Apoptosis and Cancer Chemotherapy

  • Stuart G. Lutzker
  • Arnold J. Levine
Part of the Cancer Treatment and Research book series (CTAR, volume 87)

Abstract

For many years oncologists have focused on the proliferative capacity of tumors as an indication of their aggressiveness. Mitotic index and S-phase fraction are routinely reported in some tumors and have been used to guide treatment in some instances. It is only recently than we have come to appreciate that the net growth of a tumor is directly related to both its proliferative capacity as well as the rate of programmed cell death, termed apoptosis. Although first described in 1972 [1] and viewed largely as a distinctive form of cell death occurring during development and normal tissue turnover [2], apoptosis occurs spontaneously in tumor cells both in vitro and in vivo, and apoptosis can be induced in cancer cells by such diverse stimuli as DNA damage and growth factor withdrawl. As is discussed in this chapter, there appears to be a heavy selection pressure for genetic changes that inhibit apoptosis in cancer cells, and inhibition of apoptosis may represent a new form of drug resistance in cancer treatment.

Keywords

Lymphoma Leukemia Recombination Shrinkage Oncol 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Kerr J, Searle J (1972) A suggested explanation for the paradoxically slow growth rate of basal-cell carcinomas that contain numerous mitotic figures. J Pathol 107:41–44.PubMedCrossRefGoogle Scholar
  2. 2.
    Kerr J, Wyllie A, Currie A (1972) Apoptosis: A basic biological phenomenon with wide-ranging implifications in tissue kinetics. Br J Cancer 26:239–257.PubMedCrossRefGoogle Scholar
  3. 3.
    Searle J, Kerr J, Bishop C (1982) Necrosis and apoptosis: Distinct modes of cell death with fundamentally different significance. Pathol Annu 17:229–259.PubMedGoogle Scholar
  4. 4.
    Savill J, Dransfield I, Hogg N, Haslett C (1990) Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis. Nature 343:170–173.PubMedCrossRefGoogle Scholar
  5. 5.
    Cohen J, Duke R (1984) Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death. J Immunol 132:38–42.PubMedGoogle Scholar
  6. 6.
    Wyllie A (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endonuclease activation. Nature 284:555–556.PubMedCrossRefGoogle Scholar
  7. 7.
    Fesus L, Davies P, Piacentini M (1991) Apoptosis: Molecular mechanisms in programmed cell death. Eur J Cell Biol 56:170–177.PubMedGoogle Scholar
  8. 8.
    Baffy G, Miyashita T, Williamson J, Reed J (1993) Apoptosis induced by withdrawl of iterleukin-3 (IL-3) from an IL-3-dependent hematopoietic cell line is associated with repartitioning of intracellular calcium and is blocked by Bcl-2 oncoprotein production. J Biol Chem 268:6511–6519.PubMedGoogle Scholar
  9. 9.
    Wesselberg S, Kabelitz D (1993) Activation-driven death of human T cell clones: Time course kinetics of the induction of cell shrinkage, DNA fragmentation and cell death. Cell Immunol 148:234–241.CrossRefGoogle Scholar
  10. 10.
    Dean M, Levine R, Ran W, Kindy M, Sonenshein G, Campisi J (1986) Regulation of c-myc transcription and mRNA abundance by serum growth factors and cell contact. J Biol Chem 261:9161–9166.PubMedGoogle Scholar
  11. 11.
    Leder P, Battey J, Lenoir G, Moulding C, Murphy W, Potter H, Stewart T, Taub R (1983) Translocations among antibody genes. Science 222:765–771.PubMedCrossRefGoogle Scholar
  12. 12.
    Potter M, Mushinski J, Mushinski E, Brust S, Wax J, Wiener F, Babonits M, Rapp U, Morse H (1987) Avian v-myc replaces chromosomal translocation in murine plasmacytomagenesis. Science 235:787–789.PubMedCrossRefGoogle Scholar
  13. 13.
    Langdon W, Harris A, Cory S, Adams J (1986) The c-myc oncogene perturbs B lymphocyte development in E-mu-myc transgenic mice. Cell 47:11–18.PubMedCrossRefGoogle Scholar
  14. 14.
    Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC (1992) Induction of apoptosis in fibroblasts by c-myc protein. Cell 69:119–128.PubMedCrossRefGoogle Scholar
  15. 15.
    Lotem J, Sachs L (1993) Hematopoietic cells from mice deficient in wild-type p53 are more resistant to induction of apoptosis by some agents. Blood 82:1092–1096.PubMedGoogle Scholar
  16. 16.
    Rao L, Debbas M, Sabbatini P, Hockenbery D, Korsmeyer S, White E (1992) The adenovirus E1A proteins induce apoptosis, which is inhibited by the E1B 19-kDa and Bcl-2 proteins. Proc Natl Acad Sci USA 89:7742–7746.PubMedCrossRefGoogle Scholar
  17. 17.
    White A, Livanos E, Tlsty T (1994) Differential disruption of genomic integrity and cell cycle regulation in normal human fibroblasts by the HPV oncoproteins. Genes Dev 8:666–667.PubMedCrossRefGoogle Scholar
  18. 18.
    Bakhshi A, Jensen J, Goldman P, Wright J, McBride O, Epstein A, Korsmeyer S (1985) Cloning the chromsomal breakpoint of t(14;18) human lymphomas: Clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 41:889–906.CrossRefGoogle Scholar
  19. 19.
    Cleary M, Sklar J (1985) Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint cluster region near a transcriptionally active locus on chromosome 18. Proc Natl Acad Sci USA 82:7439–7443.PubMedCrossRefGoogle Scholar
  20. 20.
    Hockenbery D, Nunez G, Milliman C, Schreiber R, Korsmeyer S (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348:334–336.PubMedCrossRefGoogle Scholar
  21. 21.
    Vaux D, Cory S, Adams J (1988) Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335:440–442.PubMedCrossRefGoogle Scholar
  22. 22.
    Bissonnette R, Echeverri F, Mahboubi A, Green D (1992) Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature 359:552–554.PubMedCrossRefGoogle Scholar
  23. 23.
    Fanidi A, Harrington E, Evan G (1992) Cooperative interaction between c-myc and bcl-2 proto-oncogenes. Nature 359:554–556.PubMedCrossRefGoogle Scholar
  24. 24.
    Strasser A, Harris A, Cory S (1991) Bcl-2 transgene inhibits T cell death and perturbs thymic sensorship. Cell 67:889–899.PubMedCrossRefGoogle Scholar
  25. 25.
    McDonnell T, Deane N, Platt F, Nunez G, Jaeger U, McKearn J, Korsmeyer S (1989) Bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell 57:79–88.PubMedCrossRefGoogle Scholar
  26. 26.
    McDonnell T, Korsmeyer S (1991) Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature 349:254–256.PubMedCrossRefGoogle Scholar
  27. 27.
    Strasser A, Harris A, Bath M, Cory S (1990) Novel primitive tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348:331–333.PubMedCrossRefGoogle Scholar
  28. 28.
    Hockenbery D, Oltvai Z, Yin X-M, Milliman C, Korsmeyer S (1993) Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75:241–252.PubMedCrossRefGoogle Scholar
  29. 29.
    Jacobson M, Raff M (1995) Programmed cell death and bcl-2 protection in very low oxygen. Nature 374:814–816.PubMedCrossRefGoogle Scholar
  30. 30.
    Shimizu S, Eguchi Y, Kosaka H, Kamiike W, Matsuda H, Tsujimoto Y (1995) Prevention of hypoxia-induced cell death by bcl-2 and bcl-xL. Nature 374:811–813.PubMedCrossRefGoogle Scholar
  31. 31.
    Oltvai Z, Milliman L, Korsmeyer S (1993) Bcl-2 heterodimerizes in vivo with a conserved homologue, Bax, that accelerates programmed cell death. Cell 74:609–620.PubMedCrossRefGoogle Scholar
  32. 32.
    Yin X-M, Oltvai Z, Korsmeyer S (1994) BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 369:321–323.PubMedCrossRefGoogle Scholar
  33. 33.
    Boise L, Gonzalez-Garcia M, Postema C, Ding L, Lindsten T, Turka L, Mao X, Nunez G, Thompson C (1993) bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74:597–608.PubMedCrossRefGoogle Scholar
  34. 34.
    Yang E, Zha J, Jockel J, Boise L, Thompson C, Korsmeyer S (1995) Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80:285–291.PubMedCrossRefGoogle Scholar
  35. 35.
    Boyd J, Malstrom S, Subramanian T, Venkatesh L, Schaeper U, Elangovan B, D’Sa-Eipper C, Chinnadurai G (1994) Adenovirus E1B 19kDa and Bcl-2 proteins interact with a common set of cellular proteins. Cell 79:341–351.PubMedCrossRefGoogle Scholar
