SUMMARY

Recent advances in our understanding of the mechanisms behind programmed cell death have greatly informed the design of targeted therapeutic strategies. Future research into other forms of cell death will be equally important in order to assemble a full complement of agents that induce or prevent cell death.

REFERENCES

1. Varfolomeev, E.E. and Ashkenazi, A., Tumor necrosis factor: an apoptosis JuNKie? Cell, 116 (4), 491-497, 2004.

2. Pan, G., Ni, J., Wei, Y.F., Yu, G., Gentz, R., and Dixit, V.M., An antagonist decoy receptor and a death domain-containing receptor for TRAIL, Science, 277 (5327), 815-818, 1997.

3. van Noesel, M.M., van Bezouw, S., Salomons, G.S., Voute, P.A., Pieters, R., Baylin, S.B., Herman, J.G., and Versteeg, R., Tumor-specific down-regulation of the tumor necrosis factor-related apoptosis­inducing ligand decoy receptors DcR1 and DcR2 is associated with dense promoter hypermethylation, Cancer Res, 62 (7), 2157-2161, 2002.

4. Cretney, E., Takeda, K., Yagita, H., Glaccum, M., Peschon, J.J., and Smyth, M.J., Increased suscep­tibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice, J. Immunol., 168 (3), 1356-1361, 2002.

5. Takeda, K., Hayakawa, Y., Smyth, M.J., Kayagaki, N., Yamaguchi, N., Kakuta, S., Iwakura, Y., Yagita, H., and Okumura, K., Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells, Nat. Med., 7 (1), 94-100, 2001.

6. Almasan, A. and Ashkenazi, A., Apo2L∕TRAIL: apoptosis signaling, biology, and potential for cancer therapy, Cytokine Growth Factor Rev., 14 (3-4), 337-348, 2003.

7. Mundt, B., Kuhnel, F., Zender, L., Paul, Y., Tillmann, H., Trautwein, C., Manns, M.P., and Kubicka, S., Involvement of TRAIL and its receptors in viral hepatitis, FASEB J., 17 (1), 94-96, 2003.

8. Tollefson, A.E., Toth, K., Doronin, K., Kuppuswamy, M., Doronina, O.A., Lichtenstein, D.L., Hermiston, T.W., Smith, C.A., and Wold, W.S., Inhibition of TRAIL-induced apoptosis and forced internalization of TRAIL receptor 1 by adenovirus proteins, J. Virol., 75 (19), 8875-8887, 2001.

9. Jenkins, M., Keir, M., and McCune, J.M., A membrane-bound Fas decoy receptor expressed by human thymocytes, J. Biol. Chem., 275 (11), 7988-7993, 2000.

10. Ashkenazi, A., Targeting death and decoy receptors of the tumour-necrosis factor superfamily, Nat. Rev. Cancer, 2 (6), 420-430, 2002.

11. Ashkenazi, A., Pai, R.C., Fong, S., Leung, S., Lawrence, D.A., Marsters, S.A., Blackie, C., Chang,

L., McMurtrey, A.E., Hebert, A., DeForge, L., Koumenis, I.L., Lewis, D., Harris, L., Bussiere, J., Koeppen, H., Shahrokh, Z., and Schwall, R.H., Safety and antitumor activity of recombinant soluble Apo2 ligand, J. Clin. Invest., 104 (2), 155-162, 1999.

12. Walczak, H., Miller, R.E., Ariail, K., Gliniak, B., Griffith, T.S., Kubin, M., Chin, W., Jones, J., Woodward, A., Le, T., Smith, C., Smolak, P., Goodwin, R.G., Rauch, C.T., Schuh, J.C., and Lynch,

D. H., Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo, Nat. Med., 5 (2), 157-163, 1999.

13. Jo, M., Kim, T.H., Seol, D.W., Esplen, J.E., Dorko, K., Billiar, T.R., and Strom, S.C., Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand, Nat. Med., 6 (5), 564-567, 2000.

14. Kelley, S.K., Harris, L.A., Xie, D., Deforge, L., Totpal, K., Bussiere, J., and Fox, J.A., Preclinical studies to predict the disposition of Apo2L∕tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety, J.

15. Xu, Z.W., Kleeff, J., Friess, H., Buchler, M.W., and Solioz, M., Synergistic cytotoxic effect of TRAIL and gemcitabine in pancreatic cancer cells, Anticancer Res., 23 (1A), 251-258, 2003.

16. Ray, S. and Almasan, A., Apoptosis induction in prostate cancer cells and xenografts by combined treatment with Apo2 ligand∕tumor necrosis factor-related apoptosis-inducing ligand and CPT-11, Cancer Res., 63 (15), 4713-4723, 2003.

17. Zhang, H.G., Wang, J., Yang, X., Hsu, H.C., and Mountz, J.D., Regulation of apoptosis proteins in cancer cells by ubiquitin, Oncogene, 23 (11), 2009-2015, 2004.

18. Clem, R.J. and Miller, L.K., Control of programmed cell death by the baculovirus genes p35 and iap, Mol. Cell Biol., 14 (8), 5212-5222, 1994.

19. Uren, A.G., Pakusch, M., Hawkins, C.J., Puls, K.L., and Vaux, D.L., Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and∕or bind tumor necrosis factor receptor-associated factors, Proc. Natl. Acad. Sci. U.S.A., 93 (10), 4974-4978, 1996.

20. Rothe, M., Pan, M.G., Henzel, W.J., Ayres, T.M., and Goeddel, D.V., The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins, Cell, 83 (7), 1243-1252, 1995.

21. Liston, P., Fong, W.G., and Korneluk, R.G., The inhibitors of apoptosis: there is more to life than Bcl2, Oncogene, 22 (53), 8568-8580, 2003.

22. Baens, M., Maes, B., Steyls, A., Geboes, K., Marynen, P., and De Wolf-Peeters, C., The product of the t(11;18), an API2-MLT fusion, marks nearly half of gastric MALT type lymphomas without large cell proliferation, Am. J. Pathol., 156 (4), 1433-1439, 2000.

23. Sasaki, H., Sheng, Y., Kotsuji, F., and Tsang, B.K., Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells, Cancer Res., 60 (20), 5659-5666, 2000.

24. Li, J., Feng, Q., Kim, J.M., Schneiderman, D., Liston, P., Li, M., Vanderhyden, B., Faught, W., Fung,

M.

25. Hu, Y., Cherton-Horvat, G., Dragowska, V., Baird, S., Korneluk, R.G., Durkin, J.P., Mayer, L.D., and LaCasse, E.C., Antisense oligonucleotides targeting XIAP induce apoptosis and enhance chemother­apeutic activity against human lung cancer cells in vitro and in vivo, Clin. Cancer Res., 9 (7), 2826-2836, 2003.

26. Holmlund, J.T., Applying antisense technology: Affinitak and other antisense oligonucleotides in clinical development, Ann. N.Y. Acad. Sci., 1002, 244-251, 2003.

27. Schimmer, A.D., Welsh, K., Pinilla, C., Wang, Z., Krajewska, M., Bonneau, M.J., Pedersen, I.M., Kitada, S., Scott, F.L., Bailly-Maitre, B., Glinsky, G., Scudiero, D., Sausville, E., Salvesen, G., Nefzi, A., Ostresh, J.M., Houghten, R.A., and Reed, J.C., Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity, Cancer Cell., 5 (1), 25-35, 2004.

