Application of Apoptosis to Cancer Treatment pp 293-320 | Cite as
Basis of Cell Kill Following Clinical Radiotherapy
Abstract
Over one half of cancer patients are treated radiotherapy. Technological advances in radiation targeting and concurrent chemotherapy continue to improve clinical radiotherapy outcome. Modem radiotherapy clinical trials are ongoing with novel molecular-targeted agents, requiring an increased understanding of cell death signals in a tissue-specific manner. Herein, we critically appraise the relative roles of apoptosis, mitotic catastrophe and terminal growth arrest in relation to final clonogenic cell kill following radiotherapy. Mitotic catastrophe and terminal growth arrest form the basis of the majority of cell kill during radiotherapy for common epithelial tumors (e.g. prostate, breast, lung, etc.) whereas more sensitive tumors (e.g. lymphomas or germ cell tumors) undergo apoptosis. Targeting of apoptotic, cell cycle checkpoint and DNA repair pathways may further augment cell kill from all three death pathways. Using intra-treatment biopsies or non-invasive imaging may soon allow for prediction of individual patient response and judicial selection of molecular targeting based on specific tumor cell signaling.
Key words
radiobiology apoptosis mitotic catastrophe cell cycle arrest radiotherapy clonogenic survival survivin p53 ceramide senescencePreview
Unable to display preview. Download preview PDF.
References
- 1.Ma, B.B., et al., Combined-modality treatment of solid tumors using radiotherapy and molecular targeted agents. J Clin Oncol, 2003. 21(14): p. 2760–76.Google Scholar
- 2.Bristow, R.G. and R. Hill, Molecular and Celullar Basis of Radiotherapy. Basic Science of Oncology, 1998: p. McGraw Hill Publishers, New York.Google Scholar
- 3.Ward, J.F., Radiation mutagenesis: the initial DNA lesions responsible. Radiat Res, 1995. 142(3): p. 362–8.Google Scholar
- 4.Kolesnick, R. and Z. Fuks, Radiation and ceramide-induced apoptosis. Oncogene, 2003. 22(37): p. 5897–906.Google Scholar
- 5.Morgan, W.F., et al., Genomic instability induced by ionizing radiation. Radiat Res, 1996. 146(3): p. 247–58.Google Scholar
- 6.Snyder, A.R. and W.F. Morgan, Gene expression profiling after irradiation: clues to understanding acute and persistent responses? Cancer Metastasis Rev, 2004. 23(3–4): p. 259–68.Google Scholar
- 7.Kim, I.A., et al., The influence of Ras pathway signaling on tumor radiosensitivity. Cancer Metastasis Rev, 2004. 23(3–4): p. 227–36.Google Scholar
- 8.Gupta, A.K., et al., Local recurrence in head and neck cancer: relationship to radiation resistance and signal transduction. Clin Cancer Res, 2002. 8(3): p. 885–92.Google Scholar
- 9.Harari, P.M. and S.M. Huang, Combining EGFR inhibitors with radiation or chemotherapy: will preclinical studies predict clinical results? Int J Radiat Oncol Biol Phys, 2004. 58(3): p. 976–83.Google Scholar
- 10.Hahn, S.M., et al., A Phase I trial of the farnmesyltransferase inhibitor L-778,123 and radiotherapy for locally advanced lung and head and neck cancer. Clin Cancer Res, 2002. 8(5): p. 1065–72.Google Scholar
- 11.Pilch, D.R., et al., Characteristics of gamma-H2AX foci at DNA double-strand breaks sites. Biochem Cell Biol, 2003. 81(3): p. 123–9.Google Scholar
- 12.Bakkenist, C.J. and M.B. Kastan, Initiating cellular stress responses. Cell, 2004. 118(1): p. 9–17.Google Scholar
- 13.Willers, H., J. Dahm-Daphi, and S.N. Powell, Repair of radiation damage to DNA. Br J Cancer, 2004. 90(7): p. 1297–301.Google Scholar
