-based assay for the determination of estrogenic and anti-estrogenic activities. Meth Cell Sci 19:37–43.CrossRefGoogle Scholar
  308. 308.
    Chang LC, Bhat KP, Pisha E, Kennelly EJ, Fong HH, Pezzuto JM, Kinghorn AD. 1998. Activity-guided isolation of steroidal alkaloid antiestrogen-binding site from Pachysandra procumbens. J Nat Prod 61:1257–1262.PubMedCrossRefGoogle Scholar
  309. 309.
    Jeong HJ, Shin YG, Kim IH, Pezzuto JM. 1999. Inhibition of aromatase activity by flavonoids. Arch Pharm Res 22:309–312.PubMedCrossRefGoogle Scholar
  310. 310.
    White EL, Ross LJ, Steele VE, Kelloff GJ, Hill DL. 1999. Screening of potential cancer preventing chemicals as aromatase inhibitors in an in vitro assay. Anticancer Res 19:1017–1020.PubMedGoogle Scholar
  311. 311.
    Suh N, Luyengi L, Fong HH, Kinghorn AD, Pezzuto JM. Discovery of natural product chemopreventive agents utilizing HL-60 cell differentiation as a model. Anticancer Res 15:233–239.Google Scholar
  312. 312.
    Luyengi L, Suh N, Fong HH, Pezzuto JM, Kinghorn AD. 1996. A lignan and four terpenoids from Brucea javanica that induce differentiation with cultured HL-60 promyelocytic leukemia cells. Phytochemistry 43:409–412.PubMedCrossRefGoogle Scholar
  313. 313.
    Ito A, Shamon LA, Yu BY, Mata-Greenwood E, Lee SK, van Breemen RB, Mehta RG, Farnsworth NR, Fong HHS, Pezzuto JM, Kinghorn AD. 1998. Antimutagenic constituents of Casimiroa edulis with potential cancer chemopreventive activity. J Agric Food Chem 46:3509–3516.CrossRefGoogle Scholar
  314. 314.
    Mehta RG, Moon RC. 1991. Characterization of effective chemopreventive agents in mammary gland in vitro using an initiation-promotion protocol. Anticancer Res 11:593–596.PubMedGoogle Scholar
  315. 315.
    Steele VE, Sharma S, Mehta R, Elmore E, Redpath L, Rudd C, Bagheri D, Sigman CC, Kelloff GJ. 1996. Use of in vitro assays to predict the efficacy of chemopreventive agents in whole animals. J Cell Biochem (Suppl) 26:29–53.CrossRefGoogle Scholar
  316. 316.
    Steele VE, Boone CW, Lubet RA, Crowell JA, Holmes CA, Sigman CC, Kelloff GJ 1999. Preclinical drug development paradigms for chemopreventives. Hematol Oncol Clin North Am 12:943–961.CrossRefGoogle Scholar
  317. 317.
    Sharma S, Stutzman JD, Kelloff GJ, Steele VE. 1994. Screening of potential chemopreventive agents using biochemical markers of carcinogenesis. Cancer Res 54:5848–5855.PubMedGoogle Scholar
  318. 318.
    Fischer SM, Baldwin JK, Adams LM. 1986. Effects of anti-promoters and strain of mouse on tumor promoter-induced oxidants in murine epidermal cells. Carcinogenesis 7:915–918.PubMedCrossRefGoogle Scholar
  319. 319.
    Prough RA, Webb SJ, Wu HQ, Lapenson DP, Waxman DJ. 1994. Induction of microsomal and peroxisomal enzymes by dehydroepiandrosterone and its reduced metabolite in rats. Cancer Res 54:2878–2886.PubMedGoogle Scholar
  320. 320.
    Kelloff GJ, Boone CW, Steele VE, Fay JR, Lubet RA, Crowell JA, Sigman CC. 1994. Mechanistic considerations in chemopreventive drug development. J Cell Biochem (Suppl) 20:1–24.CrossRefGoogle Scholar
  321. 321.
    Kelloff GJ, Fay JR, Steele VE, Lubet RA, Boone CW, Crowell JA, Sigman CC. 1996. Epidermal growth factor receptor tyrosine kinase inhibitors as potential cancer chemopreventives. Cancer Epidemiol Biomarkers Prey 5:657–666.Google Scholar
  322. 322.
    Lin JK, Chen YC, Huang YT, Lin-Shiau SY. 1997. Suppression of protein kinase C and nuclear oncogene expression as possible molecular mechanisms of cancer chemoprevention by apigenin and curcumin. J Cell Biochem (Suppl) 28–29:39–48.CrossRefGoogle Scholar
  323. 323.
    Yu SY, Ao P, Wang LM, Huang SL, Chen HC, Lu XP, Liu QY. 1988. Biochemical and cellular aspects of the anticancer activity of selenium. Biol Trace Elem Res 15:243–255.PubMedCrossRefGoogle Scholar
  324. 324.
    Kelloff GJ, Lubet RA, Fay JR, Steele VE, Boone CW, Crowell JA, Sigman CC. 1997. Famesyl protein transferase inhibitors as potential cancer chemopreventives. Cancer Epidemiol Biomarkers Prey 6:267–282.Google Scholar
  325. 325.
    Borek C, Morgan WF, Ong A, Cleaver JE. 1984. Inhibition of malignant transformation in vitro by inhibitors of poly(ADP-ribose) synthesis. Proc Natl Acad Sci USA 81:243–247.PubMedCrossRefGoogle Scholar
  326. 326.
    Kelloff GJ, Lieberman R, Steele VE, Boone CW, Lubet RA, Kopelov itch L, Malone WA, Crowell JA, Sigman CC. 1999. Chemoprevention of prostate cancer: concepts and strategies. Eur Urol 35:342–350.PubMedCrossRefGoogle Scholar
  327. 327.
    Rao KN. 1995. The significance of the cholesterol biosynthetic pathway in cell growth and carcinogenesis (review). Anticancer Res 15:309–314.PubMedGoogle Scholar
  328. 328.
    Agarwal B, Rao CV, Bhendwal S, Ramey WR, Shirin H, Reddy BS, Holt PR. 1999. Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac. Gastroenterology 117:838–847.PubMedCrossRefGoogle Scholar
  329. 329.
    Lingen MW. 1999. Angiogenesis in the development of head and neck cancer and its inhibition by chemopreventive agents. Crit Rev Oral Biol Med 10:153–164.PubMedCrossRefGoogle Scholar
  330. 330.
    Li M, Lotan R, Levin B, Tahara E, Lippman SM, Xu XC. Aspirin induction of apoptosis in esophageal cancer: a potential for chemoprevention. Cancer Epidemiol Biomarkers Prey 9:545–549.Google Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Jerome W. KosmederII
  • John M. Pezzuto

There are no affiliations available

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