28. Wu, T.Y., Wagner, K.W., Bursulaya, B., Schultz, P.G., and Deveraux, Q.L., Development and char­acterization of nonpeptidic small molecule inhibitors of the XIAP/caspase-3 interaction, Chem. Biol., 10 (8), 759-767, 2003.

29. Fulda, S., Wick, W., Weller, M., and Debatin, K.M., Smac agonists sensitize for Apo2L∕TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo, Nat. Med., 8 (8), 808-815, 2002.

30. Yang, L., Mashima, T., Sato, S., Mochizuki, M., Sakamoto, H., Yamori, T., Oh-Hara, T., and Tsuruo, T., Predominant suppression of apoptosome by inhibitor of apoptosis protein in non-small cell lung cancer H460 cells: therapeutic effect of a novel polyarginine-conjugated Smac peptide, Cancer Res., 63 (4), 831-837, 2003.

31. Liston, P., Roy, N., Tamai, K., Lefebvre, C., Baird, S., Cherton-Horvat, G., Farahani, R., McLean, M., Ikeda, J.E., MacKenzie, A., and Korneluk, R.G., Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes, Nature, 379 (6563), 349-353, 1996.

32. Xu, D.G., Crocker, S.J., Doucet, J.P., St.-Jean, M., Tamai, K., Hakim, A.M., Ikeda, J.E., Liston, P., Thompson, C.S., Korneluk, R.G., MacKenzie, A., and Robertson, G.S., Elevation of neuronal expres­sion of NAIP reduces ischemic damage in the rat hippocampus, Nat. Med., 3 (9), 997-1004, 1997.

33. Perrelet, D., Ferri, A., Liston, P., Muzzin, P., Korneluk, R.G., and Kato, A.C., IAPs are essential for GDNF-mediated neuroprotective effects in injured motor neurons in vivo, Nat. Cell Biol., 4 (2), 175-179, 2002.

34. Iwata, A., Harlan, J.M., Vedder, N.B., and Winn, R.K., The caspase inhibitor z-VAD is more effective than CD18 adhesion blockade in reducing muscle ischemia-reperfusion injury: implication for clinical trials, Blood, 100 (6), 2077-2080, 2002.

35. Hara, H., Friedlander, R.M., Gagliardini, V., Ayata, C., Fink, K., Huang, Z., Shimizu-Sasamata, M., Yuan, J., and Moskowitz, M.A., Inhibition of interleukin 1 converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage, Proc. Natl. Acad. Sci. U.S.A., 94 (5), 2007-2012, 1997.

36. Natori, S., Higuchi, H., Contreras, P., and Gores, G.J., The caspase inhibitor IDN-6556 prevents caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injury, Liver Transpl., 9 (3), 278-284, 2003.

37. Valentino, K.L., Gutierrez, M., Sanchez, R., Winship, M.J., and Shapiro, D.A., First clinical trial of a novel caspase inhibitor: anti-apoptotic caspase inhibitor, IDN-6556, improves liver enzymes, Int. J. Clin. Pharmacol. Ther., 41 (10), 441-449, 2003.

38. Cauwels, A., Janssen, B., Waeytens, A., Cuvelier, C., and Brouckaert, P., Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2, Nat. Immunol., 4 (4), 387-393, 2003.

39. Nguyen, J.T. and Wells, J.A., Direct activation of the apoptosis machinery as a mechanism to target cancer cells, Proc. Natl. Acad. Sci. U.S.A., 100 (13), 7533-7538, 2003.

40.

41. Liu, X., Kim, C.N., Yang, J., Jemmerson, R., and Wang, X., Induction of apoptotic program in cell- free extracts: requirement for dATP and cytochrome c, Cell, 86 (1), 147-157, 1996.

42. Tsujimoto, Y., Finger, L.R., Yunis, J., Nowell, P.C., and Croce, C.M., Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation, Science, 226 (4678), 1097-1099, 1984.

43. Vaux, D.L., Cory, S., and Adams, J.M., Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells, Nature, 335 (6189), 440-442, 1988.

44. McDonnell, T.J., Deane, N., Platt, F.M., Nunez, G., Jaeger, U., McKearn, J.P., and Korsmeyer, S.J., Bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphop­roliferation, Cell, 57 (1), 79-88, 1989.

45. Cory, S. and Adams, J.M., The Bcl2 family: regulators of the cellular life-or-death switch, Nat. Rev. Cancer, 2 (9), 647-656, 2002.

46. Wei, M.C., Zong, W.X., Cheng, E.H., Lindsten, T., Panoutsakopoulou, V., Ross, A.J., Roth, K.A., MacGregor, G.R., Thompson, C.B., and Korsmeyer, S.J., Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death, Science, 292 (5517), 727-730, 2001.

47. Scorrano, L., Oakes, S.A., Opferman, J.T., Cheng, E.H., Sorcinelli, M.D., Pozzan, T., and Korsmeyer, S.J., BAX and BAK regulation of endoplasmic reticulum Ca²+: a control point for apoptosis, Science, 300 (5616), 135-139, 2003.

48. Zong, W.X., Li, C., Hatzivassiliou, G., Lindsten, T., Yu, Q.C., Yuan, J., and Thompson, C.B., Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis, J. Cell Biol., 162 (1), 59-69, 2003.

49. Vander Heiden, M.G., Chandel, N.S., Schumacker, P.T., and Thompson, C.B., Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ADP exchange, Mol. Cell, 3 (2), 159-167, 1999.

50. Bouillet, P. and Strasser, A., BH3-only proteins — evolutionarily conserved proapoptotic Bcl-2 family members essential for initiating programmed cell death, J. Cell Sci., 115 (Pt. 8), 1567-1574, 2002.

51. Letai, A., Bassik, M.C., Walensky, L.D., Sorcinelli, M.D., Weiler, S., and Korsmeyer, S.J., Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer thera­peutics, Cancer Cell, 2 (3), 183-192, 2002.

52. Webb, A., Cunningham, D., Cotter, F., Clarke, P.A., di Stefano, F., Ross, P., Corbo, M., and Dziewanowska, Z., BCL-2 antisense therapy in patients with non-Hodgkin lymphoma, Lancet, 349 (9059), 1137-1141, 1997.

53. Marcucci, G., Byrd, J.C., Dai, G., Klisovic, M.I., Kourlas, PJ., Young, D.C., Cataland, S.R., Fisher,

D. B., Lucas, D., Chan, K.K., Porcu, P., Lin, Z.P., Farag, S.F., Frankel, S.R., Zwiebel, J.A., Kraut,

E. H., Balcerzak, S.P., Bloomfield, C.D., Grever, M.R., and Caligiuri, M.A., Phase 1 and pharmaco­dynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia, Blood, 101 (2), 425-432, 2003.

54. Jansen, B., Wacheck, V., Heere-Ress, E., Schlagbauer-Wadl, H., Hoeller, C., Lucas, T., Hoermann, M., Hollenstein, U., Wolff, K., and Pehamberger, H., Chemosensitisation of malignant melanoma by BCL2 antisense therapy, Lancet, 356 (9243), 1728-1733, 2000.

55. Rudin, C.M., Kozloff, M., Hoffman, P.C., Edelman, M.J., Karnauskas, R., Tomek, R., Szeto, L., and Vokes, E.E., Phase I study of G3139, a Bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer, J. Clin. Oncol., 22 (6), 1110-1117, 2004.

