Enhanced radiation response through directed molecular targeting approaches

Cancer and Metastasis Reviews - Tập 23 - Trang 277-292 - 2004
Spencer J. Collis1, Theodore L. DeWeese1
1Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins Oncology Center, Johns Hopkins University School of Medicine, Baltimore

Tóm tắt

In both the pre- and post-human genome sequencing eras, there has been an increase in the understanding of the molecular mechanisms influencing cellular sensitivity to DNA damaging agents such as ionizing radiation. Out of this work have arisen many cellular factors that could be specifically targeted, at the molecular level, to alter the functionality of a single protein or pathway involved in the response to radiation damage as a means to increase cell killing following radiation treatment. As such, there are many promising new combination radio-gene therapy approaches being developed and assessed in pre-clinical and clinical studies for several different malignancies. Combination of such modalities aims to increase the therapeutic index, giving rise to increased tumor cell killing with a simultaneous reduction in normal cell toxicity. Restricted delivery and/or targeting modalities combined with conformal radiotherapy regimes could provide significant local control of tumors, impeding their development into metastatic disease, which poses a greater challenge for palliative and curative treatments. This review will summarize current and novel gene therapy strategies that are being developed aimed at enhancing the effects of radiotherapy through the use of directed molecular targeting approaches.

Tài liệu tham khảo

Wheldon TE, Mairs RJ, Rampling RP, Barrett A: Modeling the enhancement of fractionated radiotherapy by gene transfer to sensitize tumor cells to radiation. Radiother Oncol, 48: 5–13, 1998 Ma BB, Bristow RG, Kim J, Siu LL: Combined-modality treatment of solid tumors using radiotherapy and molecular targeted agents. J Clin Oncol, 21: 2760–2776, 2003 Greco O, Scott SD, Marples B, Dachs GU: Cancer gene therapy: 'Delivery, delivery, delivery'. Front Biosci, 7: d1516–1524, 2002 Burton EA, Bai Q, Goins WF, Glorioso JC: Replication-defective genomic herpes simplex vectors: design and production. Curr Opin Biotechnol, 13: 424–428, 2002 Burton EA, Fink DJ, Glorioso JC: Gene delivery using herpes simplex virus vectors. DNA Cell Biol, 21: 915–936, 2002 Breyer B, Jiang W, Cheng H, Zhou L, Paul R, Feng T, He TC: Adenoviral vector-mediated gene transfer for human gene therapy. Curr Gene Ther, 1: 149–162, 2001 Lai CM, Lai YK, Rakoczy PE: Adenovirus and adenoassociated virus vectors. DNA Cell Biol, 21: 895–913, 2002 Vorburger SA, Hunt KK: Adenoviral gene therapy. Oncologist, 7: 46–59, 2002 Quinonez R, Sutton RE: Lentiviral vectors for gene delivery into cells. DNA Cell Biol, 21: 937–951, 2002 Peplinski GR, Tsung K, Norton JA: Vaccinia virus for human gene therapy. Surg Oncol Clin N Am, 7: 575–588, 1998 Hope MJ, Mui B, Ansell S, Ahkong QF: Cationic lipids, phosphatidylethanolamine and the intracellular delivery of polymeric, nucleic acid-based drugs (review). Mol Membr Biol, 15: 1–14, 1998 Herweijer H, Wolff JA: Progress and prospects: Naked DNA gene transfer and therapy. Gene Ther, 10: 453–458, 2003 Bogoyevitch MA, Kendrick TS, Ng DC, Barr RK: Taking the cell by stealth or storm? Protein transduction domains (PTDs) as versatile vectors for delivery. DNA Cell Biol, 21: 879–894, 2002 Hudson AJ, Normand N, Ackroyd J, Akhtar S: Cellular delivery of hammerhead ribozymes conjugated to a transferrin receptor antibody. Int J Pharm, 182: 49–58, 1999 Smyth Templeton N: