Supportive Care in Cancer

, Volume 14, Issue 7, pp 713–731 | Cite as

Intestinal mucositis: the role of the Bcl-2 family, p53 and caspases in chemotherapy-induced damage

  • Joanne M. BowenEmail author
  • Rachel J. Gibson
  • Adrian G. Cummins
  • Dorothy M. K. Keefe
Review Article


Intestinal mucositis occurs as a consequence of cytotoxic treatment through multiple mechanisms including induction of crypt cell death (apoptosis) and cytostasis. The molecular control of these actions throughout the gastrointestinal tract has yet to be fully elucidated; however, they are known to involve p53, the Bcl-2 family and caspases. This review will provide an overview of current research as well as identify areas where gaps in knowledge exist.


Mucositis p53 Bcl-2 family caspases 


  1. 1.
    Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322–1326PubMedGoogle Scholar
  2. 2.
    Akgul C, Moulding DA, Edwards SW (2004) Alternative splicing of Bcl-2-related genes: functional consequences and potential therapeutic applications. Cell Mol Life Sci 61:2189–2199PubMedGoogle Scholar
  3. 3.
    Anilkumar TV, Sarraf CE, Hunt T, Alison MR (1992) The nature of cytotoxic drug-induced cell death in murine intestinal crypts. Br J Cancer 65:552–558PubMedGoogle Scholar
  4. 4.
    Antonsson B, Conti F, Ciavatta A, Montessuit S, Lewis S, Martinou I, Bernasconi L, Bernard A, Mermod JJ, Mazzei G, Maundrell K, Gambale F, Sadoul R, Martinou JC (1997) Inhibition of Bax channel-forming activity by Bcl-2. Science 277:370–372PubMedGoogle Scholar
  5. 5.
    Araki E, Ishikawa M, Iigo M, Koide T, Itabashi M, Hoshi A (1993) Relationship between development of diarrhea and the concentration of SN-38, an active metabolite of CPT-11, in the intestine and the blood plasma of athymic mice following intraperitoneal administration of CPT-11. Jpn J Cancer Res 84:697–702PubMedGoogle Scholar
  6. 6.
    Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281:1305–1308PubMedGoogle Scholar
  7. 7.
    Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B (1990) Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249:912–915PubMedGoogle Scholar
  8. 8.
    Bartek J, Lukas J (2003) DNA repair: damage alert. Nature 421:486–488PubMedGoogle Scholar
  9. 9.
    Beck PL, Wong JF, Li Y, Swaminathan S, Xavier RJ, Devaney KL, Podolsky DK (2004) Chemotherapy- and radiotherapy-induced intestinal damage is regulated by intestinal trefoil factor. Gastroenterology 126:796–808PubMedGoogle Scholar
  10. 10.
    Benchimol S (2001) p53-dependent pathways of apoptosis. Cell Death Differ 8:1049–1051PubMedGoogle Scholar
  11. 11.
    Booth D, Potten CS (2001) Protection against mucosal injury by growth factors and cytokines. J Natl Cancer Inst Monographs 29:16–20PubMedGoogle Scholar
  12. 12.
    Borner C (2003) The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions. Mol Immunol 39:615–647PubMedGoogle Scholar
  13. 13.
    Boushey RP, Yusta B, Drucker DJ (2001) Glucagon-like peptide (GLP)-2 reduces chemotherapy-associated mortality and enhances cell survival in cells expressing a transfected GLP-2 receptor. Cancer Res 61:687–693PubMedGoogle Scholar
  14. 14.
    Bradham CA, Qian T, Streetz C, Trautwein C, Brenner DA, Lemasters JJ (1998) The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release. Mol Cell Biol 18:6353–6364PubMedGoogle Scholar
  15. 15.
    Cao S, Black JD, Troutt AB, Rustum YM (1998) Interleukin 15 offers selective protection from irinotecan-induced intestinal toxicity in a preclinical animal model. Cancer Res 58:3270–3274PubMedGoogle Scholar
  16. 16.
    Catz SD, Johnson JL (2001) Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. Oncogene 20:7342–7351PubMedGoogle Scholar
  17. 17.
    Chao DT, Korsmeyer SJ (1998) BCL-2 family: regulators of cell death. Annu Rev Immunol 16:395–419PubMedGoogle Scholar
  18. 18.
    Chen C, Edelstein LC, Gelinas C (2000) The Rel/NF-kappaB family directly activates expression of the apoptosis inhibitor Bcl-x(L). Mol Cell Biol 20:2687–2695PubMedGoogle Scholar
  19. 19.
    Chernavsky AC, Rubio AE, Vanzulli S, Rubinstein N, de Rosa S, Fainboim L (2002) Evidences of the involvement of Bak, a member of the Bcl-2 family of proteins, in active coeliac disease. Autoimmunity 35:29–37PubMedGoogle Scholar
  20. 20.
    Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR (2004) Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303:1010–1014PubMedGoogle Scholar
  21. 21.
    Chu KU, Higashide S, Evers BM, Rajaraman S, Ishizuka J, Townsend CM, Thompson JC (1994) Bombesin improves survival from methotrexate-induced enterocolitis. Ann Surg 220:570–576; discussion 576–577PubMedGoogle Scholar
  22. 22.
    Cohen GM (1997) Caspases: the executioners of apoptosis. Biochem J 326:1–16PubMedGoogle Scholar
  23. 23.
    Cory S, Huang DC, Adams JM (2003) The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 22:8590–8607PubMedGoogle Scholar
  24. 24.
    Creagh EM, Conroy H, Martin SJ (2003) Caspase-activation pathways in apoptosis and immunity. Immunol Rev 193:10–21PubMedGoogle Scholar
  25. 25.
    Crompton M (1999) The mitochondrial permeability transition pore and its role in cell death. Biochem J 341:233–249PubMedGoogle Scholar
  26. 26.
    Culmsee C, Zhu X, Yu QS, Chan SL, Camandola S, Guo Z, Greig NH, Mattson MP (2001) A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide. J Neurochem 77:220–228PubMedGoogle Scholar
  27. 27.