56. Sattler, M., Liang, H., Nettesheim, D., Meadows, R.P., Harlan, J.E., Eberstadt, M., Yoon, H.S., Shuker, S.B., Chang, B.S., Minn, A.J., Thompson, C.B., and Fesik, S.W., Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis, Science, 275 (5302), 983-986, 1997.

57. Wang, J.L., Zhang, Z.J., Choksi, S., Shan, S., Lu, Z., Croce, C.M., Alnemri, E.S., Korngold, R., and Huang, Z., Cell permeable Bcl-2 binding peptides: a chemical approach to apoptosis induction in tumor cells, Cancer Res., 60 (6), 1498-1502, 2000.

58. Degterev, A., Lugovskoy, A., Cardone, M., Mulley, B., Wagner, G., Mitchison, T., and Yuan, J., Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL, Nat. Cell Biol., 3 (2), 173-182, 2001.

59. Tzung, S.P., Kim, K.M., Basanez, G., Giedt, C.D., Simon, J., Zimmerberg, J., Zhang, K.Y., and Hockenbery, D.M., Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3, Nat. Cell Biol., 3 (2), 183-191, 2001.

60. Polster, B.M., Kinnally, K.W., and Fiskum, G., BH3 death domain peptide induces cell type-selective mitochondrial outer membrane permeability, J. Biol. Chem., 276 (41), 37887-37894, 2001.

61. Chan, S.L., Lee, M.C., Tan, K.O., Yang, L.K., Lee, A.S., Flotow, H., Fu, N.Y., Butler, M.S., Soejarto, D.D., Buss, A.D., and Yu, V.C., Identification of chelerythrine as an inhibitor of BclXL function, J. Biol. Chem., 278 (23), 20453-20456, 2003.

62. Dubois-Dauphin, M., Frankowski, H., Tsujimoto, Y., Huarte, J., and Martinou, J.C., Neonatal moto­neurons overexpressing the Bcl-2 protooncogene in transgenic mice are protected from axotomy- induced cell death, Proc. Natl. Acad. Sci. U.S.A., 91 (8), 3309-3313, 1994.

63. Linnik, M.D., Zahos, P., Geschwind, M.D., and Federoff, H.J., Expression of Bcl-2 from a defective herpes simplex virus-1 vector limits neuronal death in focal cerebral ischemia, Stroke, 26 (9), 1670-1674, discussion 1675, 1995.

64. Kostic, V., Jackson-Lewis, V., de Bilbao, F., Dubois-Dauphin, M., and Przedborski, S., Bcl-2: pro­longing life in a transgenic mouse model of familial amyotrophic lateral sclerosis, Science, 277 (5325), 559-562, 1997.

65. Fawell, S., Seery, J., Daikh, Y., Moore, C., Chen, L.L., Pepinsky, B., and Barsoum, J., Tat- mediated delivery of heterologous proteins into cells, Proc. Natl. Acad. Sci. U.S.A., 91 (2), 664-668, 1994.

66. Schwarze, S.R., Ho, A., Vocero-Akbani, A., and Dowdy, S.F., In vivo protein transduction: delivery of a biologically active protein into the mouse, Science, 285 (5433), 1569-1572, 1999.

67. Wadia, J.S., Stan, R.V., and Dowdy, S.F., Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis, Nat. Med., 10 (3), 310-315, 2004.

68. Asoh, S., Ohsawa, I., Mori, T., Katsura, K., Hiraide, T., Katayama, Y., Kimura, M., Ozaki, D., Yamagata, K., and Ohta, S., Protection against ischemic brain injury by protein therapeutics, Proc. Natl. Acad. Sci. U.S.A., 99 (26), 17107-17112, 2002.

69. Sharkey, J. and Butcher, S.P., Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia, Nature, 371 (6495), 336-339, 1994.

70. Liu, J., Farmer, J.D., Jr., Lane, W.S., Friedman, J., Weissman, I., and Schreiber, S.L., Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes, Cell, 66 (4), 807-815, 1991.

71. Okonkwo, D.O. and Povlishock, J.T., An intrathecal bolus of cyclosporin A before injury preserves mitochondrial integrity and attenuates axonal disruption in traumatic brain injury, J. Cereb. Blood Flow Metab., 19 (4), 443-451, 1999.

72. Uchino, H., Minamikawa-Tachino, R., Kristian, T., Perkins, G., Narazaki, M., Siesjo, B.K., and Shibasaki, F., Differential neuroprotection by cyclosporin A and FK506 following ischemia corre­sponds with differing abilities to inhibit calcineurin and the mitochondrial permeability transition, Neurobiol. Dis., 10 (3), 219-233, 2002.

73. Keep, M., Elmer, E., Fong, K.S., and Csiszar, K., Intrathecal cyclosporin prolongs survival of late­stage ALS mice, Brain Res., 894 (2), 327-331, 2001.

74. Polster, B.M., Basanez, G., Young, M., Suzuki, M., and Fiskum, G., Inhibition of Bax-induced cytochrome c release from neural cell and brain mitochondria by dibucaine and propranolol, J. Neurosci., 23 (7), 2735-2743, 2003.

75. El-Deiry, W.S., The role of p53 in chemosensitivity and radiosensitivity, Oncogene, 22 (47), 7486-7495, 2003.

76. Hoffman, W.H., Biade, S., Zilfou, J.T., Chen, J., and Murphy, M., Transcriptional repression of the anti-apoptotic survivin gene by wild type p53, J. Biol. Chem., 277 (5), 3247-3257, 2002.

77. Caelles, C., Helmberg, A., and Karin, M., p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes, Nature, 370 (6486), 220-223, 1994.

78. Chipuk, J.E., Kuwana, T., Bouchier-Hayes, L., Droin, N.M., Newmeyer, D.D., Schuler, M., and Green, D.R., Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apo­ptosis, Science, 303 (5660), 1010-1014, 2004.

79. Dumont, P., Leu, J.I., Della Pietra, A.C., III, George, D.L., and Murphy, M., The codon 72 poly­morphic variants of p53 have markedly different apoptotic potential, Nat. Genet., 33 (3), 357-365,

2003.

80. Mihara, M., Erster, S., Zaika, A., Petrenko, O., Chittenden, T., Pancoska, P., and Moll, U.M., p53 has a direct apoptogenic role at the mitochondria, Mol. Cell, 11 (3), 577-590, 2003.

81. Leu, J.I., Dumont, P., Hafey, M., Murphy, M.E., and George, D.L., Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex, Nat. Cell Biol., 6 (5), 443-450, 2004.

82. Nishizaki, M., Meyn, R.E., Levy, L.B., Atkinson, E.N., White, R.A., Roth, J.A., and Ji, L., 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., 7 (9), 2887-2897, 2001.

83. Merritt, J.A., Roth, J.A., and Logothetis, C.J., Clinical evaluation of adenoviral-mediated p53 gene transfer: review of INGN 201 studies, Semin. Oncol., 28 (5, Suppl. 16), 105-114, 2001.

84. Buller, R.E., Shahin, M.S., Horowitz, J.A., Runnebaum, I.B., Mahavni, V., Petrauskas, S., Kreien- berg, R., Karlan, B., Slamon, D., and Pegram, M., Long term follow-up of patients with recurrent ovarian cancer after Ad p53 gene replacement with SCH 58500, Cancer Gene Ther., 9 (7), 567-572,

2002.