Liposomal delivery of nucleic acids in vivo. DNA Cell Biol, 21: 857–867, 2002 Gratton JP, Yu J, Griffith JW, Babbitt RW, Scotland RS, Hickey R, Giordano FJ, Sessa WC: Cell-permeable peptides improve cellular uptake and therapeutic gene delivery of replication-deficient viruses in cells and in vivo. Nat Med, 9: 357–363, 2003 Derossi D, Chassaing G, Prochiantz A: Trojan peptides: The penetratin system for intracellular delivery. Trends Cell Biol, 8: 84–87, 1998 Trezise AE: In vivo DNA electrotransfer. DNA Cell Biol, 21: 869–877, 2002 Collis SJ, Khater K, DeWeese TL: Novel therapeutic strategies in prostate cancer management using gene therapy in combination with radiation therapy. World J Urol, 21: 275–289, 2003 Lundstrom K: Latest development in viral vectors for gene therapy. Trends Biotechnol, 21: 117–122, 2003 Pierce ML, Ruffner DE: Construction of a directed hammerhead ribozyme library: Towards the identification of optimal target sites for antisense-mediated gene inhibition. Nucleic Acids Res, 26: 5093–5101, 1998 Dash P, Lotan I, Knapp M, Kandel ER, Goelet P: Selective elimination of mRNAs in vivo: Complementary oligodeoxynucleotides promote RNA degradation by an RNase H-like activity. Proc Natl Acad Sci USA, 84: 7896–7900, 1987 Walder RY, Walder JA: Role of RNase H in hybridarrested translation by antisense oligonucleotides. Proc Natl Acad Sci USA, 85: 5011–5015, 1988 Myers KJ, Dean NM: Sensible use of antisense: How to use oligonucleotides as research tools. Trends Pharmacol Sci, 21: 19–23, 2000 Branch AD: Antisense drug discovery: Can cell-free screens speed the process? Antisense Nucleic Acid Drug Dev, 8: 249–254, 1998 Gleave M, Miyake H, Zangemeister-Wittke U, Jansen B: Antisense therapy: Current status in prostate cancer and other malignancies. Cancer Metastasis Rev, 21: 79–92, 2002 Jansen B, Zangemeister-Wittke U: Antisense therapy for cancer—the time of truth. Lancet Oncol, 3: 672–683, 2002 Cech TR: Ribozymes, the first 20 years. Biochem Soc Trans, 30: 1162–1166, 2002 Amado RG, Mitsuyasu RT, Symonds G, Rosenblatt JD, Zack J, Sun LQ, Miller M, Ely J, Gerlach W: A phase I trial of autologous CD34+ hematopoietic progenitor cells transduced with an anti-HIV ribozyme. Hum Gene Ther, 10: 2255–2270, 1999 Sandberg JA, Parker VP, Blanchard KS, Sweedler D, Powell JA, Kachensky A, Bellon L, Usman N, Rossing T, Borden E, Blatt LM: Pharmacokinetics and tolerability of an antiangiogenic ribozyme (ANGIOZYME) in healthy volunteers. J Clin Pharmacol, 40: 1462–1469, 2000 Welch PJ, Barber JR, Wong-Staal F: Expression of ribozymes in gene transfer systems to modulate target RNA levels. Curr Opin Biotechnol, 9: 486–496, 1998 Wong-Staal F, Poeschla EM, Looney DJ: A controlled, Phase 1 clinical trial to evaluate the safety and effects in HIV-1 infected humans of autologous lymphocytes transduced with a ribozyme that cleaves HIV-1 RNA. Hum Gene Ther, 9: 2407–2425, 1998 Bettinger T, Read ML: Recent developments in RNAbased strategies for cancer gene therapy. Curr Opin Mol Ther, 3: 116–124, 2001 Freelove AC, Zheng R: The power of ribozyme technologies: The logical way ahead for molecular medicine and gene therapy? Curr Opin Mol Ther, 4: 419–422, 2002 Kashani-Sabet M: Ribozyme therapeutics. J Investig Dermatol Symp Proc, 7: 76–78, 2002 Wright L, Kearney P: Current status of ribozymes as gene therapy agents for cancer. Cancer Invest, 19: 495–509, 2001 Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T: Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature, 411: 494–498, 2001 Hammond SM, Caudy AA, Hannon GJ: Post-transcriptional gene silencing by double-stranded RNA. Nat Rev Genet, 2: 