    Decary S, Decesse JT, Ogryzko V, Reed JC, Naguibneva I, Harel-Bellan A, Cremisi CE (2002) The retinoblastoma protein binds the promoter of the survival gene bcl-2 and regulates its transcription in epithelial cells through transcription factor AP-2. Mol Cell Biol 22:7877–7888PubMedGoogle Scholar
  28. 28.
    Decker-Baumann C, Buhl K, Frohmuller S, von Herbay A, Dueck M, Schlag PM (1999) Reduction of chemotherapy-induced side-effects by parenteral glutamine supplementation in patients with metastatic colorectal cancer. Eur J Cancer 35:202–207PubMedGoogle Scholar
  29. 29.
    DeLeo AB, Jay G, Appella E, Dubois GC, Law LW, Old LJ (1979) Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse. Proc Natl Acad Sci U S A 76:2420–2424PubMedGoogle Scholar
  30. 30.
    Dippold WG, Jay G, DeLeo AB, Khoury G, Old LJ (1981) p53 transformation-related protein: detection by monoclonal antibody in mouse and human cells. Proc Natl Acad Sci U S A 78:1695–1699PubMedGoogle Scholar
  31. 31.
    Erster S, Mihara M, Kim RH, Petrenko O, Moll UM (2004). In vivo mitochondrial p53 translocation triggers a rapid first wave of cell death in response to DNA damage that can precede p53 target gene activation. Mol Cell Biol 24:6728–6741PubMedGoogle Scholar
  32. 32.
    Eskes R, Desagher S, Antonsson B, Martinou JC (2000) Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol Cell Biol 20:929–935PubMedGoogle Scholar
  33. 33.
    Fadeel B, Zhivotovsky B, Orrenius S (1999) All along the watchtower: on the regulation of apoptosis regulators. FASEB J 13:1647–1657PubMedGoogle Scholar
  34. 34.
    Finlay CA, HindsPW, Levine AJ (1989) The p53 proto-oncogene can act as a suppressor of transformation. Cell 57:1083–1093PubMedGoogle Scholar
  35. 35.
    Fleischer A, Rebollo A, Ayllon V (2003) BH3-only proteins: the lords of death. Arch Immunol Ther Exp 51:9–17Google Scholar
  36. 36.
    Foyouzi-Youssefi R, Arnaudeau S, Borner C, Kelley WL, Tschopp J, Lew DP, Demaurex N, Krause KH (2000) Bcl-2 decreases the free Ca2+ concentration within the endoplasmic reticulum. Proc Natl Acad Sci U S A 97:5723–5728PubMedGoogle Scholar
  37. 37.
    Funk MA, Baker DH (1991) Effect of soy products on methotrexate toxicity in rats. J Nutr 121:1684–1692PubMedGoogle Scholar
  38. 38.
    Gauthier R, Harnois C, Drolet JF, Reed JC, Vezina A, Vachon PH (2001) Human intestinal epithelial cell survival: differentiation state-specific control mechanisms. Am J Physiol Cell Physiol 280:C1540–C1554PubMedGoogle Scholar
  39. 39.
    Gauthier R, Laprise P, Cardin E, Harnois C, Plourde A, Reed JC, Vezina A, Vachon PH (2001) Differential sensitivity to apoptosis between the human small and large intestinal mucosae: linkage with segment-specific regulation of BCL-2 homologs and involvement of signaling pathways. J Cell Biochem 82:339–355PubMedGoogle Scholar
  40. 40.
    Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501PubMedGoogle Scholar
  41. 41.
    Ghribi O, DeWitt DA, Forbes MS, Herman MM, Savory J (2001) Co-involvement of mitochondria and endoplasmic reticulum in regulation of apoptosis: changes in cytochrome c, Bcl-2 and Bax in the hippocampus of aluminum-treated rabbits. Brain Res 903:66–73PubMedGoogle Scholar
  42. 42.
    Gibson LF, Fortney J, Magro G, Ericson SG, Lynch JP, Landreth KS (1999) Regulation of BAX and BCL-2 expression in breast cancer cells by chemotherapy. Breast Cancer Res Treat 55:107–117PubMedGoogle Scholar
  43. 43.
    Gibson RJ, Keefe DM, Clarke JM, Regester GO, Thompson FM, Goland GJ, Edwards BG, Cummins AG (2002) The effect of keratinocyte growth factor on tumour growth and small intestinal mucositis after chemotherapy in the rat with breast cancer. Cancer Chemother Pharmacol 50:53–58PubMedGoogle Scholar
  44. 44.
    Gibson RJ, Keefe DM, Thompson FM, Clarke JM, Goland GJ, Cummins AG (2002) Effect of interleukin-11 on ameliorating intestinal damage after methotrexate treatment of breast cancer in rats. Dig Dis Sci 47:2751–2757PubMedGoogle Scholar
  45. 45.
    Gibson RJ, Bowen JM, Inglis MR, Cummins AG, Keefe DM (2003) Irinotecan causes severe small intestinal damage, as well as colonic damage, in the rat with implanted breast cancer. J Gastroenterol Hepatol 18:1095–1100PubMedGoogle Scholar
  46. 46.
    Gibson RJ, Bowen JM, Keefe DM (2005) Palifermin reduces diarrhea and increases survival following irinotecan treatment in tumor-bearing DA rats. Int J Cancer 116:464–470PubMedGoogle Scholar
  47. 47.
    Govindarajan R (2002) Irinotecan/thalidomide in metastatic colorectal cancer. Oncology (Huntington) 16:23–26Google Scholar
  48. 48.
    Govindarajan R, Heaton KM, Broadwater R, Zeitlin A, Lang NP, Hauer-Jensen M (2000) Effect of thalidomide on gastrointestinal toxic effects of irinotecan. Lancet 356:566–567PubMedGoogle Scholar
  49. 49.
    Green D, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309–1312PubMedGoogle Scholar
  50. 50.
    Greider C, Chattopadhyay A, Parkhurst C, Yang E (2002) BCL-x(L) and BCL2 delay Myc-induced cell cycle entry through elevation of p27 and inhibition of G1 cyclin-dependent kinases. Oncogene 21:7765–7775PubMedGoogle Scholar
  51. 51.
    Gross A, McDonnell JM, Korsmeyer SJ (1999) BCL-2 family members and the mitochondria in apoptosis. Genes Dev 13:1899–1911PubMedGoogle Scholar
  52. 52.