85. Zhang, J.Y., Apoptosis-based anticancer drugs, Nat. Rev. Drug Discov., 1 (2), 101-102, 2002.

86. Pearson, S., Jia, H., and Kandachi, K., China approves first gene therapy, Nat. Biotechnol., 22 (1), 3-4, 2004.

87. Dobbelstein, M., Replicating adenoviruses in cancer therapy, Curr. Top. Microbiol. Immunol., 273, 291-334, 2004.

88. Khuri, F.R., Nemunaitis, J., Ganly, I., Arseneau, J., Tannock, I.F., Romel, L., Gore, M., Ironside, J., MacDougall, R.H., Heise, C., Randlev, B., Gillenwater, A.M., Bruso, P., Kaye, S.B., Hong, W.K., and Kirn, D.H., A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer, Nat. Med., 6 (8), 879-885, 2000.

89. Rudin, C.M., Cohen, E.E., Papadimitrakopoulou, V.A., Silverman, S., Jr., Recant, W., El-Naggar, A.K., Stenson, K., Lippman, S.M., Hong, W.K., and Vokes, E.E., An attenuated adenovirus, ONYX-015, as mouthwash therapy for premalignant oral dysplasia, J. Clin. Oncol., 21 (24), 4546-4552, 2003.

90. Foster, B.A., Coffey, H.A., Morin, M.J., and Rastinejad, F., Pharmacological rescue of mutant p53 conformation and function, Science, 286 (5449), 2507-2510, 1999.

91. Rippin, T.M., Bykov, V.J., Freund, S.M., Selivanova, G., Wiman, K.G., and Fersht, A.R., Character­ization of the p53-rescue drug CP-31398 in vitro and in living cells, Oncogene, 21 (14), 2119-2129,

2002.

92. Takimoto, R., Wang, W., Dicker, D.T., Rastinejad, F., Lyssikatos, J., and el-Deiry, W.S., The mutant p53-conformation modifying drug, CP-31398, can induce apoptosis of human cancer cells and can stabilize wild-type p53 protein, Cancer Biol. Ther., 1 (1), 47-55, 2002.

93. Bykov, V.J., Issaeva, N., Shilov, A., Hultcrantz, M., Pugacheva, E., Chumakov, P., Bergman, J., Wiman, K.G., and Selivanova, G., Restoration of the tumor suppressor function to mutant p53 by a low- molecular-weight compound, Nat. Med., 8 (3), 282-288, 2002.

94. Hupp, T.R., Sparks, A., and Lane, D.P., Small peptides activate the latent sequence-specific DNA binding function of p53, Cell, 83 (2), 237-245, 1995.

95. Snyder, E.L., Meade, B.R., Saenz, C.C., and Dowdy, S.F., Treatment of terminal peritoneal carcino­matosis by a transducible p53-activating peptide, PLoS Biol., 2 (2), E36, 186-193, 2004.

96. Chene, P., Inhibiting the p53-MDM2 interaction: an important target for cancer therapy, Nat. Rev. Cancer, 3 (2), 102-109, 2003.

97. Eymin, B., Gazzeri, S., Brambilla, C., and Brambilla, E., Mdm2 overexpression and p14(ARF) inactivation are two mutually exclusive events in primary human lung tumors, Oncogene, 21 (17), 2750-2761, 2002.

98. Bueso-Ramos, C.E., Manshouri, T., Haidar, M.A., Yang, Y., McCown, P., Ordonez, N., Glassman, A., Sneige, N., and Albitar, M., Abnormal expression of MDM-2 in breast carcinomas, Breast Cancer Res. Treat., 37 (2), 179-188, 1996.

99. Momand, J., Jung, D., Wilczynski, S., and Niland, J., The MDM2 gene amplification database, Nucleic Acids Res., 26 (15), 3453-3459, 1998.

100. Burri, N., Shaw, P., Bouzourene, H., Sordat, I., Sordat, B., Gillet, M., Schorderet, D., Bosman, F.T., and Chaubert, P., Methylation silencing and mutations of the p14ARF and p16INK4a genes in colon cancer, Lab. Invest., 81 (2), 217-229, 2001.

101. Tortora, G., Caputo, R., Damiano, V., Bianco, R., Chen, J., Agrawal, S., Bianco, A.R., and Ciardiello,

F., A novel MDM2 anti-sense oligonucleotide has anti-tumor activity and potentiates cytotoxic drugs acting by different mechanisms in human colon cancer, Int. J. Cancer, 88 (5), 804-809, 2000.

102. Zhang, R. and Wang, H., Antisense oligonucleotide inhibitors of MDM2 oncogene expression, Meth­ods Mol. Med., 85, 205-222, 2003.

103. Capoulade, C., Mir, L.M., Carlier, K., Lecluse, Y., Tetaud, C., Mishal, Z., and Wiels, J., Apoptosis of tumoral and nontumoral lymphoid cells is induced by both mdm2 and p53 antisense oligodeoxynu­cleotides, Blood, 97 (4), 1043-1049, 2001.

104. Vassilev, L.T., Vu, B.T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., Fotouhi, N., and Liu, E.A., In vivo activation of the p53 pathway by small­molecule antagonists of MDM2, Science, 303 (5659), 844-848, 2004.

105. Nikolaev, A.Y., Li, M., Puskas, N., Qin, J., and Gu, W., Parc: a cytoplasmic anchor for p53, Cell, 112 (1), 29-40, 2003.

106. Datta, S.R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y., and Greenberg, M.E., Akt phosphory­lation of BAD couples survival signals to the cell-intrinsic death machinery, Cell, 91 (2), 231-241, 1997.

107. Dudek, H., Datta, S.R., Franke, T.F., Birnbaum, M.J., Yao, R., Cooper, G.M., Segal, R.A., Kaplan, D.R., and Greenberg, M.E., Regulation of neuronal survival by the serine-threonine protein kinase Akt, Science, 275 (5300), 661-665, 1997.

108. Burgering, B.M. and Medema, R.H., Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty, J. Leukoc. Biol., 73 (6), 689-701, 2003.

109. Manning, B.D. and Cantley, L.C., United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling, Biochem. Soc. Trans., 31 (Pt. 3), 573-578, 2003.

110. Plas, D.R., Talapatra, S., Edinger, A.L., Rathmell, J.C., and Thompson, C.B., Akt and Bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology, J. Biol. Chem., 276 (15), 12041-12048, 2001.

111. Vander Heiden, M.G., Plas, D.R., Rathmell, J.C., Fox, C.J., Harris, M.H., and Thompson, C.B., Growth factors can influence cell growth and survival through effects on glucose metabolism, Mol. Cell Biol., 21 (17), 5899-5912, 2001.

112. Stambolic, V., Suzuki, A., de la Pompa, J.L., Brothers, G.M., Mirtsos, C., Sasaki, T., Ruland, J., Penninger, J.M., Siderovski, D.P., and Mak, T.W., Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN, Cell, 95 (1), 29-39, 1998.

113. Cunningham, C.C., Holmlund, J.T., Geary, R.S., Kwoh, T.J., Dorr, A., Johnston, J.F., Monia, B., and Nemunaitis, J., A phase I trial of H-ras antisense oligonucleotide ISIS 2503 administered as a continuous intravenous infusion in patients with advanced carcinoma, Cancer, 92 (5), 1265-1271, 2001.