  36. 36.
    Levine AJ, Momand J, Finlay CA (1991) The p53 tumor suppressor gene. Nature 351:453–456.PubMedCrossRefGoogle Scholar
  37. 37.
    Funk WD, Pak DJ, Karas RH, Wright WE, Shay JW (1992) A transcriptionally active DNA binding site for human p53 protein complexes. Mol Cell Biol 12:2866–2871.PubMedGoogle Scholar
  38. 38.
    Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW (1991) Participation of p53 protein in the cellular response to DNA damage. Cancer Res 51:6304–6311.PubMedGoogle Scholar
  39. 39.
    Nelson W, Kastan M (1994) DNA strand breaks: The DNA template alterations that trigger p53-dependent DNA damage response pathways. Mol Cell Biol 14:1815–1823.PubMedGoogle Scholar
  40. 40.
    El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75:817–825.PubMedCrossRefGoogle Scholar
  41. 41.
    Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D (1993) p21 is a universal inhibitor of cyclin kinases. Nature 366:701–704.PubMedCrossRefGoogle Scholar
  42. 42.
    Livingstone LR, White A, Sprouse J, Livanos E, Jacks T, Tlsty T (1992) Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70:923–935.PubMedCrossRefGoogle Scholar
  43. 43.
    Harvey M, Sands A, Weiss R, Hegi M, Wiseman R, Pantazis P, Giovanella B, Tainsky M, Bradley A, Donehower L (1993) In vitro growth characteristics of embryo fibroblasts isoalted from p53-deficient mice. Oncogene 8:2457–2567.PubMedGoogle Scholar
  44. 44.
    Yonish-Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M (1991) Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 352:345–347.PubMedCrossRefGoogle Scholar
  45. 45.
    Shaw P, Bovey R, Tardy S, Sahli R, Sordat B, Costa J (1992) Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line. Proc Natl Acad Sci USA 89:4495–4499.PubMedCrossRefGoogle Scholar
  46. 46.
    Clarke A, Purdie C, Harrison D, Morris R, Bird C, Hooper M, Wyllie A (1993) Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362:849–852.PubMedCrossRefGoogle Scholar
  47. 47.
    Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T (1993) p53 is required for radiation induced apoptosis in mouse thymocytes. Nature 362:••-••.Google Scholar
  48. 48.
    Debbas M, White E (1993) Wild-type p53 mediates apoptosis by E1A which is inhibited by E1B. Genes Dev 7:546–554.PubMedCrossRefGoogle Scholar
  49. 49.
    Wu X, Levine AJ (1994) p53 and E2F-1 cooperate to mediate apoptosis. Proc Natl Acad Sci USA 91:3602–3606.PubMedCrossRefGoogle Scholar
  50. 50.
    Canman C, Gilmer T, Coutts S, Kastan M (1995) Growth factor modulation of p53-mediated growth arrest versus apoptosis. Genes Dev 9:600–611.PubMedCrossRefGoogle Scholar
  51. 51.
    Symonds H, Krall L, Remington L, Saenz-Robles M, Lowe S, Jacks T, Van Dyke T (1994) p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell 4:703–712.Google Scholar
  52. 52.
    Caelles C, Heimberg A, Karin M (1994) p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature 370:220–223.CrossRefGoogle Scholar
  53. 53.
    Wagner A, Kokontis J, Hay N (1994) Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 tp induce p21/waf1/cip1. Genes Dev 8:2817–2830.PubMedCrossRefGoogle Scholar
  54. 54.
    Myashita T, Reed J (1995) Tumor suppressor p53 is a direct transcriptional activator of human Bax gene. Cell 80:293–299.CrossRefGoogle Scholar
  55. 55.
    Miyashita T, Krajewski S, Krajewska M, Wang H-K, Lieberman D, Hoffman B, Reed J (1994) Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 9:1799–1805.PubMedGoogle Scholar
  56. 56.
    Selvakumaran M, Lin H-K, Wang H-G, Krajewski S, Reed J, Hoffman B, Lieberman D (1994) Immediate early upregulation of bax expression by p53 but not TGF-beta: A paradigm for distinct apoptotic pathways. Oncogene 9:1791–1798.PubMedGoogle Scholar
  57. 57.