    Grossmann J, Artinger M, Grasso AW, Kung HJ, Scholmerich J, Fiocchi C, Levine AD (2001) Hierarchical cleavage of focal adhesion kinase by caspases alters signal transduction during apoptosis of intestinal epithelial cells (comment). Gastroenterology 120:79–88PubMedGoogle Scholar
  53. 53.
    Haldar S, Jena N, Croce CM (1995) Inactivation of Bcl-2 by phosphorylation. Proc Natl Acad Sci U S A 92:4507–4511PubMedGoogle Scholar
  54. 54.
    Hall PA, Coates PJ, Ansari B, Hopwood D (1994) Regulation of cell number in the mammalian gastrointestinal tract: the importance of apoptosis. J Cell Sci 107:3569–3577PubMedGoogle Scholar
  55. 55.
    Hanada M, Aime-Sempe C, Sato T, Reed JC (1995) Structure–function analysis of Bcl-2 protein. Identification of conserved domains important for homodimerization with Bcl-2 and heterodimerization with Bax. J Biol Chem 270:11962–11969PubMedGoogle Scholar
  56. 56.
    Hannun YA (1997) Apoptosis and the dilemma of cancer chemotherapy. Blood 89:1845–1853PubMedGoogle Scholar
  57. 57.
    Hengartner MO (1999) Programmed cell death in the nematode C. elegans. Ann N Y Acad Sci 887:92–104PubMedGoogle Scholar
  58. 58.
    Hengartner MO, Horvitz HR (1994) The ins and outs of programmed cell death during C. elegans development. Philos Trans R Soc Lond B Biol Sci 345:243–246PubMedGoogle Scholar
  59. 59.
    Henry-Mowatt J, Dive C, Martinou JC, James D (2004) Role of mitochondrial membrane permeabilization in apoptosis and cancer. Oncogene 23:2850–2860PubMedGoogle Scholar
  60. 60.
    Herr I, Debatin KM (2001) Cellular stress response and apoptosis in cancer therapy. Blood 98:2603–2614PubMedGoogle Scholar
  61. 61.
    Herr I, Wilhelm D, Bohler T, Angel P, Debatin KM (1997) Activation of CD95 (APO-1/Fas) signaling by ceramide mediates cancer therapy-induced apoptosis. EMBO J 16:6200–6208PubMedGoogle Scholar
  62. 62.
    Hershko T, Ginsberg D (2004) Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis. J Biol Chem 279:8627–8634PubMedGoogle Scholar
  63. 63.
    Hickman JA, Potten CS, Merritt AJ, Fisher TC (1994). Apoptosis and cancer chemotherapy. Philos Trans R Soc Lond B Biol Sci 345:319–325PubMedGoogle Scholar
  64. 64.
    Hinds P, Finlay C, Levine AJ (1989) Mutation is required to activate the p53 gene for cooperation with the ras oncogene and transformation. J Virol 63:739–746PubMedGoogle Scholar
  65. 65.
    Hockenbery DM, Oltvai ZN, Yin XM, Milliman CM, Korsmeyer SJ (1993) Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75:241–251PubMedGoogle Scholar
  66. 66.
    Horie T, Matsumoto H, Kasagi M, Sugiyama A, Kikuchi M, Karasawa C, Awazu S, Itakura Y, Fuwa T (1999) Protective effect of aged garlic extract on the small intestinal damage of rats induced by methotrexate treatment. Planta Med 65:545–548PubMedGoogle Scholar
  67. 67.
    Howarth G, Francis GL, Cool JC, Xu X, Byard RW, Read LC (1996) Milk growth factors enriched from cheese whey ameliorate intestinal damage by methotrexate when administered orally to rats. J Nutr 126:2519–2530PubMedGoogle Scholar
  68. 68.
    Howarth GS, Shoubridge CA (2001) Enhancement of intestinal growth and repair by growth factors. Curr Opin Pharmacol 1:568–574PubMedGoogle Scholar
  69. 69.
    Hsu YT, Wolter KG, Youle RJ (1997) Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis. Proc Natl Acad Sci U S A 94:3668–3672PubMedGoogle Scholar
  70. 70.
    Hu ZB, Minden MD, McCulloch EA (1996) Regulation of the synthesis of bcl-2 protein by growth factors. Leukemia 10:1925–1929PubMedGoogle Scholar
  71. 71.
    Huennekens FM (1994) The methotrexate story: a paradigm for development of cancer chemotherapeutic agents. Adv Enzyme Regul 34:397–419PubMedGoogle Scholar
  72. 72.
    Ijiri K, Potten CS (1983) Response of intestinal cells of differing topographical and hierarchical status to ten cytotoxic drugs and five sources of radiation. Br J Cancer 47:175–185PubMedGoogle Scholar
  73. 73.
    Ijiri K, Potten CS (1987) Further studies on the response of intestinal crypt cells of different hierarchical status to eighteen different cytotoxic agents. Br J Cancer 55:113–123PubMedGoogle Scholar
  74. 74.
    Ikuno N, Soda H, Watanabe M, Oka M (1995) Irinotecan (CPT-11) and characteristic mucosal changes in the mouse ileum and cecum. J Natl Cancer Inst 87:1876–1883PubMedGoogle Scholar
  75. 75.
    Inomata A, Horii I, Suzuki K (2002) 5-Fluorouracil-induced intestinal toxicity: what determines the severity of damage to murine intestinal crypt epithelia? Toxicol Lett 133:231–240PubMedGoogle Scholar
  76. 76.
    Jones BA, Gores GJ (1997) Physiology and pathophysiology of apoptosis in epithelial cells of the liver, pancreas, and intestine. Am J Physiol 273:G1174–G1188PubMedGoogle Scholar
  77. 77.
    Junqueira L, Carnerio J, Long J (eds) (1986) Basic histology. Lange, Los Altos, pp 327–353Google Scholar
  78. 78.
    Kannan K, Amariglio N, Rechavi G, Jakob-Hirsch J, Kela I, Kaminski N, Getz G, Domany E, Givol D (2001) DNA microarrays identification of primary and secondary target genes regulated by p53. Oncogene 20:2225–2234PubMedGoogle Scholar
  79. 79.