114. Baselga, J., Tripathy, D., Mendelsohn, J., Baughman, S., Benz, C.C., Dantis, L., Sklarin, N.T., Seidman, A.D., Hudis, C.A., Moore, J., Rosen, P.P., Twaddell, T., Henderson, I.C., and Norton, L., Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2∕neu-overexpressing metastatic breast cancer, J. Clin. Oncol., 14 (3), 737-744, 1996.

115. Slamon, D.J., Leyland-Jones, B., Shak, S., Fuchs, H., Paton, V., Bajamonde, A., Fleming, T., Eiermann, W., Wolter, J., Pegram, M., Baselga, J., and Norton, L., Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2, N. Engl. J. Med., 344 (11), 783-792, 2001.

116. Druker, B.J., Tamura, S., Buchdunger, E., Ohno, S., Segal, G.M., Fanning, S., Zimmermann, J., and Lydon, N.B., Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells, Nat. Med., 2 (5), 561-566, 1996.

117. Deininger, M.W. and Druker, B.J., Specific targeted therapy of chronic myelogenous leukemia with imatinib, Pharmacol. Rev., 55 (3), 401-423, 2003.

118. Demetri, G.D., von Mehren, M., Blanke, C.D., Van den Abbeele, A.D., Eisenberg, B., Roberts, PJ., Heinrich, M.C., Tuveson, D.A., Singer, S., Janicek, M., Fletcher, J.A., Silverman, S.G., Silberman, S.L., Capdeville, R., Kiese, B., Peng, B., Dimitrijevic, S., Druker, B.J., Corless, C., Fletcher, C.D., and Joensuu, H., Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors, N. Engl. J. Med., 347 (7), 472-480, 2002.

119. Lynch, T.J., Bell, D.W., Sordella, R., Gurubhagavatula, S., Okimoto, R.A., Brannigan, B.W., Harris, P.L., Haserlat, S.M., Supko, J.G., Haluska, F.G., Louis, D.N., Christiani, D.C., Settleman, J., and Haber, D.A., Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib, N. Engl. J. Med., 350 (21), 2129-2139, 2004.

120. Bianco, R., Shin, I., Ritter, C.A., Yakes, F.M., Basso, A., Rosen, N., Tsurutani, J., Dennis, P.A., Mills,

G. B., and Arteaga, C.L., Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells coun­teracts the antitumor action of EGFR tyrosine kinase inhibitors, Oncogene, 22 (18), 2812-2822, 2003.

121. Eaton, S.R., Cody, W.L., Doherty, A.M., Holland, D.R., Panek, R.L., Lu, G.H., Dahring, T.K., and Rose, D.R., Design of peptidomimetics that inhibit the association of phosphatidylinositol 3-kinase with platelet-derived growth factor- receptor and possess cellular activity, J. Med. Chem., 41 (22), 4329-4342, 1998.

122. Djordjevic, S. and Driscoll, P.C., Structural insight into substrate specificity and regulatory mecha­nisms of phosphoinositide 3-kinases, Trends Biochem. Sci., 27 (8), 426-432, 2002.

123. Bjornsti, M.A. and Houghton, PJ., The TOR pathway: a target for cancer therapy, Nat. Rev. Cancer, 4 (5), 335-348, 2004.

124. Fox, C.J., Hammerman, P.S., Cinalli, R.M., Master, S.R., Chodosh, L.A., and Thompson, C.B., The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor, Genes Dev., 17 (15), 1841-1854, 2003.

125. Davies, H., Bignell, G.R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M.J., Bottomley, W., Davis, N., Dicks, E., Ewing, R., Floyd, Y., Gray, K., Hall, S., Hawes, R., Hughes, J., Kosmidou, V., Menzies, A., Mould, C., Parker, A., Stevens, C., Watt, S., Hooper, S., Wilson, R., Jayatilake, H., Gusterson, B.A., Cooper, C., Shipley, J., Hargrave, D., Pritchard-Jones, K., Maitland, N., Chenevix-Trench, G., Riggins, G.J., Bigner, D.D., Palmieri, G., Cossu, A., Flanagan, A., Nicholson, A., Ho, J.W., Leung, S.Y., Yuen, S.T., Weber, B.L., Seigler, H.F., Darrow, T.L., Paterson,

H., Marais, R., Marshall, C.J., Wooster, R., Stratton, M.R., and Futreal, P.A., Mutations of the BRAF gene in human cancer, Nature, 417 (6892), 949-954, 2002.

126. Hingorani, S.R., Jacobetz, M.A., Robertson, G.P., Herlyn, M., and Tuveson, D.A., Suppression of BRAF(V599E) in human melanoma abrogates transformation, Cancer Res., 63 (17), 5198-5202,

2003.

127. Lyons, J.F., Wilhelm, S., Hibner, B., and Bollag, G., Discovery of a novel Raf kinase inhibitor, Endocr. Relat. Cancer, 8 (3), 219-225, 2001.

128. Bollag, G., Freeman, S., Lyons, J.F., and Post, L.E., Raf pathway inhibitors in oncology, Curr. Opin. Investig. Drugs, 4 (12), 1436-1441, 2003.

129. Ghosh, S., May, M.J., and Kopp, E.B., NF-B and Rel proteins: evolutionarily conserved mediators of immune responses, Annu. Rev. Immunol., 16(1), 225-260, 1998.

130. Finco, T.S., Westwick, J.K., Norris, J.L., Beg, A.A., Der, C.J., and Baldwin, A.S., Jr., Oncogenic Ha­Ras-induced signaling activates NF-B transcriptional activity, which is required for cellular transfor­mation, J. Biol. Chem., 272 (39), 24113-24116, 1997.

131. Karin, M., Cao, Y., Greten, F.R., and Li, Z.W., NF-B in cancer: from innocent bystander to major culprit, Nat. Rev. Cancer, 2 (4), 301-310, 2002.

132. Reuther, J.Y., Reuther, G.W., Cortez, D., Pendergast, A.M., and Baldwin, A.S., Jr., A requirement for NF-B activation in Bcr-Abl-mediated transformation, Genes Dev., 12 (7), 968-981, 1998.

133. Chu, Z.L., DiDonato, J.A., Hawiger, J., and Ballard, D.W., The tax oncoprotein of human T-cell leukemia virus type 1 associates with and persistently activates IκB kinases containing IKKα and IKKβ, J. Biol. Chem., 273 (26), 15891-15894, 1998.

134. Karin, M. and Ben-Neriah, Y., Phosphorylation meets ubiquitination: the control of NF-κB activity, Annu. Rev. Immunol., 18(1), 621-663, 2000.

135. Karin, M., Yamamoto, Y., and Wang, Q.M., The IKK NF-κB system: a treasure trove for drug development, Nat. Rev. Drug Discov., 3 (1), 17-26, 2004.

136. Haefner, B., NF-κB: arresting a major culprit in cancer, Drug Discov. Today, 7 (12), 653-663, 2002.

137. Epinat, J.C. and Gilmore, T.D., Diverse agents act at multiple levels to inhibit the Rel/NF-B signal transduction pathway, Oncogene, 18 (49), 6896-6909, 1999.