110–119, 2001 Hannon GJ: RNA interference. Nature, 418: 244–251, 2002 Zamore PD: RNA interference: Listening to the sound of silence. Nat Struct Biol, 8: 746–750, 2001 Paddison PJ, Caudy AA, Bernstein E, Hannon GJ, Conklin DS: Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev, 16: 948–958, 2002 Lewis DL, Hagstrom JE, Loomis AG, Wolff JA, Herweijer H: Efficient delivery of siRNA for inhibition of gene expression in postnatal mice. Nat Genet, 32: 107–108, 2002 Abbas-Terki T, Blanco-Bose W, Deglon N, Pralong W, Aebischer P: Lentiviral-mediated RNA interference. Hum Gene Ther, 13: 2197–2201, 2002 McCaffrey AP, Meuse L, Pham TT, Conklin DS, Hannon GJ, Kay MA: RNA interference in adult mice. Nature, 418: 38–39, 2002 Shen C, Buck AK, Liu X, Winkler M, Reske SN: Gene silencing by adenovirus-delivered siRNA. FEBS Lett, 539: 111–114, 2003 Zhao LJ, Jian H, Zhu H: Specific gene inhibition by adenovirus-mediated expression of small interfering RNA. Gene, 316: 137–141, 2003 Ward JF: DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability. Prog Nucleic Acid Res Mol Biol, 35: 95–125, 1988 Hoeijmakers, JH: Genome maintenance mechanisms for preventing cancer. Nature, 411: 366–374, 2001 Jackson SP: Detecting, signaling and repairing DNA double-strand breaks. Biochem Soc Trans, 29: 655–661, 2001 Shiloh Y: ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer, 3: 155–168, 2003 Petrini JH, Stracker TH: The cellular response to DNA double-strand breaks: defining the sensors and mediators. Trends Cell Biol, 13: 458–462, 2003 Valerie K, Povirk LF: Regulation and mechanisms of mammalian double-strand break repair. Oncogene, 22: 5792–5812, 2003 Yang J, Yu Y, Hamrick HE, Duerksen-Hughes PJ: ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses. Carcinogenesis, 24: 1571–1580, 2003 Iliakis G: The role of DNA double strand breaks in ionizing radiation-induced killing of eukaryotic cells. Bioessays, 13: 641–648, 1991 Iliakis G, Wang Y, Guan J, Wang H: DNA damage checkpoint control in cells exposed to ionizing radiation. Oncogene, 22: 5834–5847, 2003 Moses RE: DNA damage processing defects and disease. Annu Rev Genomics Hum Genet, 2: 41–68, 2001 Levitt NC, Hickson ID: Caretaker tumor suppressor genes that defend genome integrity. Trends Mol Med, 8: 179–186, 2002 Thompson LH, Schild D: Recombinational DNA repair and human disease. Mutat Res, 509: 49–78, 2002 Shiloh Y: ATM and ATR: networking cellular responses to DNA damage. Curr Opin Genet Dev, 11: 71–77, 2001 Yoshida M, Hosoi Y, Miyachi H, Ishii N, Matsumoto Y, Enomoto A, Nakagawa K, Yamada S, Suzuki N, Ono T: Roles of DNA-dependent protein kinase and ATM in cellcycle-dependent radiation sensitivity in human cells. Int J Radiat Biol, 78: 503–512, 2002 Rotman G, Shiloh Y: ATM: from gene to function. Hum Mol Genet, 7: 1555–1563, 1998 van den Bosch M, Bree RT, Lowndes NF: The MRN complex: coordinating and mediating the response to broken chromosomes. EMBO Rep, 4: 844–849,2003 Powell SN, Kachnic LA: Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene, 22: 5784–5791, 2003 Powell SN, Willers H, Xia F: BRCA2 keeps Rad51 in line. High-fidelity homologous recombination prevents breast and ovarian cancer? Mol Cell, 10: 1262–1263, 2002 Yoshikawa K, Ogawa T, Baer R, Hemmi H, Honda K, Yamauchi A, Inamoto T, Ko K, Yazumi S, Motoda H, Kodama H, Noguchi S, Gazdar AF, Yamaoka Y, Takahashi R: Abnormal expression of BRCA1 and BRCA1-interactive DNA-repair proteins in breast carcinomas. Int J Cancer, 88: 28–36, 2000 Hansen LT, Lundin C, Spang-Thomsen M, Petersen LN, Helleday T: The role of RAD51 in etoposide (VP16) resistance in small cell lung cancer. Int J