    Keefe DM (1998) The effect of cytotoxic chemotherapy on the mucosa of the small intestine. M.D. thesis, University of Adelaide, AdelaideGoogle Scholar
  80. 80.
    Keefe DM (2004) Gastrointestinal mucositis: a new biological model. Support Care Cancer 12:6–9PubMedGoogle Scholar
  81. 81.
    Keefe DM, Cummins AG, Dale BM, Kotasek D, Robb TA, Sage RE (1997) Effect of high-dose chemotherapy on intestinal permeability in humans. Clin Sci 92:385–389PubMedGoogle Scholar
  82. 82.
    Keefe DM, Brealey J, Goland GJ, Cummins AG (2000) Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans. Gut 47:632–637PubMedGoogle Scholar
  83. 83.
    Keefe DM, Gibson RJ, Hauer-Jensen M (2004) Gastrointestinal mucositis. Semin Oncol Nurs 20:38–47PubMedGoogle Scholar
  84. 84.
    Kelekar A, Thompson CB (1998) Bcl-2-family proteins: the role of the BH3 domain in apoptosis. Trends Cell Biol 8:324–330PubMedGoogle Scholar
  85. 85.
    Kelekar A, Chang BS, Harlan JE, Fesik SW, Thompson CB (1997) Bad is a BH3 domain-containing protein that forms an inactivating dimer with Bcl-XL. Mol Cell Biol 17:7040–7046PubMedGoogle Scholar
  86. 86.
    Kerr JF (1971) Shrinkage necrosis: a distinct mode of cellular death. J Pathol 105:13–20PubMedGoogle Scholar
  87. 87.
    Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257PubMedGoogle Scholar
  88. 88.
    Kerr JF, Winterford CM, Harmon BV (1994) Apoptosis. Its significance in cancer and cancer therapy [erratum appears in Cancer 1994 Jun 15; 73(12):3108]. Cancer 73:2013–2026PubMedGoogle Scholar
  89. 89.
    Khaled AR, Kim K, Hofmeister R, Muegge K, Durum SK (1999) Withdrawal of IL-7 induces Bax translocation from cytosol to mitochondria through a rise in intracellular pH. Proc Natl Acad Sci U S A 96:14476–14481PubMedGoogle Scholar
  90. 90.
    Kitada S, Krajewski S, Miyashita T, Krajewska M, Reed JC (1996) Gamma-radiation induces upregulation of Bax protein and apoptosis in radiosensitive cells in vivo. Oncogene 12:187–192PubMedGoogle Scholar
  91. 91.
    Kitada S, Krajewska M, Zhang X, Scudiero D, Zapata JM, Wang HG, Shabaik A, Tudor G, Krajewski S, Myers TG, Johnson GS, Sausville EA, Reed JC (1998) Expression and localization of pro-apoptotic Bcl-2 family protein bad in normal human tissue and tumor cell lines. Am J Pathol 152:51–61PubMedGoogle Scholar
  92. 92.
    Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD (1997) The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis (comment). Science 275:1132–1136PubMedGoogle Scholar
  93. 93.
    Ko LJ, Prives C (1996) p53: puzzle and paradigm. Genes Dev 10:1054–1072PubMedGoogle Scholar
  94. 94.
    Komarov PG (1999) A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 285:1733–1737PubMedGoogle Scholar
  95. 95.
    Komarova EA, Gudkov AV (1998) Could p53 be a target for therapeutic suppression? Semin Cancer Biol 8:389–400PubMedGoogle Scholar
  96. 96.
    Komarova EA, Gudkov AV (2000) Suppression of p53: a new approach to overcome side effects of antitumor therapy. Biochemistry (Moscow) 65:41–48Google Scholar
  97. 97.
    Komarova EA, Gudkov AV (2001) Chemoprotection from p53-dependent apoptosis: potential clinical applications of the p53 inhibitors. Biochem Pharmacol 62:657–667PubMedGoogle Scholar
  98. 98.
    Komarova EA, Neznanov N, Komarov PG, Chernov MV, Wang K, Gudkov AV (2003) p53 inhibitor pifithrin alpha can suppress heat shock and glucocorticoid signaling pathways. J Biol Chem 278:15465–15468PubMedGoogle Scholar
  99. 99.
    Komarova EA, Kondratov RV, Wang K, Christov K, Golovkina TV, Goldblum JR, Gudkov AV (2004) Dual effect of p53 on radiation sensitivity in vivo: p53 promotes hematopoietic injury, but protects from gastro-intestinal syndrome in mice. Oncogene 23:3265–3271PubMedGoogle Scholar
  100. 100.
    Konopleva M, Zhao S, Xie Z, Segall H, Younes A, Claxton DF, Estrov Z, Kornblau SM, Andreeff M (1999) Apoptosis. Molecules and mechanisms. Adv Exp Med Biol 457:217–236PubMedGoogle Scholar
  101. 101.
    Krajewski S, Krajewska M, Shabaik A, Miyashita T, Wang HG, Reed JC (1994) Immunohistochemical determination of in vivo distribution of Bax, a dominant inhibitor of Bcl-2. Am J Pathol 145:1323–1336PubMedGoogle Scholar
  102. 102.
    Krajewski S, Krajewska M, Shabaik A, Wang HG, Irie S, Fong L, Reed JC (1994) Immunohistochemical analysis of in vivo patterns of Bcl-X expression. Cancer Res 54:5501–5507PubMedGoogle Scholar
  103. 103.
    Krajewski S, Bodrug S, Krajewska M, Shabaik A, Gascoyne R, Berean K, Reed JC (1995) Immunohistochemical analysis of Mcl-1 protein in human tissues. Differential regulation of Mcl-1 and Bcl-2 protein production suggests a unique role for Mcl-1 in control of programmed cell death in vivo. Am J Pathol 146:1309–1319PubMedGoogle Scholar
  104. 104.
    Krajewski S, Krajewska M, Reed JC (1996) Immunohistochemical analysis of in vivo patterns of Bak expression, a proapoptotic member of the Bcl-2 protein family. Cancer Res 56:2849–2855PubMedGoogle Scholar
  105. 105.