- 14.Rothkamm, K., et al., Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol, 2003. 23(16): p. 5706–15.Google Scholar
- 15.Olive, P.L. and J.P. Banath, Phosphorylation of histone H2AX as a measure of radiosensitivity. Int J Radiat Oncol Biol Phys, 2004. 58(2): p. 331–5.Google Scholar
- 16.Lukas, J., C. Lukas, and J. Bartek, Mammalian cell cycle checkpoints: signalling pathways and their organization in space and time. DNA Repair (Amst), 2004. 3(8–9): p. 997–1007.Google Scholar
- 17.Dimri, G.P., et al., A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A, 1995. 92(20): p. 9363–7.Google Scholar
- 18.Cuddihy, A.R. and R.G. Bristow, The p53 protein family and radiation sensitivity: Yes or no? Cancer Metastasis Rev, 2004. 23(3–4): p. 237–57.Google Scholar
- 19.Roninson, I.B., Tumor cell senescence in cancer treatment. Cancer Res, 2003. 63(11): p. 2705–15.Google Scholar
- 20.Ponten, F., et al., Induction of p53 expression in skin by radiotherapy and UV radiation: a randomized study. J Natl Cancer Inst, 2001. 93(2): p. 128–33.Google Scholar
- 21.Pawlik, T.M. and K. Keyomarsi, Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys, 2004. 59(4): p. 928–42.Google Scholar
- 22.Kao, G.D., W.G. McKenna, and T.J. Yen, Detection of repair activity during the DNA damage-induced G2 delay in human cancer cells. Oncogene, 2001. 20(27): p. 3486–96.Google Scholar
- 23.Wilson, G.D., Radiation and the cell cycle, revisited. Cancer Metastasis Rev, 2004. 23(3–4): p. 209–25.Google Scholar
- 24.Bromfield, G.P., et al., Cell death in irradiated prostate epithelial cells: role of apoptotic and clonogenic cell kill. Prostate Cancer Prostatic Dis, 2003. 6(1): p. 73–85.Google Scholar
- 25.Brown, J.M. and B.G. Wouters, Apoptosis: mediator or mode of cell killing by anticancer agents? Drug Resist Updat, 2001. 4(2): p. 135–6.Google Scholar
- 26.Abend, M., Reasons to reconsider the significance of apoptosis for cancer therapy. Int J Radiat Biol, 2003. 79(12): p. 927–41.Google Scholar
- 27.Shankar, S., T.R. Singh, and R.K. Srivastava, Ionizing radiation enhances the therapeutic potential of TRAIL in prostate cancer in vitro and in vivo: Intracellular mechanisms. Prostate, 2004. 61(1): p. 35–49.Google Scholar
- 28.Abou El Hassan, M.A., et al., Overexpression of Bcl2 abrogates chemo-and radiotherapy-induced sensitisation of NCI-H460 non-small-cell lung cancer cells to adenovirus-mediated expression of full-length TRAIL. Br J Cancer, 2004. 91(1): p. 171–7.Google Scholar
- 29.Marini, P. and C. Belka, Death receptor ligands: new strategies for combined treatment with ionizing radiation. Curr Med Chem Anti-Canc Agents, 2003. 3(5): p. 334–42.Google Scholar
- 30.Chauhan, D., et al., Cytochrome c-dependent and-independent induction of apoptosis in multiple myeloma cells. J Biol Chem, 1997. 272(48): p. 29995–7.Google Scholar
- 31.Yu, Y. and J.B. Little, p53 is involved in but not required for ionizing radiation-induced caspase-3 activation and apoptosis in human lymphoblast cell lines. Cancer Res, 1998. 58(19): p. 4277–81.Google Scholar
- 32.Herr, I. and K.M. Debatin, Cellular stress response and apoptosis in cancer therapy. Blood, 2001. 98(9): p. 2603–14.Google Scholar
- 33.Rudner, J., et al., Radiation sensitivity and apoptosis in human lymphoma cells. Int J Radiat Biol, 2001. 77(1): p. 1–11.Google Scholar
- 34.Mackey, T.J., et al., bcl-2/bax ratio as a predictive marker for therapeutic response to radiotherapy in patients with prostate cancer. Urology, 1998. 52(6): p. 1085–90.Google Scholar
- 35.Matsumoto, H., et al., Bax to Bcl-2 ratio and Ki-67 index are useful predictors of neoadjuvant chemoradiation therapy in bladder cancer. Jpn J Clin Oncol, 2004. 34(3): p. 124–30.Google Scholar