138. Castrillo, A., Diaz-Guerra, M.J., Hortelano, S., Martin-Sanz, P., and Bosca, L., Inhibition of IB kinase and IB phosphorylation by 15-deoxy-Delta(12,14)-prostaglandin J(2) in activated murine macro­phages, Mol. Cell Biol., 20 (5), 1692-1698, 2000.

139. Cernuda-Morollon, E., Pineda-Molina, E., Canada, F.J., and Perez-Sala, D., 15-Deoxy-12,14-prostag- landin J2 inhibition of NF-B-DNA binding through covalent modification of the p50 subunit, J. Biol. Chem., 276 (38), 35530-35536, 2001.

140. Diab, A., Deng, C., Smith, J.D., Hussain, R.Z., Phanavanh, B., Lovett-Racke, A.E., Drew, P.D., and Racke, M.K., Peroxisome proliferator-activated receptor-gamma agonist 15-deoxy-(12,14)-prostag- landin J(2) ameliorates experimental autoimmune encephalomyelitis, J. Immunol., 168 (5), 2508-2515,

2002.

141. Kawahito, Y., Kondo, M., Tsubouchi, Y., Hashiramoto, A., Bishop-Bailey, D., Inoue, K., Kohno, M., Yamada, R., Hla, T., and Sano, H., 15-deoxy-(12,14)-PGJ(2) induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats, J. Clin. Invest., 106 (2), 189-197, 2000.

142. Lee, W.P., Tai, D.I., Tsai, S.L., Yeh, C.T., Chao, Y., Lee, S.D., and Hung, M.C., Adenovirus type 5 E1A sensitizes hepatocellular carcinoma cells to gemcitabine, Cancer Res., 63 (19), 6229-6236,

2003.

143. Chattopadhyay, D., Ghosh, M.K., Mal, A., and Harter, M.L., Inactivation of p21 by E1A leads to the induction of apoptosis in DNA-damaged cells, J. Virol., 75 (20), 9844-9856, 2001.

144. Wagner, J.A., Technology evaluation: tgDCC-E1A, targeted genetics/MD Anderson, Curr. Opin. Mol. Ther., 1 (2), 266-270, 1999.

145. Villaret, D., Glisson, B., Kenady, D., Hanna, E., Carey, M., Gleich, L., Yoo, G.H., Futran, N., Hung, M.C., Anklesaria, P., and Heald, A.E., A multicenter phase II study of tgDCC-E1A for the intratumoral treatment of patients with recurrent head and neck squamous cell carcinoma, Head Neck, 24 (7), 661-669, 2002.

146. Hefti, F., Neurotrophic factor therapy for nervous system degenerative diseases, J. Neurobiol., 25 (11), 1418-1435, 1994.

147. Haase, G., Kennel, P., Pettmann, B., Vigne, E., Akli, S., Revah, F., Schmalbruch, H., and Kahn, A., Gene therapy of murine motor neuron disease using adenoviral vectors for neurotrophic factors, Nat. Med., 3 (4), 429-436, 1997.

148. Aebischer, P., Schluep, M., Deglon, N., Joseph, J.M., Hirt, L., Heyd, B., Goddard, M., Hammang, J.P., Zurn, A.D., Kato, A.C., Regli, F., and Baetge, E.E., Intrathecal delivery of CNTF using encap­sulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients, Nat. Med., 2

(6), 696-699, 1996.

149. Pan, W., Banks, W.A., and Kastin, A.J., Permeability of the blood-brain barrier to neurotrophins, Brain Res., 788 (1-2), 87-94, 1998.

150. Wu, D. and Pardridge, W.M., Neuroprotection with noninvasive neurotrophin delivery to the brain, Proc. Natl. Acad. Sci. U.S.A., 96 (1), 254-259, 1999.

151. Song, B.W., Vinters, H.V., Wu, D., and Pardridge, W.M., Enhanced neuroprotective effects of basic fibroblast growth factor in regional brain ischemia after conjugation to a blood-brain barrier delivery vector, J. Pharmacol. Exp. Ther., 301 (2), 605-610, 2002.

152. Pollack, S.J. and Harper, S.J., Small molecule Trk receptor agonists and other neurotrophic factor mimetics, Curr. Drug Targets CNS Neurol. Disord., 1 (1), 59-80, 2002.

153. Digicaylioglu, M. and Lipton, S.A., Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-B signalling cascades, Nature, 412 (6847), 641-647, 2001.

154. Parsa, C.J., Matsumoto, A., Kim, J., Riel, R.U., Pascal, L.S., Walton, G.B., Thompson, R.B., Petrofski, J.A., Annex, B.H., Stamler, J.S., and Koch, W.J., A novel protective effect of erythropoietin in the infarcted heart, J. Clin. Invest., 112 (7), 999-1007, 2003.

155. Ehrenreich, H., Hasselblatt, M., Dembowski, C., Cepek, L., Lewczuk, P., Stiefel, M., Rustenbeck, H.H., Breiter, N., Jacob, S., Knerlich, F., Bohn, M., Poser, W., Ruther, E., Kochen, M., Gefeller, O., Gleiter, C., Wessel, T.C., De Ryck, M., Itri, L., Prange, H., Cerami, A., Brines, M., and Siren, A.L., Erythropoietin therapy for acute stroke is both safe and beneficial, Mol. Med., 8 (8), 495-505, 2002.

156. Erbayraktar, S., Grasso, G., Sfacteria, A., Xie, Q.W., Coleman, T., Kreilgaard, M., Torup, L., Sager, T., Erbayraktar, Z., Gokmen, N., Yilmaz, O., Ghezzi, P., Villa, P., Fratelli, M., Casagrande, S., Leist, M., Helboe, L., Gerwein, J., Christensen, S., Geist, M.A., Pedersen, L.O., Cerami-Hand, C., Wuerth, J.P., Cerami, A., and Brines, M., Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo, Proc. Natl. Acad. Sci. U.S.A., 100 (11), 6741-6746, 2003.

157. Adams, J., The development of proteasome inhibitors as anticancer drugs, Cancer Cell, 5 (5), 417-421,

2004.

158. Mitra-Kaushik, S., Harding, J.C., Hess, J., and Ratner, L., Effects of the proteasome inhibitor PS-341 on tumor growth in HTLV-1 tax transgenic mice and tax tumor transplants, Blood, 104(3), 802-809,

2004.

159. Orlowski, R.Z., Stinchcombe, T.E., Mitchell, B.S., Shea, T.C., Baldwin, A.S., Stahl, S., Adams, J., Esseltine, D.L., Elliott, PJ., Pien, C.S., Guerciolini, R., Anderson, J.K., Depcik-Smith, N.D., Bhagat, R., Lehman, M.J., Novick, S.C., O'Connor, O.A., and Soignet, S.L., Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies, J. Clin. Oncol., 20 (22), 4420-4427, 2002.

160. Soengas, M.S., Capodieci, P., Polsky, D., Mora, J., Esteller, M., Opitz-Araya, X., McCombie, R., Herman, J.G., Gerald, W.L., Lazebnik, Y.A., Cordon-Cardo, C., and Lowe, S.W., Inactivation of the apoptosis effector Apaf-1 in malignant melanoma, Nature, 409 (6817), 207-211, 2001.