    Krajewska M, Zapata JM, Meinhold-Heerlein I, Hedayat H, Monks A, Handorf H, Shabaik A, Bebendorf L, Lallioniemi O, Kim H, Heifenberger L, Reed JC, Krajewski S (2002) Expression of Bcl-2 family member Bid in normal and malignant tissues. Neoplasia 4:129–140PubMedGoogle Scholar
  106. 106.
    Lane DP, Crawford LV (1979) T antigen is bound to a host protein in SV40-transformed cells. Nature 278:261–263PubMedGoogle Scholar
  107. 107.
    Lane DP, Lu X, Hupp T, Hall PA (1994) The role of the p53 protein in the apoptotic response. Philos Trans R Soc Lond B Biol Sci 345:277–280PubMedGoogle Scholar
  108. 108.
    Leu JI, Dumont P, Hafey M, Murphy ME, George DL (2004) Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol 6:443–450PubMedGoogle Scholar
  109. 109.
    Leung LK, Wang TT (1999) Differential effects of chemotherapeutic agents on the Bcl-2/Bax apoptosis pathway in human breast cancer cell line MCF-7. Breast Cancer Res Treat 55:73–83PubMedGoogle Scholar
  110. 110.
    Linette GP, Li Y, Roth K, Korsmeyer SJ (1996) Cross talk between cell death and cell cycle progression: BCL-2 regulates NFAT-mediated activation. Proc Natl Acad Sci U S A 93:9545–9552PubMedGoogle Scholar
  111. 111.
    Linseman DA, Phelps RA, Bouchard RJ, Le SS, Laessig TA, McClure ML, Heidenreich KA (2002) Insulin-like growth factor-I blocks Bcl-2 interacting mediator of cell death (Bim) induction and intrinsic death signaling in cerebellar granule neurons. J Neurosci 22:9287–9297PubMedGoogle Scholar
  112. 112.
    Linzer DI, Levine AJ (1979) Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17:43–52PubMedGoogle Scholar
  113. 113.
    Liu QA, Hengartner MO (1999) The molecular mechanism of programmed cell death in C. elegans. Ann N Y Acad Sci 887:92–104PubMedGoogle Scholar
  114. 114.
    Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481–490PubMedGoogle Scholar
  115. 115.
    Marshman E, Ottewell PD, Potten CS, Watson AJ (2001) Caspase activation during spontaneous and radiation-induced apoptosis in the murine intestine. J Pathol 195:285–292PubMedGoogle Scholar
  116. 116.
    Martinon F, Tschopp J (2004) Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117:561–574PubMedGoogle Scholar
  117. 117.
    Marzo I, Brenner C, Zamzami N, Susin SA, Beutner G, Brdiczka D, Remy R, Xie ZH, Reed JC, Kroemer G (1998) The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins. J Exp Med 187:1261–1271PubMedGoogle Scholar
  118. 118.
    McDonnell TJ, Beham A, Sarkiss M, Andersen MM, Lo P (1996) Importance of the Bcl-2 family in cell death regulation. Experientia 52:1008–1017PubMedGoogle Scholar
  119. 119.
    Merritt AJ, Potten CS, Kemp CJ, Hickman JA, Balmain A, Lane DP, Hall PA (1994) The role of p53 in spontaneous and radiation-induced apoptosis in the gastrointestinal tract of normal and p53-deficient mice. Cancer Res 54:614–617PubMedGoogle Scholar
  120. 120.
    Merritt AJ, Potten CS, Watson AJ, Loh DY, Nakayama K, Hickman JA (1995) Differential expression of bcl-2 in intestinal epithelia. Correlation with attenuation of apoptosis in colonic crypts and the incidence of colonic neoplasia. J Cell Sci 108:2261–2271PubMedGoogle Scholar
  121. 121.
    Mitchell EP, Schein PS (1984) Gastrointestinal toxicity of chemotherapeutic agents. In: Perry MC, Yarbro JW (eds) Toxicity of chemotherapy. Grune and Stratton, Orlando, pp 269–289Google Scholar
  122. 122.
    Miyashita T, Reed JC (1993) Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood 81:151–157PubMedGoogle Scholar
  123. 123.
    Miyashita T, Reed JC (1995) Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80:293–299PubMedGoogle Scholar
  124. 124.
    Miyashita T, Harigai M, Hanada M, Reed JC (1994) Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res 54:3131–3135PubMedGoogle Scholar
  125. 125.
    Morelli D, Menard S, Colnaghi MI, Balsari A (1996) Oral administration of anti-doxorubicin monoclonal antibody prevents chemotherapy-induced gastrointestinal toxicity in mice. Cancer Res 56:2082–2085PubMedGoogle Scholar
  126. 126.
    Moss SF, Agarwal B, Arber N, Buan RJ, Krajewska M, Krajewski S, Reed JC, Holt PR (1996) Increased intestinal Bak expression results in apoptosis. Biochem Biophys Res Commun 223:199–203PubMedGoogle Scholar
  127. 127.
    Muller M, Scaffidi CA, Galle PA, Stremmel W, Krammer PH (1998) The role of p53 and the CD95 (APO-1/Fas) death system in chemotherapy-induced apoptosis. Eur Cytokine Netw 9:685–686PubMedGoogle Scholar
  128. 128.
    Muller M, Wilder S, Bannasch D, Israeli D, Lehlbach K, Li-Weber M, Friedman SL, Galle PR, Stremmel W, Oren M, Krammer PH (1998) p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J Exp Med 188:2033–2045PubMedGoogle Scholar
  129. 129.
    Nagai Y, Horie T, Awazu S (1993) Vitamin A, a useful biochemical modulator capable of preventing intestinal damage during methotrexate treatment. Pharmacol Toxicol 73:69–74PubMedCrossRefGoogle Scholar
  130. 130.
    Nagata S (1994) Apoptosis regulated by a death factor and its receptor: Fas ligand and Fas. Philos Trans R Soc Lond B Biol Sci 345:281–287PubMedGoogle Scholar
  131. 131.
    Nakano K, Vousden KH (2001) PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 7:683–694PubMedGoogle Scholar
  132. 132.
    Narita M, Shimizu S, Ito T, Chittenden T, Lutz RJ, Matsuda H, Tsujimoto Y (1998) Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria. Proc Natl Acad Sci U S A 95:14681–14686PubMedGoogle Scholar
  133. 133.