- 36.Scopa, C.D., et al., bcl-2/bax ratio as a predictive marker for therapeutic response to radiotherapy in patients with rectal cancer. Appl Immunohistochem Mol Morphol, 2001. 9(4): p. 329–34.Google Scholar
- 37.Wacheck, V., et al., Bcl-x(L) antisense oligonucleotides radiosensitise colon cancer cells. Br J Cancer, 2003. 89(7): p. 1352–7.Google Scholar
- 38.Lowe, S.L., et al., Prostate-specific expression of Bax delivered by an adenoviral vector induces apoptosis in LNCaP prostate cancer cells. Gene Ther, 2001. 8(18): p. 1363–71.Google Scholar
- 39.Belka, C. and W. Budach, Anti-apoptotic Bcl-2 proteins: structure, function and relevance for radiation biology. Int J Radiat Biol, 2002. 78(8): p. 643–58.Google Scholar
- 40.Arafat, W.O., et al., An adenovirus encoding proapoptotic Bax synergistically radiosensitizes malignant glioma. Int J Radiat Oncol Biol Phys, 2003. 55(4): p. 1037–50.Google Scholar
- 41.Yip, K.W., et al., Potential utility of bim(s) as a novel apoptotic therapeutic molecule. Mol Ther, 2004. 10(3): p. 533–44.Google Scholar
- 42.Belka, C., et al., Apoptosis-modulating agents in combination with radiotherapy-current status and outlook. Int J Radiat Oncol Biol Phys, 2004. 58(2): p. 542–54.Google Scholar
- 43.Wachsberger, P., R. Burd, and A.P. Dicker, Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: exploring mechanisms of interaction. Clin Cancer Res, 2003. 9(6): p. 1957–71.Google Scholar
- 44.Fridman, J.S. and S.W. Lowe, Control of apoptosis by p53. Oncogene, 2003. 22(56): p. 9030–40.Google Scholar
- 45.Slee, E.A., D.J. O’Connor, and X. Lu, To die or not to die: how does p53 decide? Oncogene, 2004. 23(16): p. 2809–18.Google Scholar
- 46.Fei, P., E.J. Bernhard, and W.S. El-Deiry, Tissue-specific induction of p53 targets in vivo. Cancer Res, 2002. 62(24): p. 7316–27.Google Scholar
- 47.Lowe, S.W., et al., p53 status and the efficacy of cancer therapy in vivo. Science, 1994. 266(5186): p. 807–10.Google Scholar
- 48.Gasco, M. and T. Crook, p53 family members and chemoresistance in cancer: what we know and what we need to know. Drug Resist Updat, 2003. 6(6): p. 323–8.Google Scholar
- 49.Leo, C., A.J. Giaccia, and N.C. Denko, The hypoxic tumor microenvironment and gene expression. Semin Radiat Oncol, 2004. 14(3): p. 207–14.Google Scholar
- 50.Hammond, E.M. and A.J. Giaccia, The role of ATM and ATR in the cellular response to hypoxia and re-oxygenation. DNA Repair (Amst), 2004. 3(8–9): p. 1117–22.Google Scholar
- 51.Graeber, T.G., et al., Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature, 1996. 379(6560): p. 88–91.Google Scholar
- 52.Geoerger, B., et al., Potentiation of radiation therapy by the oncolytic adenovirus d11520 (ONYX-015) in human malignant glioma xenografts. Br J Cancer, 2003. 89(3): p. 577–84.Google Scholar
- 53.Nishizaki, M., et al., Synergistic inhibition of human lung cancer cell growth by adenovirus-mediated wild-type p53 gene transfer in combination with docetaxel and radiation therapeutics in vitro and in vivo. Clin Cancer Res, 2001. 7(9): p. 2887–97.Google Scholar
- 54.Swisher, S.G., et al., Induction of p53-regulated genes and tumor regression in lung cancer patients after intratumoral delivery of adenoviral p53 (INGN 201) and radiation therapy. Clin Cancer Res, 2003. 9(1): p. 93–101.Google Scholar
- 55.Fang, B. and J.A. Roth, The role of gene therapy in combined modality treatment strategies for cancer. Curr Opin Mol Ther, 2003. 5(5): p. 475–82.Google Scholar