Cancer, 105: 472–479, 2003 Maacke H, Jost K, Opitz S, Miska S, Yuan Y, Hasselbach L, Luttges J, Kalthoff H, Sturzbecher HW: DNA repair and recombination factor Rad51 is over-expressed in human pancreatic adenocarcinoma. Oncogene, 19: 2791–2795, 2000 Maacke H, Opitz S, Jost K, Hamdorf W, Henning W, Kruger S, Feller AC, Lopens A, Diedrich K, Schwinger E, Sturzbecher HW: Over-expression of wild-type Rad51 correlates with histological grading of invasive ductal breast cancer. Int J Cancer, 88: 907–913, 2000 Sirzen F, Nilsson A, Zhivotovsky B, Lewensohn R: DNA-dependent protein kinase content and activity in lung carcinoma cell lines: correlation with intrinsic radiosensitivity. Eur J Cancer, 35: 111–116, 1999 Zhao HJ, Hosoi Y, Miyachi H, Ishii K, Yoshida M, Nemoto K, Takai Y, Yamada S, Suzuki N, Ono T: DNA-dependent protein kinase activity correlates with Ku70 expression and radiation sensitivity in esophageal cancer cell lines. Clin Cancer Res, 6: 1073–1078, 2000 Shintani S, Mihara M, Li C, Nakahara Y, Hino S, Nakashiro K, Hamakawa H: Up-regulation of DNAdependent protein kinase correlates with radiation resistance in oral squamous cell carcinoma. Cancer Sci, 94: 894–900, 2003 Wilson CR, Davidson SE, Margison GP, Jackson SP, Hendry JH, West CM: Expression of Ku70 correlates with survival in carcinoma of the cervix. Br J Cancer, 83: 1702–1706, 2000 Angele S, Treilleux I, Bremond A, Taniere P, Hall J: Altered expression of DNA double-strand break detection and repair proteins in breast carcinomas. Histopathology, 43: 347–353, 2003 Lieber MR, Ma Y, Pannicke U, Schwarz K: Mechanism and regulation of human non-homologous DNA endjoining. Nat Rev Mol Cell Biol, 4: 712–720, 2003 Zhang N, Chen P, Gatei M, Scott S, Khanna KK, Lavin MF: An anti-sense construct of full-length ATM cDNA imposes a radiosensitive phenotype on normal cells. Oncogene, 17: 811–818, 1998 Uhrhammer N, Fritz E, Boyden L, Meyn MS: Human fibroblasts transfected with an ATM antisense vector respond abnormally to ionizing radiation. Int J Mol Med, 4: 43–47, 1999 Fan Z, Chakravarty P, Alfieri A, Pandita TK, Vikram B, Guha C: Adenovirus-mediated antisense ATM gene transfer sensitizes prostate cancer cells to radiation. Cancer Gene Ther, 7: 1307–1314, 2000 Guha C, Guha U, Tribius S, Alfieri A, Casper D, Chakravarty P, Mellado W, Pandita TK, Vikram B: Antisense ATM gene therapy: a strategy to increase the radiosensitivity of human tumors. Gene Ther, 7: 852–858, 2000 Collis SJ, Swartz MJ, Nelson WG, DeWeese TL: Enhanced radiation and chemotherapy-mediated cell killing of human cancer cells by small inhibitory RNA silencing of DNA repair factors. Cancer Res, 63: 1550–1554, 2003 Morgan SE, Lovly C, Pandita TK, Shiloh Y, Kastan MB: Fragments of ATM which have dominant-negative or complementing activity. Mol Cell Biol, 17: 2020–2029, 1997 Chen S, Paul P, Price BD: ATM's leucine-rich domain and adjacent sequences are essential for ATM to regulate the DNA damage response. Oncogene, 22: 6332–6339, 2003 Durocher D, Jackson SP: DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? Curr Opin Cell Biol, 13: 225–231, 2001 Featherstone C, Jackson SP: DNA-dependent protein kinase gets a break: its role in repairing DNA and maintaining genomic integrity. Br J Cancer, 80: 14–19, 1999 Smith GC, Jackson SP: The DNA-dependent protein kinase. Genes Dev, 13: 916–934, 1999 Jeggo PA, Taccioli GE, Jackson SP: Menage a trois: double strand break repair, V(D)J recombination and DNA-PK. Bioessays, 17: 949–957, 1995 Marangoni E, Le Romancer M, Foray N, Muller C, Douc-Rasy S, Vaganay S, Abdulkarim B, Barrois M, Calsou P, Bernier J, Salles B, Bourhis