    Nicholson DW, Thornberry NA (1997) Caspases: killer proteases. Trends Biochem Sci 22:299–306PubMedGoogle Scholar
  134. 134.
    Nita ME, Nagawa H, Tominaga O, Tsuno N, Fujii S, Sasaki S, Fu CG, Takenoue T, Tsuruo T, Muto T (1998) 5-Fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins. Br J Cancer 78:986–992PubMedGoogle Scholar
  135. 135.
    Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N (2000) Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288:1053–1058PubMedGoogle Scholar
  136. 136.
    Okuno S, Shimizu S, Ito T, Nomura M, Hamada E, Tsujimoto Y, Matsuda H (1998) Bcl-2 prevents caspase-independent cell death. J Biol Chem 273:34272–34277PubMedGoogle Scholar
  137. 137.
    Oltvai ZN, Milliman CL, Korsmeyer SJ (1993) Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74:609–619PubMedGoogle Scholar
  138. 138.
    O’Reilly LA, Cullen L, Visvader J, Lindeman GJ, Print C, Bath ML, Huang DC, Strasser A (2000) The proapoptotic BH3-only protein bim is expressed in hematopoietic, epithelial, neuronal, and germ cells. Am J Pathol 157:449–461PubMedGoogle Scholar
  139. 139.
    O’Reilly LA, Print C, Hausmann G, Moriishi K, Cory S, Huang DC, Strasser A (2001) Tissue expression and subcellular localization of the pro-survival molecule Bcl-w. Cell Death Differ 8:486–494PubMedGoogle Scholar
  140. 140.
    Papaconstantinou HT, Chung DH, Zhang W, Ansari NH, Hellmich MR, Townsend CM, Ko TC (2000) Prevention of mucosal atrophy: role of glutamine and caspases in apoptosis in intestinal epithelial cells. J Gastrointest Surg 4:416–423PubMedGoogle Scholar
  141. 141.
    Papaconstantinou HT, Xie C, Zhang W, Ansari NH, Hellmich MR, Townsend CM, Ko TC (2001) The role of caspases in methotrexate-induced gastrointestinal toxicity. Surgery 130:859–865PubMedGoogle Scholar
  142. 142.
    Park J, Hockenbery DM (1996) BCL-2, a novel regulator of apoptosis. J Cell Biochem 60:12–17PubMedGoogle Scholar
  143. 143.
    Pico J, Avila-Garavito A, Naccache P (1998) Mucositis: its occurrence, consequences and treatment in the oncology setting. Oncologist 3:446–451PubMedGoogle Scholar
  144. 144.
    Pinkoski MJ, Brunner T, Green DR, Lin T (2000) Fas and Fas ligand in gut and liver. Am J Physiol Gastrointest Liver Physiol 278:G354–G366PubMedGoogle Scholar
  145. 145.
    Potten CS (1990) A comprehensive study of the radiobiological response of the murine (BDF1) small intestine. Int J Radiat Biol 58:925–973PubMedGoogle Scholar
  146. 146.
    Potten CS (1992) The significance of spontaneous and induced apoptosis in the gastrointestinal tract of mice. Cancer Metastasis Rev 11:179–195PubMedGoogle Scholar
  147. 147.
    Potten CS (1997) Epithelial cell growth and differentiation. II. Intestinal apoptosis. Am J Physiol 273:G253–G257PubMedGoogle Scholar
  148. 148.
    Potten CS (1998) Stem cells in gastrointestinal epithelium: numbers, characteristics and death. Philos Trans R Soc Lond B Biol Sci 353:821–830PubMedGoogle Scholar
  149. 149.
    Potten CS, Grant HK (1998) The relationship between ionizing radiation-induced apoptosis and stem cells in the small and large intestine. Br J Cancer 78:993–1003PubMedGoogle Scholar
  150. 150.
    Potten CS, Loeffler M (1990) Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110:1001–1020PubMedGoogle Scholar
  151. 151.
    Potten CS, Owen G, Hewitt D, Chadwick CA, Hendry H, Lord BI, Woolford LB (1995) Stimulation and inhibition of proliferation in the small intestinal crypts of the mouse after in vivo administration of growth factors. Gut 36:864–873PubMedGoogle Scholar
  152. 152.
    Potten CS, Booth C, Pritchard DM (1997) The intestinal epithelial stem cell: the mucosal governor. Int J Exp Pathol 78:219–243PubMedGoogle Scholar
  153. 153.
    Potten CS, Wilson JW, Booth C (1997) Regulation and significance of apoptosis in the stem cells of the gastrointestinal epithelium. Stem Cells 15:82–93PubMedGoogle Scholar
  154. 154.
    Pratesi G, Perego P, Zunino F (2001) Role of Bcl-2 and its post-transcriptional modification in response to antitumor therapy. Biochem Pharmacol 61:381–386PubMedGoogle Scholar
  155. 155.
    Pritchard DM, Potten CS, Hickman JA (1998) The relationships between p53-dependent apoptosis, inhibition of proliferation, and 5-fluorouracil-induced histopathology in murine small intestinal epithelia. Cancer Res 58:5453–5465PubMedGoogle Scholar
  156. 156.
    Pritchard DM, Potten CS, Korsmeyer SJ, Roberts S, Hickman JA (1999) Damage-induced apoptosis in intestinal epithelia from bcl-2-null and bax-null mice: investigations of the mechanistic determinants of epithelial apoptosis in vivo. Oncogene 18:7287–7293PubMedGoogle Scholar
  157. 157.
    Pritchard DM, Print C, O’Reilly L, Adams JM, Potten CS, Hickman JA (2000) Bcl-w is an important determinant of damage-induced apoptosis in epithelia of small and large intestine. Oncogene 19:3955–3959PubMedGoogle Scholar
  158. 158.
    Puthalakath DC, Huang LA, O’Reilly SM, King A, Strasser A (1999) The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell 3:287–296PubMedGoogle Scholar
  159. 159.
    Puthalakath H, Strasser A (2002) Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ 9:505–512PubMedGoogle Scholar
  160. 160.
    Raisova M, Hossini AM, Eberle J, Riebeling C, Wieder T, Sturm I, Daniel PT, Orfanos PE, Geilen CC (2001) The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis. J Invest Dermatol 117:333–340PubMedGoogle Scholar
  161. 161.