161. Esteller, M., Cordon-Cardo, C., Corn, P.G., Meltzer, S.J., Pohar, K.S., Watkins, D.N., Capella, G., Peinado, M.A., Matias-Guiu, X., Prat, J., Baylin, S.B., and Herman, J.G., p14ARF silencing by promoter hypermethylation mediates abnormal intracellular localization of MDM2, Cancer Res., 61

(7), 2816-2821, 2001.

162. Teitz, T., Wei, T., Valentine, M.B., Vanin, E.F., Grenet, J., Valentine, V.A., Behm, F.G., Look, A.T., Lahti, J.M., and Kidd, V.J., Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN, Nat. Med., 6 (5), 529-535, 2000.

163. Fulda, S., Kufer, M.U., Meyer, E., van Valen, F., Dockhorn-Dworniczak, B., and Debatin, K.M., Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer, Oncogene, 20 (41), 5865-5877, 2001.

164. Flynn, J., Fang, J.Y., Mikovits, J.A., and Reich, N.O., A potent cell-active allosteric inhibitor of murine DNA cytosine C5 methyltransferase, J. Biol. Chem., 278 (10), 8238-8243, 2003.

165. Lyons, J., Bayar, E., Fine, G., McCullar, M., Rolens, R., Rubinfeld, J., and Rosenfeld, C., Decitabine: development of a DNA methyltransferase inhibitor for hematological malignancies, Curr. Opin. Investig. Drugs, 4 (12), 1442-1450, 2003.

166. Piekarz, R.L., Robey, R., Sandor, V., Bakke, S., Wilson, W.H., Dahmoush, L., Kingma, D.M., Turner, M.L., Altemus, R., and Bates, S.E., Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report, Blood, 98 (9), 2865-2868, 2001.

167. Richon, V.M. and O'Brien, J.P., Histone deacetylase inhibitors: a new class of potential therapeutic agents for cancer treatment, Clin. Cancer Res., 8 (3), 662-664, 2002.

168. Breckenridge, D.G., Germain, M., Mathai, J.P., Nguyen, M., and Shore, G.C., Regulation of apoptosis by endoplasmic reticulum pathways, Oncogene, 22 (53), 8608-8618, 2003.

169. Nakagawa, T., Zhu, H., Morishima, N., Li, E., Xu, J., Yankner, B.A., and Yuan, J., Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-, Nature, 403 (6765), 98-103, 2000.

170. Saleh, M., Vaillancourt, J.P., Graham, R.K., Huyck, M., Srinivasula, S.M., Alnemri, E.S., Steinberg, M.H., Nolan, V., Baldwin, C.T., Hotchkiss, R.S., Buchman, T.G., Zehnbauer, B.A., Hayden, M.R., Farrer, L.A., Roy, S., and Nicholson, D.W., Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms, Nature, 429 (6987), 75-79, 2004.

171. Li, H., Kolluri, S.K., Gu, J., Dawson, M.I., Cao, X., Hobbs, P.D., Lin, B., Chen, G., Lu, J., Lin, F., Xie, Z., Fontana, J.A., Reed, J.C., and Zhang, X., Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3, Science, 289 (5482), 1159-1164, 2000.

172. Cohen, F.E. and Kelly, J.W., Therapeutic approaches to protein-misfolding diseases, Nature, 426 (6968), 905-909, 2003.

173. Ankarcrona, M., Dypbukt, J.M., Orrenius, S., and Nicotera, P., Calcineurin and mitochondrial function in glutamate-induced neuronal cell death, FEBS Lett., 394 (3), 321-324, 1996.

174. Koch, H.J., Szecsey, A., and Haen, E., NMDA-antagonism (memantine): an alternative pharmacolog­ical therapeutic principle in Alzheimer's and vascular dementia, Curr. Pharm. Des., 10 (3), 253-259,

2004.

175. Tariot, P.N., Farlow, M.R., Grossberg, G.T., Graham, S.M., McDonald, S., and Gergel, I., Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial, JAMA, 291 (3), 317-324, 2004.

176. Chandel, N.S., Schumacker, P.T., and Arch, R.H., Reactive oxygen species are downstream products of TRAF-mediated signal transduction, J. Biol. Chem., 276 (46), 42728-42736, 2001.

177. Sakon, S., Xue, X., Takekawa, M., Sasazuki, T., Okazaki, T., Kojima, Y., Piao, J.H., Yagita, H., Okumura, K., Doi, T., and Nakano, H., NF-B inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death, EMBO J., 22 (15), 3898-3909, 2003.

178. Holler, N., Zaru, R., Micheau, O., Thome, M., Attinger, A., Valitutti, S., Bodmer, J.L., Schneider, P., Seed, B., and Tschopp, J., Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule, Nat. Immunol., 1 (6), 489-495, 2000.

179. Chan, F.K., Shisler, J., Bixby, J.G., Felices, M., Zheng, L., Appel, M., Orenstein, J., Moss, B., and Lenardo, M.J., A role for tumor necrosis factor receptor-2 and receptor-interacting protein in pro­grammed necrosis and antiviral responses, J. Biol. Chem., 278 (51), 51613-51621, 2003.

180. Lin, Y., Choksi, S., Shen, H.M., Yang, Q.F., Hur, G.M., Kim, Y.S., Tran, J.H., Nedospasov, S.A., and Liu, Z.G., Tumor necrosis factor-induced nonapoptotic cell death requires receptor-interacting protein- mediated cellular reactive oxygen species accumulation, J. Biol. Chem., 279 (11), 10822-10828, 2004.

181. Radi, R., Nitric oxide, oxidants, and protein tyrosine nitration, Proc. Natl. Acad. Sci. U.S.A., 101 (12), 4003-4008, 2004.

182. Pratico, D., Uryu, K., Leight, S., Trojanoswki, J.Q., and Lee, V.M., Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis, J. Neurosci., 21 (12), 4183-4187, 2001.

183. Nunomura, A., Perry, G., Aliev, G., Hirai, K., Takeda, A., Balraj, E.K., Jones, P.K., Ghanbari, H., Wataya, T., Shimohama, S., Chiba, S., Atwood, C.S., Petersen, R.B., and Smith, M.A., Oxidative damage is the earliest event in Alzheimer disease, J. Neuropathol. Exp. Neurol., 60 (8), 759-767, 2001.

184. Funk, C.D. and Cyrus, T., 12/15-lipoxygenase, oxidative modification of LDL and atherogenesis, Trends Cardiovasc. Med., 11 (3-4), 116-124, 2001.

185. Pratico, D., Zhukareva, V., Yao, Y., Uryu, K., Funk, C.D., Lawson, J.A., Trojanowski, J.Q., and Lee, V.M., 12/15-lipoxygenase is increased in Alzheimer's disease: possible involvement in brain oxidative stress, Am. J. Pathol., 164 (5), 1655-1662, 2004.

186. Li, Y., Maher, P., and Schubert, D., A role for 12-lipoxygenase in nerve cell death caused by glutathione depletion, Neuron, 19 (2), 453-463, 1997.

187. Huang, J.T., Welch, J.S., Ricote, M., Binder, C.J., Willson, T.M., Kelly, C., Witztum, J.L., Funk, C.D., Conrad, D., and Glass, C.K., Interleukin-4-dependent production of PPAR- ligands in macrophages by 12/15-lipoxygenase, Nature, 400 (6742), 378-382, 1999.