J: Transfer of Ku86 RNA antisense decreases the radioresistance of human fibroblasts. Cancer Gene Ther, 7: 339–346, 2000 Belenkov AI, Paiement JP, Panasci LC, Monia BP, Chow TY: An antisense oligonucleotide targeted to human Ku86 messenger RNA sensitizes M059K malignant glioma cells to ionizing radiation, bleomycin, and etoposide but not DNA cross-linking agents. Cancer Res, 62: 5888–5896, 2002 Li GC, He F, Shao X, Urano M, Shen L, Kim D, Borrelli M, Leibel SA, Gutin PH, Ling CC: Adenovirus-mediated heat-activated antisense Ku70 expression radiosensitizes tumor cells in vitro and in vivo. Cancer Res, 63: 3268–3274, 2003 Omori S, Takiguchi Y, Suda A, Sugimoto T, Miyazawa H, Tanabe N, Tatsumi K, Kimura H, Pardington PE, Chen F, Chen DJ, Kuriyama T: Suppression of a DNA double-strand break repair gene, Ku70, increases radioand chemosensitivity in a human lung carcinoma cell line. DNA Repair (Amst), 1: 299–310, 2002 Sak A, Stuschke M, Wurm R, Schroeder G, Sinn B, Wolf G, Budach V: Selective inactivation of DNA-dependent protein kinase with antisense oligodeoxynucleotides: consequences for the rejoining of radiation-induced DNA double-strand breaks and radiosensitivity of human cancer cell lines. Cancer Res, 62: 6621–6624, 2002 Peng Y, Zhang Q, Nagasawa H, Okayasu R, Liber HL, Bedford JS: Silencing expression of the catalytic subunit of DNA-dependent protein kinase by small interfering RNA sensitizes human cells for radiation-induced chromosome damage, cell killing, and mutation. Cancer Res, 62: 6400–6404, 2002 Gao Y, Chaudhuri J, Zhu C, Davidson L, Weaver DT, Alt FW: A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination. Immunity, 9: 367–376, 1998 Li S, Takeda Y, Wragg S, Barrett J, Phillips A, Dynan WS: Modification of the ionizing radiation response in living cells by an scFv against the DNA-dependent protein kinase. Nucleic Acids Res, 31: 5848–5857, 2003 Lees-Miller SP, Long MC, Kilvert MA, Lam V, Rice SA, Spencer CA: Attenuation of DNA-dependent protein kinase activity and its catalytic subunit by the herpes simplex virus type 1 transactivator ICP0. J Virol, 70: 7471–7477, 1996 Parkinson J, Lees-Miller SP, Everett RD: Herpes simplex virus type 1 immediate-early protein vmw110 induces the proteasome-dependent degradation of the catalytic subunit of DNA-dependent protein kinase. J Virol, 73: 650–657, 1999 Jorgensen TJ, Katz S, Wittmack EK, Varghese S, Todo T, Rabkin SD, Martuza RL: Ionizing radiation does not alter the antitumor activity of herpes simplex virus vector G207 in subcutaneous tumor models of human and murine prostate cancer. Neoplasia, 3: 451–456, 2001 Boyer J, Rohleder K, Ketner G: Adenovirus E4 34k and E4 11k inhibit double strand break repair and are physically associated with the cellular DNA-dependent protein kinase. Virology, 263: 307–312, 1999 Collis SJ, Ketner GW, Hicks JL, Nelson WG, Demarzo AM, Deweese TL: Expression of the DNA-PK binding protein E4-34K fails to confer radiation sensitivity to mammalian cells. Int J Radiat Biol, 79: 53–60, 2003 Carson CT, Schwartz RA, Stracker TH, Lilley CE, Lee DV, Weitzman MD: The Mre11 complex is required for ATM activation and the G(2)/M checkpoint. Embo J, 22: 6610–6620, 2003 Stracker TH, Carson CT, Weitzman MD: Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex. Nature, 418: 348–352, 2002 Chen Y, DeWeese T, Dilley J, Zhang Y, Li Y, Ramesh N, Lee J, Pennathur-Das R, Radzyminski J, Wypych J, Brignetti D, Scott S, Stephens J, Karpf DB, Henderson DR, Yu DC: CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity. Cancer Res, 61: 5453–5460, 2001 Kim YC, Koh JT, Shin BA, Ahn KY, Choi BK, Kim CG, Kim KK: An