    Reed JC (2000) Mechanisms of apoptosis. Am J Pathol 157:1415–1430PubMedGoogle Scholar
  162. 162.
    Renehan A, Gossiel R, Davidson SE, Roberts SA, Chadwick C, Wilks DP, Potten CS, Hendry JH, Hunter RD, Renehan AG (1995) What is apoptosis, and why is it important? Radiother Oncol 37:1–9PubMedGoogle Scholar
  163. 163.
    Renehan AG, Bach SP, Potten CS (2001) The relevance of apoptosis for cellular homeostasis and tumorigenesis in the intestine. Can J Gastroenterol 15:166–176PubMedGoogle Scholar
  164. 164.
    Rosse T (1998) Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c. Nature 391:486–499Google Scholar
  165. 165.
    Sabbatini M, Bozzo C, Castellucci M, Cannas M (2004) Morphometric quantification of apoptotic stages in cell culture. Cells Tissues Organs 178:139–145PubMedGoogle Scholar
  166. 166.
    Sax JK, Fei P, Murphy ME, Bernhard E, Korsmeyer SJ, El-Deiry WS (2002) BID regulation by p53 contributes to chemosensitivity. Nat Cell Biol 4:842–849PubMedGoogle Scholar
  167. 167.
    Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17:1675–1687PubMedGoogle Scholar
  168. 168.
    Schafer T, Scheuer C, Roemer K, Menger MD, Vollmar B (2003) Inhibition of p53 protects liver tissue against endotoxin-induced apoptotic and necrotic cell death. FASEB J 17:660–667PubMedGoogle Scholar
  169. 169.
    Schinzel A, Kaufmann T, Borner C (2004) Bcl-2 family members: intracellular targeting, membrane-insertion, and changes in subcellular localization. Biochim Biophys Acta 1644:95–105PubMedGoogle Scholar
  170. 170.
    Sedlak TW, Oltvai ZN, Yang E, Wang K, Boise LH, Thompson CB, Korsmeyer SJ (1995) Multiple Bcl-2 family members demonstrate selective dimerizations with Bax. Proc Natl Acad Sci U S A 92:7834–7838PubMedGoogle Scholar
  171. 171.
    Sherwood L (1997) Human physiology—from cells to systems, 3rd edn. Wadsworth, Belmont, pp 446–600Google Scholar
  172. 172.
    Shibue T, Takeda K, Oda E, Tanaka H, Murasawa H, Takaoka A, Morishita Y, Akira S, Taniguchi T, Tanaka N (2003) Integral role of Noxa in p53-mediated apoptotic response. Genes Dev 17:2233–2238PubMedGoogle Scholar
  173. 173.
    Shimizu S, Konishi A, Kodama T, Tsujimoto Y (2000) BH4 domain of antiapoptotic Bcl-2 family members closes voltage-dependent anion channel and inhibits apoptotic mitochondrial changes and cell death. [erratum appears in Proc Natl Acad Sci U S A 2000 Aug 1; 97(16):9347]. Proc Natl Acad Sci U S A 97:3100–3105PubMedGoogle Scholar
  174. 174.
    Shinohara H, Killion JJ, Kuniyasu H, Kumar R, Fidler IJ (1998) Prevention of intestinal toxic effects and intensification of irinotecan’s therapeutic efficacy against murine colon cancer liver metastases by oral administration of the lipopeptide JBT 3002. Clin Cancer Res 4:2053–2063PubMedGoogle Scholar
  175. 175.
    Slee EA, Adrain C, Martin SJ (1999) Serial killers: ordering caspase activation events in apoptosis. Cell Death Differ 6:1067–1074PubMedGoogle Scholar
  176. 176.
    Slee EA, O’Connor DJ, Lu X (2004) To die or not to die: how does p53 decide? Oncogene 23:2809–2818PubMedGoogle Scholar
  177. 177.
    Smith ND, Rubenstein JN, Eggener SE, Kozlowski JM (2003) The p53 tumor suppressor gene and nuclear protein: basic science review and relevance in the management of bladder cancer. J Urol 169:1219–1228PubMedGoogle Scholar
  178. 178.
    Solary E, Favre B, Caillot D, Sidaner I, Guy H (2000) Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies. Leukemia 14:1833–1849PubMedGoogle Scholar
  179. 179.
    Sonis ST (2004) The pathobiology of mucositis. Nat Rev Cancer 4:277–284PubMedGoogle Scholar
  180. 180.
    Sonis ST (2004) Pathobiology of mucositis. Semin Oncol Nurs 20:11–15PubMedGoogle Scholar
  181. 181.
    Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M, Bekele BN, Raber-Durlacher J, Donnelly JP, Rubenstein EB (2004) Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100:1995–2025PubMedGoogle Scholar
  182. 182.
    Srivastava RK, Srivastava AR, Korsmeyer SJ, Nesterova M, Cho-Chung YS, Longo DL (1998) Involvement of microtubules in the regulation of Bcl2 phosphorylation and apoptosis through cyclic AMP-dependent protein kinase. Mol Cell Biol 18:3509–3517PubMedGoogle Scholar
  183. 183.
    Strasser A, O’Connor L, Dixit VM (2000) Apoptosis signaling. Ann Rev Biochem 69:217–245PubMedGoogle Scholar
  184. 184.
    Strasser A, Puthalakath H, Bouillet P, Huang DC, O’Connor L, O’Reilly LA, Cullen L, Cory S, Adams JM (2000) The role of bim, a proapoptotic BH3-only member of the Bcl-2 family in cell-death control. Ann N Y Acad Sci 917:541–548PubMedGoogle Scholar
  185. 185.
    Susin SA, Zamzami N, Kroemer G (1998) Mitochondria as regulators of apoptosis: doubt no more. Biochim Biophys Acta 1366:151–165PubMedGoogle Scholar
  186. 186.
    Takasuna K, Hagiwara T, Hirohashi M, Kato M, Nomura M, Nagai E, Yokoi T, Kamataki T (1996) Involvement of beta-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res 56:3752–3757PubMedGoogle Scholar
  187. 187.