- 56.Komarova, E.A., et al., Dual effect of p53 on radiation sensitivity in vivo: p53 promotes hematopoietic injury, but protects from gastro-intestinal syndrome in mice. Oncogene, 2004. 23(19): p. 3265–71.Google Scholar
- 57.Komarov, P.G., et al., A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science, 1999. 285(5434): p. 1733–7.Google Scholar
- 58.Santana, P., et al., Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell, 1996. 86(2): p. 189–99.Google Scholar
- 59.Pena, L.A., Z. Fuks, and R.N. Kolesnick, Radiation-induced apoptosis of endothelial cells in the murine central nervous system: protection by fibroblast growth factor and sphingomyelinase deficiency. Cancer Res, 2000. 60(2): p. 321–7.Google Scholar
- 60.Paris, F., et al., Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science, 2001. 293(5528): p. 293–7.Google Scholar
- 61.Brown, M., et al., Comment on "Tumor response to radiotherapy regulated by endothelial cell apoptosis” (II). Science, 2003. 302(5652): p. 1894; author reply 1894.Google Scholar
- 62.Garcia-Barros, M., et al., Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science, 2003. 300(5622): p. 1155–9.Google Scholar
- 63.Hill, R.P., et al., Normal tissue radiobiology: from the laboratory to the clinic. Int J Radiat Oncol Biol Phys, 2001. 49(2): p. 353–65.Google Scholar
- 64.Aldridge, D.R., M.J. Arends, and I.R. Radford, Increasing the susceptibility of the rat 208F fibroblast cell line to radiation-induced apoptosis does not alter its clonogenic survival dose-response. Br J Cancer, 1995. 71(3): p. 571–7.Google Scholar
- 65.Sheridan, M.T. and C.M. West, Ability to undergo apoptosis does not correlate with the intrinsic radiosensitivity (SF2) of human cervix tumor cell lines. Int J Radiat Oncol Biol Phys, 2001. 50(2): p. 503–9.Google Scholar
- 66.Pollack, A., et al., The early supra-additive apoptotic response of R3327-G prostate tumors to androgen ablation and radiation is not sustained with multiple fractions. Int J Radiat Oncol Biol Phys, 2000. 46(1): p. 153–8.Google Scholar
- 67.Hintz, B.L., C. Koo, and J.F. Murphy, Pattern of proliferative index (Ki-67) after anti-androgen manipulation reflects the ability of irradiation to control prostate cancer. Am J Clin Oncol, 2004. 27(1): p. 85–8.Google Scholar
- 68.Musacchio, A. and K.G. Hardwick, The spindle checkpoint: structural insights into dynamic signalling. Nat Rev Mol Cell Biol, 2002. 3(10): p. 731–41.Google Scholar
- 69.Okada, H. and T.W. Mak, Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer, 2004. 4(8): p. 592–603.Google Scholar
- 70.Sudo, T., et al., Activation of Cdhl-dependent APC is required for G1 cell cycle arrest and DNA damage-induced G2 checkpoint in vertebrate cells. Embo J, 2001. 20(22): p. 6499–508.Google Scholar
- 71.Roninson, I.B., Tumor senescence as a determinant of drug response in vivo. Drug Resist Updat, 2002. 5(5): p. 204–8.Google Scholar
- 72.Jonathan, E.C., E.J. Bernhard, and W.G. McKenna, How does radiation kill cells? Curr Opin Chem Biol, 1999. 3(1): p. 77–83.Google Scholar
- 73.Elliott, M.J., et al., Bcl-2 inhibits early apoptotic events and reveals post-mitotic multinucleation without affecting cell cycle arrest in human epithelial tumor cells exposed to etoposide. Cancer Chemother Pharmacol, 1999. 44(1): p. 1–11.Google Scholar
- 74.Castedo, M., et al., Cell death by mitotic catastrophe: a molecular definition. Oncogene, 2004. 23(16): p. 2825–37.Google Scholar
- 75.Nitta, M., et al., Spindle checkpoint function is required for mitotic catastrophe induced by DNA-damaging agents. Oncogene, 2004. 23(39): p. 6548–58.Google Scholar