188. Cutler, R.G., Kelly, J., Storie, K., Pedersen, W.A., Tammara, A., Hatanpaa, K., Troncoso, J.C., and Mattson, M.P., Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metab­olism in brain aging and Alzheimer's disease, Proc. Natl. Acad. Sci. U.S.A., 101 (7), 2070-2075, 2004.

189. Wolozin, B., Kellman, W., Ruosseau, P., Celesia, G.G., and Siegel, G., Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors, Arch. Neurol., 57 (10), 1439-1443, 2000.

190. Fassbender, K., Simons, M., Bergmann, C., Stroick, M., Lutjohann, D., Keller, P., Runz, H., Kuhl, S., Bertsch, T., von Bergmann, K., Hennerici, M., Beyreuther, K., and Hartmann, T., Simvastatin strongly reduces levels of Alzheimer's disease -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo, Proc. Natl. Acad. Sci. U.S.A., 98 (10), 5856-5861, 2001.

191. Kellner-Weibel, G., Geng, Y.J., and Rothblat, G.H., Cytotoxic cholesterol is generated by the hydrolysis of cytoplasmic cholesteryl ester and transported to the plasma membrane, Atherosclerosis, 146 (2), 309-319, 1999.

192. Buxbaum, J.D., Geoghagen, N.S., and Friedhoff, L.T., Cholesterol depletion with physiological con­centrations of a statin decreases the formation of the Alzheimer amyloid Abeta peptide, J. Alzheimers Dis., 3 (2), 221-229, 2001.

193. Zhao, Z.Q., Oxidative stress-elicited myocardial apoptosis during reperfusion, Curr. Opin. Pharmacol., 4 (2), 159-165, 2004.

194. Li, C. and Jackson, R.M., Reactive species mechanisms of cellular hypoxia-reoxygenation injury, Am. J. Physiol. Cell Physiol., 282 (2), C227-C241, 2002.

195. Deshpande, J.K., Siesjo, B.K., and Wieloch, T., Calcium accumulation and neuronal damage in the rat hippocampus following cerebral ischemia, J. Cereb. Blood Flow Metab., 7 (1), 89-95, 1987.

196. Verma, S., Fedak, P.W., Weisel, R.D., Butany, J., Rao, V., Maitland, A., Li, R.K., Dhillon, B., and Yau, T.M., Fundamentals of reperfusion injury for the clinical cardiologist, Circulation, 105 (20), 2332-2336, 2002.

197. De Vries, B., Matthijsen, R.A., Wolfs, T.G., Van Bijnen, A.A., Heeringa, P., and Buurman, W.A., Inhibition of complement factor C5 protects against renal ischemia-reperfusion injury: inhibition of late apoptosis and inflammation, Transplantation, 75 (3), 375-382, 2003.

198. Baker, K., Marcus, C.B., Huffman, K., Kruk, H., Malfroy, B., and Doctrow, S.R., Synthetic combined superoxide dismutase/catalase mimetics are protective as a delayed treatment in a rat stroke model: a key role for reactive oxygen species in ischemic brain injury, J. Pharmacol. Exp. Ther., 284 (1), 215-221, 1998.

199. Gianello, P., Saliez, A., Bufkens, X., Pettinger, R., Misseleyn, D., Hori, S., and Malfroy, B., EUK- 134, a synthetic superoxide dismutase and catalase mimetic, protects rat kidneys from ischemia­reperfusion-induced damage, Transplantation, 62 (11), 1664-1666, 1996.

200. Pucheu, S., Boucher, F., Sulpice, T., Tresallet, N., Bonhomme, Y., Malfroy, B., and de Leiris, J., EUK-8 a synthetic catalytic scavenger of reactive oxygen species protects isolated iron-overloaded rat heart from functional and structural damage induced by ischemia/reperfusion, Cardiovasc. Drugs Ther., 10 (3), 331-339, 1996.

201. Jung, C., Rong, Y., Doctrow, S., Baudry, M., Malfroy, B., and Xu, Z., Synthetic superoxide dismu- tase/catalase mimetics reduce oxidative stress and prolong survival in a mouse amyotrophic lateral sclerosis model, Neurosci. Lett., 304 (3), 157-160, 2001.

202. McDonald, M.C., d'Emmanuele di Villa Bianca, R., Wayman, N.S., Pinto, A., Sharpe, M.A., Cuzzocrea, S., Chatterjee, P.K., and Thiemermann, C., A superoxide dismutase mimetic with catalase activity (EUK-8) reduces the organ injury in endotoxic shock, Eur. J. Pharmacol., 466 (1-2), 181-189, 2003.

203. Luksiene, Z., Photodynamic therapy: mechanism of action and ways to improve the efficiency of treatment, Medicina (Kaunas), 39 (12), 1137-1150, 2003.

204. Lustig, R.A., Vogl, T.J., Fromm, D., Cuenca, R., Alex Hsi, R., D’Cruz, A.K., Krajina, Z., Turic, M., Singhal, A., and Chen, J.C., A multicenter phase I safety study of intratumoral photoactivation of talaporfin sodium in patients with refractory solid tumors, Cancer, 98 (8), 1767-1771, 2003.

205. Sun, S.Y., Hail, N., Jr., and Lotan, R., Apoptosis as a novel target for cancer chemoprevention, J. Natl. Cancer Inst., 96 (9), 662-672, 2004.

206. Lister, T.A., The management of follicular lymphoma, Ann. Oncol., 2 (Suppl. 2), 131-135, 1991.

207. Zong, W.X., Ditsworth, D., Bauer, D.E., Wang, Z.Q., and Thompson, C.B., Alkylating DNA damage stimulates a regulated form of necrotic cell death, Genes Dev., 18 (11), 1272-1282, 2004.

208. Greenberg, J.H., LaPlaca, M.C., and McIntosh, T.K., PARP inhibitors as neuroprotective agents for brain injury, in PARP as a Therapeutic Target, Zhang, J., Ed., CRC Press, Boca Raton, FL, 2002, pp. 83-115.

209. Klionsky, D.J. and Emr, S.D., Autophagy as a regulated pathway of cellular degradation, Science, 290 (5497), 1717-1721, 2000.

210. Edinger, A.L. and Thompson, C.B., Defective autophagy leads to cancer, Cancer Cell., 4 (6), 422-424,

2003.

211. Liang, X.H., Kleeman, L.K., Jiang, H.H., Gordon, G., Goldman, J.E., Berry, G., Herman, B., and Levine, B., Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein, J. Virol., 72 (11), 8586-8596, 1998.

212. Liang, X.H., Jackson, S., Seaman, M., Brown, K., Kempkes, B., Hibshoosh, H., and Levine, B., Induction of autophagy and inhibition of tumorigenesis by beclin 1, Nature, 402 (6762), 672-676, 1999.

213. Gozuacik, D. and Kimchi, A., Autophagy as a cell death and tumor suppressor mechanism, Oncogene, 23 (16), 2891-2906, 2004.

214. Yu, L., Alva, A., Su, H., Dutt, P., Freundt, E., Welsh, S., Baehrecke, E.H., and Lenardo, M.J., Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8, Science, 304 (5676), 1500-1502,

2004.

215. Ravikumar, B., Vacher, C., Berger, Z., Davies, J.E., Luo, S., Oroz, L.G., Scaravilli, F., Easton, D.F., Duden, R., O’Kane, C.J., and Rubinsztein, D.C., Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease, Nat. Genet., 36 (6), 585-595, 2004.