    Tamatani M, Ogawa S, Nunez G, Tohyama M (1998) Growth factors prevent changes in Bcl-2 and Bax expression and neuronal apoptosis induced by nitric oxide. Cell Death Differ 5:911–919PubMedGoogle Scholar
  188. 188.
    Taminiau JA, Gall DG, Hamilton JR (1980) Response of the rat small-intestine epithelium to methotrexate. Gut 21:486–492PubMedGoogle Scholar
  189. 189.
    Tarnawski AS, Szabo I (2001) Apoptosis—programmed cell death and its relavence to gastrointestinal epithelium: survival signal from the matrix. Gastroenterology 120:294–299PubMedGoogle Scholar
  190. 190.
    Tenenbaun L (1994) Cancer chemotherapy and biotherapy. Saunders, Philadephia, pp 7–8Google Scholar
  191. 191.
    Thornberry NA (1998) Caspases: key mediators of apoptosis. Chem Biol 5:R97–R103PubMedGoogle Scholar
  192. 192.
    Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281:1312–1316PubMedGoogle Scholar
  193. 193.
    Tran CD, Howarth GS, Coyle P, Philcox JC, Rofe AM, Butler RN (2003) Dietary supplementation with zinc and a growth factor extract derived from bovine cheese whey improves methotrexate-damaged rat intestine. Am J Clin Nutr 77:1296–1303PubMedGoogle Scholar
  194. 194.
    Trier JS (1962) Morphologic alterations induced by methotrexate in the mucosa of human proximal intestine. I. Serial observations by light microscopy. Gastroenterology 42:295–305PubMedGoogle Scholar
  195. 195.
    van Loo G, Saelens X, van Gurp M, MacFarlane M, Martin SJ, Vandenabeele P (2002) The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet. Cell Death Differ 9:1031–1042PubMedGoogle Scholar
  196. 196.
    van’t Land B, Meijer HP, Frerichs J, Koetsier M, Jager D, Smeets RL, M’Rabet L, Hoijer M (2002) Transforming growth factor-beta2 protects the small intestine during methotrexate treatment in rats possibly by reducing stem cell cycling. Br J Cancer 87:113–118Google Scholar
  197. 197.
    van’t Land B, van Beek NM, van den Berg JJ, M’Rabet L (2004) Lactoferrin reduces methotrexate-induced small intestinal damage, possibly through inhibition of GLP-2-mediated epithelial cell proliferation. Dig Dis Sci 49:425–433PubMedGoogle Scholar
  198. 198.
    Verburg M, Renes IB, Meijer HP, Taminiau HP, Buller HA, Einerhand AW, Dekker J (2000) Selective sparing of goblet cells and paneth cells in the intestine of methotrexate-treated rats. Am J Physiol Gastrointest Liver Physiol 279:G1037–G1047PubMedGoogle Scholar
  199. 199.
    Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network. Nature 408:307–310PubMedGoogle Scholar
  200. 200.
    Vollmar B, El-Gibaly AM, Scheuer C, Strik MW, Bruch HP, Menger HP (2002) Acceleration of cutaneous wound healing by transient p53 inhibition. Lab Invest 82:1063–1071PubMedGoogle Scholar
  201. 201.
    Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2:594–604PubMedGoogle Scholar
  202. 202.
    Wang JY, Naderi S, Chen TT (2001) Role of retinoblastoma tumor suppressor protein in DNA damage response. Acta Oncol 40:689–695PubMedGoogle Scholar
  203. 203.
    Watson AJ (1995) Necrosis and apoptosis in the gastrointestinal tract. Aliment Pharmacol Ther 9:215–226PubMedCrossRefGoogle Scholar
  204. 204.
    Wei MC (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730PubMedGoogle Scholar
  205. 205.
    Weller M (1998) Predicting response to cancer chemotherapy: the role of p53. Cell Tissue Res 292:435–445PubMedGoogle Scholar
  206. 206.
    Westcarr S, Farshori P, Wyche J, Anderson WA (1999) Apoptosis and differentiation in the crypt-villus unit of the rat small intestine. J Submicrosc Cyto Pathol 31:15–30Google Scholar
  207. 207.
    Wilson JW, Pritchard DM, Hickman JA, Potten CS (1998) Radiation-induced p53 and p21WAF-1/CIP1 expression in the murine intestinal epithelium: apoptosis and cell cycle arrest. Am J Pathol 153:899–909PubMedGoogle Scholar
  208. 208.
    Yang E, Korsmeyer SJ (1996) Molecular thanatopsis: a discourse on the BCL2 family and cell death. Blood 88:386–401PubMedGoogle Scholar
  209. 209.
    Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ (1995) Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80:285–291PubMedGoogle Scholar
  210. 210.
    Yin XM, Oltvai ZN, Veis-Novack DJ, Linette GP (1995) Bcl-2 gene family and the regulation of programmed cell death. Biochim Biophys Acta 1271:63–66PubMedGoogle Scholar
  211. 211.
    Zhang M, Liu W, Ding D, Salvi R (2003) Pifithrin-α supresses p53 and protects cochlear and vestibular hair cells from cisplatin-induced apoptosis. Neuroscience 120:191–205PubMedGoogle Scholar
  212. 212.
    Zhu M, Yu QS, Cutler RG, Culmsee CW, Holloway HW, Lahiri DK, Mattson MP, Greig NH (2002) Novel p53 inactivators with neuroprotective action: syntheses and pharmacological evaluation of 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole and 2-imino-2,3,4,5,6,7-hexahydrobenzoxazole derivatives. J Med Chem 45:5090–5097PubMedGoogle Scholar
  213. 213.
    Zong WX, Lindsten T, Ross AJ, MacGregor GR, Thompson CB (2001) BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev 15:1481–1486PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Joanne M. Bowen
    • 1
    • 2
    Email author
  • Rachel J. Gibson
    • 1
    • 2
  • Adrian G. Cummins
    • 2
    • 3
  • Dorothy M. K. Keefe
    • 1
    • 2
  1. 1.Department of Medical OncologyRoyal Adelaide HospitalAdelaideAustralia
  2. 2.Department of MedicineUniversity of AdelaideAdelaideAustralia
  3. 3.Department of Gastroenterology and HepatologyThe Queen Elizabeth HospitalAdelaideAustralia

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