- 76.Altieri, D.C., Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene, 2003. 22(53): p. 8581–9.Google Scholar
- 77.Li, F., et al., Control of apoptosis and mitotic spindle checkpoint by survivin. Nature, 1998. 396(6711): p. 580–4.Google Scholar
- 78.Uren, A.G., et al., Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype. Curr Biol, 2000. 10(21): p. 1319–28.Google Scholar
- 79.Carvalho, A., et al., Survivin is required for stable checkpoint activation in taxol-treated HeLa cells. J Cell Sci, 2003. 116(Pt 14): p. 2987–98.Google Scholar
- 80.Lu, B., et al., Survivin as a therapeutic target for radiation sensitization in lung cancer. Cancer Res, 2004. 64(8): p. 2840–5.Google Scholar
- 81.Mirza, A., et al., Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene, 2002. 21(17): p. 2613–22.Google Scholar
- 82.Hoffmnan, W.H., et al., Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J Biol Chem, 2002. 277(5): p. 3247–57.Google Scholar
- 83.Zhou, M., et al., DNA damage induces a novel p53-survivin signaling pathway regulating cell cycle and apoptosis in acute lymphoblastic leukemia cells. J Pharmacol Exp Ther, 2002. 303(1): p. 124–31.Google Scholar
- 84.Adida, C., et al., Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation. Am J Pathol, 1998. 152(1): p. 43–9.Google Scholar
- 85.Asanuma, K., et al., A role for survivin in radioresistance of pancreatic cancer cells. Jpn J Cancer Res, 2002. 93(9): p. 1057–62.Google Scholar
- 86.Rodel, F., et al., High survivin expression is associated with reduced apoptosis in rectal cancer and may predict disease-free survival after preoperative radiochemotherapy and surgical resection. Strahlenther Onkol, 2002. 178(8): p. 426–35.Google Scholar
- 87.Rodel, C., et al., Spontaneous and radiation-induced apoptosis in colorectal carcinoma cells with different intrinsic radiosensitivities: survivin as a radioresistance factor. Int J Radiat Oncol Biol Phys, 2003. 55(5): p. 1341–7.Google Scholar
- 88.Grossman, D., et al., Expression and targeting of the apoptosis inhibitor, survivin, in human melanoma. J Invest Dermatol, 1999. 113(6): p. 1076–81.Google Scholar
- 89.Pennati, M., et al., Radiosensitization of human melanoma cells by ribozyme-mediated inhibition of survivin expression. J Invest Dermatol, 2003. 120(4): p. 648–54.Google Scholar
- 90.Cao, C., et al., XIAP and survivin as therapeutic targets for radiation sensitization in preclinical models of lung cancer. Oncogene, 2004.Google Scholar
- 91.O’Connor, D.S., et al., Control of apoptosis during angiogenesis by survivin expression in endothelial cells. Am J Pathol, 2000. 156(2): p. 393–8.Google Scholar
- 92.Mesri, M., et al., Suppression of vascular endothelial growth factor-mediated endothelial cell protection by survivin targeting. Am J Pathol, 2001. 158(5): p. 1757–65.Google Scholar
- 93.Blanc-Brude, O.P., et al., Therapeutic targeting of the survivin pathway in cancer: initiation of mitochondrial apoptosis and suppression of tumor-associated angiogenesis. Clin Cancer Res, 2003. 9(7): p. 2683–92.Google Scholar
- 94.Dixon, H. and C.J. Norbury, Therapeutic exploitation of checkpoint defects in cancer cells lacking p53 function. Cell Cycle, 2002. 1(6): p. 362–8.Google Scholar
- 95.Koniaras, K., et al., Inhibition of Chkl-dependent G2 DNA damage checkpoint radiosensitizes p53 mutant human cells. Oncogene, 2001. 20(51): p. 7453–63.Google Scholar
- 96.Hayflick, L. and P.S. Moorhead, The serial cultivation of human diploid cell strains. Exp Cell Res, 1961. 25: p. 585–621.Google Scholar