    Zhan Q, Fan S, Bae I, Guillouf C, Liebermann D, O’Connor P, Fornace A (1994) Induction of bax by genotoxic stress in human cells correlates with normal p53 state and apoptosis. Oncogene 9:3743–3751.PubMedGoogle Scholar
  58. 58.
    Zambetti GP, Levine AJ (1993) A comparison of the biological activities of wild-type and mutant p53. FASEB J 7:855–865.PubMedGoogle Scholar
  59. 59.
    Shen Y, Shenk T (1994) Relief of p53-mediated transcriptional repression by the adenovirus E1B-19kDa protein or the cellular Bcl-2 protein. Proc Natl Acad Sci USA, in press.Google Scholar
  60. 60.
    Haas-Kogan D, Kogan S, Levi D, Dazin P, T’Ang A, Fung Y-K, Israel M (1995) Inhibition of apoptosis by the retinoblastoma gene product. EMBO J 14:461–472.PubMedGoogle Scholar
  61. 61.
    Gorczyca W, Gong J, Darzynkiewicz Z (1993) Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick translation assays. Cancer Res 53:1945–1951.PubMedGoogle Scholar
  62. 62.
    Strasser A, Harris A, Jacks T, Cory S (1994) DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2. Cell 79:329–339.PubMedCrossRefGoogle Scholar
  63. 63.
    Lutzker S, Levine AJ (1995) Functional inactivation of p53 in testicular tumor cell lines is reversed by DNA damage and cellular differentiation. Submitted.Google Scholar
  64. 64.
    Lowe S, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher D, Housman D, Jacks T (1994) p53 status and the efficiancy of cancer therapy in vivo. Science 266:807–810.PubMedCrossRefGoogle Scholar
  65. 65.
    Maung Z, MacLean F, Reid M, Pearson A, Proctor S, Hamilton P, Hall A (1994) The relationship between bcl-2 expression and response to chemotherapy in acute leukemia. Br J Haematol 88:105–109.PubMedCrossRefGoogle Scholar
  66. 66.
    Campos L, Rouault J-P, Sabido O, Oriol P, Roubi N, Vasselon C, Archimbaud E, Magaud J-P, Guyotat D (1993) High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 81:3091–3096.PubMedGoogle Scholar
  67. 67.
    El Rouby S, Thomas A, Costin D, Rosenberg C, Potmesil M, Silber R, Newcomb E (1993) p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with rug resistance and is independent of MDR1/MDR3 gene expression. Blood 82:3452–3459.PubMedGoogle Scholar
  68. 68.
    Rosen P, Lesser M, Arroyo C, Cranor M, Borgen P, Norton L (1995) p53 in node-negative breast carcinoma: An immunohistochemical study of epidemiologic risk factors, histologic features and prognosis. J Clin Oncol 13:821–830.PubMedGoogle Scholar
  69. 69.
    Wattel E, Preudhomme C, Hecquet B, Vanrumbeke M, Quesnel B, Dervite I, Morel P, Fenaux P (1994) p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 84:3148–3157.PubMedGoogle Scholar
  70. 70.
    Gorczyca W, Bigman K, Mittelman A, Ahmed T, Gong J, Melamed M (1990) Induction of DNA strand breaks associated with apoptosis during treatment of leukemia. Leukemia 7:659–670.Google Scholar
  71. 71.
    Sander C, Yano T, Clark H, Harris C, Longo D, Jaffe E, Raffeld M (1993) p53 mutation is associated with progression in follicular lymphomas. Blood 82:1994–2004.PubMedGoogle Scholar
  72. 72.
    Heimdal K, Lothe RA, Lystad S, Holm R, Fossa SD, Börresen AL (1993) No germline TP3 mutations detected in familial and bilateral testicular cancers. Genes Chromosom Cancer 6:92–97.PubMedCrossRefGoogle Scholar
  73. 73.
    Peng HQ, Hogg D, Malkin D, Bailey D, Gallie BL, Bulbul M, Jewett M, Buchanan J, Goss PE (1993) Mutations of the p53 gene do not occur in testis cancer. Cancer Res 53:3574–3578.PubMedGoogle Scholar
  74. 74.
    Riou G, Barrois M, Prost S, Terrier M, Theodore C, Levine AJ (1995) The p53 and mdm-2 genes in human testicular germ-cell tumors. Mol Carcinogen 12:124–131.CrossRefGoogle Scholar
  75. 75.
    Langley R, Palayoor S, Coleman C, Bump E (1994) Radiation-induced apoptosis in F9 teratocarcinoma cells. Int J Radiat Biol 65:605–610.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1996

Authors and Affiliations

  • Stuart G. Lutzker
  • Arnold J. Levine

There are no affiliations available

Personalised recommendations