- 97.Campisi, J., From cells to organisms: can we learn about aging from cells in culture? Exp Gerontol, 2001. 36(4–6): p. 607–18.Google Scholar
- 98.Elenbaas, B. and R.A. Weinberg, Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res, 2001. 264(1): p. 169–84.Google Scholar
- 99.Sedelnikova, O.A., et al., Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat Cell Biol, 2004. 6(2): p. 168–70.Google Scholar
- 100.Wang, E., M.J. Lee, and S. Pandey, Control of fibroblast senescence and activation of programmed cell death. J Cell Biochem, 1994. 54(4): p. 432–9.Google Scholar
- 101.Spaulding, C., W. Guo, and R.B. Effros, Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp Gerontol, 1999. 34(5): p. 633–44.Google Scholar
- 102.Harrington, L. and M.O. Robinson, Telomere dysfunction: multiple paths to the same end. Oncogene, 2002. 21(4): p. 592–7.Google Scholar
- 103.Guo, C., et al., Inhibition of telomerase is related to the life span and tumorigenicity of human prostate cancer cells. J Urol, 2001. 166(2): p. 694–8.Google Scholar
- 104.Orlando, C., et al., Telomerase in urological malignancy. J Urol, 2001. 166(2): p. 666–73.Google Scholar
- 105.Rubio, M.A., S.H. Kim, and J. Campisi, Reversible manipulation of telomerase expression and telomere length. Implications for the ionizing radiation response and replicative senescence of human cells. J Biol Chem, 2002. 277(32): p. 28609–17.Google Scholar
- 106.Pandita, T.K. and J.L. Roti Roti, Role of telomerase in radiocurability (review). Oncol Rep, 2003. 10(2): p. 263–70.Google Scholar
- 107.Pirzio, L.M., et al., Human fibroblasts expressing hTERT show remarkable karyotype stability even after exposure to ionizing radiation. Cytogenet Genome Res, 2004. 104(1–4): p. 87–94.Google Scholar
- 108.Bouffier, S.D., et al., Telomeric sequences, radiation sensitivity and genomic instability. Int J Radiat Biol, 2001. 77(10): p. 995–1005.Google Scholar
- 109.Goytisolo, F.A., et al., Short telomeres result in organismal hypersensitivity to ionizing radiation in mammals. J Exp Med, 2000. 192(11): p. 1625–36.Google Scholar
- 110.Hauguel, T. and F. Bunz, Haploinsufficiency of hTERT leads to telomere dysfunction and radiosensitivity in human cancer cells. Cancer Biol Ther, 2003. 2(6): p. 679–84.Google Scholar
- 111.Wong, K.K., et al., Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation. Nat Genet, 2000. 26(1): p. 85–8.Google Scholar
- 112.Kim, H.R., et al., Change of telomerase activity in rectal cancer with chemoradiation therapy. J Korean Med Sci, 2000. 15(2): p. 167–72.Google Scholar
- 113.Ogawa, Y., et al., Changes in telomerase activity of advanced cancers of oral cavity and oropharynx during radiation therapy: correlation with clinical outcome. Int J Mol Med, 1998. 2(3): p. 301–307.Google Scholar
- 114.Sawant, S.G., et al., Telomerase activity as a measure for monitoring radiocurability of tumor cells. Faseb J, 1999. 13(9): p. 1047–54.Google Scholar
- 115.Turriziani, M., et al., Residual telomerase activity: a marker of cell survival after exposure to gamma radiation in vitro. Anticancer Res, 2003. 23(6C): p. 4561–9.Google Scholar
- 116.Chang, B.D., et al., A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res, 1999. 59(15): p. 3761–7.Google Scholar
- 117.te Poele, R.H., et al., DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res, 2002. 62(6): p. 1876–83.Google Scholar
- 118.Wouters, B.G., et al., A p53 and apoptotic independent role for p21waf1 in tumour response to radiation therapy. Oncogene, 1999. 18(47): p. 6540–5.Google Scholar
- 119.Rodemann, H.P., et al., Selective enrichment and biochemical characterization of seven human skin fibroblasts cell types in vitro. Exp Cell Res, 1989. 180(1): p. 84–93.Google Scholar
- 120.Niggli, H.J., et al., Mitomycin C-induced postmitotic fibroblasts retain the capacity to repair pyrimidine photodimers formed after UV-irradiation. Mutat Res, 1989. 219(4): p. 231–40.Google Scholar
- 121.Di Leonardo, A., et al., DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cipl in normal human fibroblasts. Genes Dev, 1994. 8(21): p. 2540–51.Google Scholar
- 122.Schmitt, C.A., et al., Dissecting p53 tumor suppressor functions in vivo. Cancer Cell, 2002. 1(3): p. 289–98.Google Scholar
- 123.Kim, J.H., J.H. Shin, and I.H. Kim, Susceptibility and radiosensitization of human glioblastoma cells to trichostatin A, a histone deacetylase inhibitor. Int J Radiat Oncol Biol Phys, 2004. 59(4): p. 1174–80.Google Scholar
- 124.Biade, S., et al., Chemical agents that promote chromatin compaction radiosensitize tumour cells. Int J Radiat Biol, 2001. 77(10): p. 1033–42.Google Scholar
- 125.Camphausen, K., et al., Enhanced radiation-induced cell killing and prolongation of gammaH2AX foci expression by the histone deacetylase inhibitor MS-275. Cancer Res, 2004. 64(1): p. 316–21.Google Scholar
- 126.Chung, Y.L., A.J. Wang, and L.F. Yao, Antitumor histone deacetylase inhibitors suppress cutaneous radiation syndrome: Implications for increasing therapeutic gain in cancer radiotherapy. Mol Cancer Ther, 2004. 3(3): p. 317–25.Google Scholar
- 127.Chang, B.D., et al., Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases. Proc Natl Acad Sci U S A, 2000. 97(8): p. 4291–6.Google Scholar
- 128.Buffa, F.M., et al., Molecular marker profiles predict locoregional control of head and neck squamous cell carcinoma in a randomized trial of continuous hyperfractionated accelerated radiotherapy. Clin Cancer Res, 2004. 10(11): p. 3745–54.Google Scholar
- 129.Gewirtz, D.A., Growth arrest and cell death in the breast tumor cell in response to ionizing radiation and chemotherapeutic agents which induce DNA damage. Breast Cancer Res Treat, 2000. 62(3): p. 223–35.Google Scholar
- 130.Lera, J., et al., Tumor proliferation, p53 expression, and apoptosis in laryngeal carcinoma: relation to the results of radiotherapy. Cancer, 1998. 83(12): p. 2493–501.Google Scholar
- 131.Li, R., et al., Ki-67 staining index predicts distant metastasis and survival in locally advanced prostate cancer treated with radiotherapy: an analysis of patients in radiation therapy oncology group protocol 86-10. Clin Cancer Res, 2004. 10(12 Pt 1): p. 4118–24.Google Scholar
- 132.Pillai, M.R., P.G. Jayaprakash, and M.K. Nair, Tumour-proliferative fraction and growth factor expression as markers of tumour response to radiotherapy in cancer of the uterine cervix. J Cancer Res Clin Oncol, 1998. 124(8): p. 456–61.Google Scholar
- 133.Qureshi, K.N., et al., Combined p21WAF1/CIP1 and p53 overexpression predict improved survival in muscle-invasive bladder cancer treated by radical radiotherapy. Int J Radiat Oncol Biol Phys, 2001. 51(5): p. 1234–40.Google Scholar
- 134.Rigaud, J., et al., Expression of p21 cell cycle protein is an independent predictor of response to salvage radiotherapy after radical prostatectomy. Prostate, 2004. 58(3): p. 269–76.Google Scholar
- 135.Santucci, M.A., et al., Radiation-induced gadd45 expression correlates with clinical response to radiotherapy of cervical carcinoma. Int J Radiat Oncol Biol Phys, 2000. 46(2): p. 411–6.Google Scholar
- 136.Sohda, M., et al., Pretreatment evaluation of combined HIF-lalpha, p53 and p21 expression is a useful and sensitive indicator of response to radiation and chemotherapy in esophageal cancer. Int J Cancer, 2004. 110(6): p. 838–44.Google Scholar
- 137.Adell, G.C., et al., Apoptosis in rectal carcinoma: prognosis and recurrence after preoperative radiotherapy. Cancer, 2001. 91(10): p. 1870–5.Google Scholar
- 138.Chang, J., et al., Apoptosis and proliferation as predictors of chemotherapy response in patients with breast carcinoma. Cancer, 2000. 89(11): p. 2145–52.Google Scholar
- 139.Chung, E.J., et al., Spontaneous apoptosis as a predictor of radiotherapy in patients with stage IIB squamous cell carcinoma of the uterine cervix. Acta Oncol, 1999. 38(4): p. 449–54.Google Scholar
- 140.Gasinska, A., et al., A ratio of apoptosis to mitosis, proliferation pattern and prediction of radiotherapy response in cervical carcinoma. Neoplasma, 2002. 49(6): p. 379–86.Google Scholar
- 141.Kim, J.Y., et al., Tumor apoptosis in cervical cancer: its role as a prognostic factor in 42 radiotherapy patients. Int J Cancer, 2001. 96(5): p. 305–12.Google Scholar
- 142.Langendijk, H., et al., Cell proliferation and apoptosis in stage III inoperable non-small cell lung carcinoma treated by radiotherapy. Radiother Oncol, 2000. 56(2): p. 197–207.Google Scholar
- 143.Lara, P.C., et al., Apoptosis in carcinoma of the bladder: relation with radiation treatment results. Int J Radiat Oncol Biol Phys, 1999. 43(5): p. 1015–9.Google Scholar
- 144.Levine, E.L., et al., Apoptosis, intrinsic radiosensitivity and prediction of radiotherapy response in cervical carcinoma. Radiother Oncol, 1995. 37(1): p. 1–9.Google Scholar
- 145.Marijnen, C.A., et al., High intrinsic apoptosis, but not radiation-induced apoptosis, predicts better survival in rectal carcinoma patients. Int J Radiat Oncol Biol Phys, 2003. 57(2): p. 434–43.Google Scholar
- 146.Paxton, J.R., et al., Apoptosis in cervical squamous carcinoma: predictive value for survival following radiotherapy. J Clin Pathol, 2000. 53(3): p. 197–200.Google Scholar
- 147.Ravi, D., et al., Apoptosis, angiogenesis and proliferation: trifunctional measure of tumour response to radiotherapy for oral cancer. Oral Oncol, 2001. 37(2): p. 164–71.Google Scholar
- 148.Rodel, C., et al., Apoptosis, p53, bcl-2, and Ki-67 in invasive bladder carcinoma: possible predictors for response to radiochemotherapy and successful bladder preservation. Int J Radiat Oncol Biol Phys, 2000. 46(5): p. 1213–21.Google Scholar
- 149.Shears, L.L., et al., Apoptosis in esophageal cancer following induction chemoradiotherapy. J Surg Res, 1998. 79(1): p. 20–4.Google Scholar
- 150.Wheeler, J.A., et al., ASTRO Research Fellowship: apoptosis as a predictor of tumor response to radiation in stage IB cervical carcinoma. American Society for Therapeutic Radiology and Oncology. Int J Radiat Oncol Biol Phys, 1995. 32(5): p. 1487–93.Google Scholar
- 151.Shah, R. and W.S. El-Deiry, p53-Dependent Activation of a Molecular Beacon in Tumor Cells Following Exposure to Doxorubicin Chemotherapy. Cancer Biol Ther, 2004. 3(9).Google Scholar
- 152.Blasberg, R.G. and J.G. Tjuvajev, Molecular-genetic imaging: current and future perspectives. J Clin Invest, 2003. 111(11): p. 1620–9.Google Scholar
- 153.Haas, R.L., et al., In vivo imaging of radiation-induced apoptosis in follicular lymphoma patients. Int J Radiat Oncol Biol Phys, 2004. 59(3): p. 782–7.Google Scholar
- 154.Lahorte, C.M., et al., Apoptosis-detecting radioligands: current state of the art and future perspectives. Eur J Nucl Med Mol Imaging, 2004. 31(6): p. 887–919.Google Scholar