antisense construct of full-length human RAD50 cDNA confers sensitivity to ionizing radiation and alkylating agents on human cell lines. Radiat Res, 157: 19–25, 2002 O'Malley BW Jr, Li D, Carney J, Rhee J, Suntharalingam M: Molecular disruption of the MRN(95) complex induces radiation sensitivity in head and neck cancer. Laryngoscope, 113: 1588–1594, 2003 Xu M, Myerson R, Hunt C, Kumar S, Moros E, Straube B, Roti JR: Treatment of cells with Mre11 siRNA increases radiation sensitivity and reduces heat induced radiosensitization. Int J Radiat Oncol Biol Phys, 57: S144–145, 2003 Goldberg M, Stucki M, Falck J, D'Amours D, Rahman D, Pappin D, Bartek J, Jackson SP: MDC1 is required for the intra-S-phase DNA damage checkpoint. Nature, 421: 952–956, 2003 Kao GD, McKenna WG, Guenther MG, Muschel RJ, Lazar MA, Yen TJ: Histone deacetylase 4 interacts with 53BP1 to mediate the DNA damage response. J Cell Biol, 160: 1017–1027, 2003 Lou Z, Chini CC, Minter-Dykhouse K, Chen J: Mediator of DNA damage checkpoint protein 1 regulates BRCA1 localization and phosphorylation in DNA damage checkpoint control. J Biol Chem, 278: 13599–13602, 2003 Lou Z, Minter-Dykhouse K, Wu X, Chen J: MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways. Nature, 421: 957–961, 2003 Qi W, Martinez JD: Reduction of 14-3-3 proteins correlates with increased sensitivity to killing of human lung cancer cells by ionizing radiation. Radiat Res, 160: 217–223, 2003 Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ: MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature, 421: 961–966, 2003 Taneja N, Davis M, Choy JS, Beckett MA, Singh R, Kron SJ, Weichselbaum RR: Histone H2AX phosphorylation as a predictor of radiosensitivity and target for radiotherapy. J Biol Chem, 15: 15, 2003 Yu Q, Rose JH, Zhang H, Pommier Y: Antisense inhibition of Chk2/hCds1 expression attenuates DNA damage-induced S and G2 checkpoints and enhances apoptotic activity in HEK-293 cells. FEBS Lett, 505: 7–12, 2001 Zhao H, Watkins JL, Piwnica-Worms H: Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints. Proc Natl Acad Sci USA, 99: 14795–14800, 2002 Taki T, Ohnishi T, Yamamoto A, Hiraga S, Arita N, Izumoto S, Hayakawa T, Morita T: Antisense inhibition of the RAD51 enhances radiosensitivity. Biochem Biophys Res Commun, 223: 434–438, 1996 Ohnishi T, Taki T, Hiraga S, Arita N, Morita T: In vitro and in vivo potentiation of radiosensitivity of malignant gliomas by antisense inhibition of the RAD51 gene. Biochem Biophys Res Commun, 245: 319–324, 1998 Collis SJ, Tighe A, Scott SD, Roberts SA, Hendry JH, Margison GP: Ribozyme minigene-mediated RAD51 down-regulation increases radiosensitivity of human prostate cancer cells. Nucleic Acids Res, 29: 1534–1538, 2001 Watson G, Jensen R: Effect of hRAD51 dominant negative mutant expression in a glioblastoma model system: altered sensitivity to ionizing radiation. Int J Radiat Oncol Biol Phys, 57: S145, 2003 Brunner TB, Gupta AK, Shi Y, Hahn SM, Muschel RJ, McKenna WG, Bernhard EJ: Farnesyltransferase inhibitors as radiation sensitizers. Int J Radiat Biol, 79: 569–576, 2003 Kasid U, Dritschilo A: RAF antisense oligonucleotide as a tumor radiosensitizer. Oncogene, 22: 5876–5884, 2003 Li Q, Zhu GD: Targeting serine/threonine protein kinase B/Akt and cell-cycle checkpoint kinases for treating cancer. Curr Top Med Chem, 2: 939–971, 2002 McKenna WG, Muschel RJ: Targeting tumor cells by enhancing radiation sensitivity. Genes Chromosomes Cancer, 38: 330–338, 2003 Shangary S, Johnson DE: Recent advances in the development of anticancer agents targeting cell death inhibitors in the Bcl-2 protein family. Leukemia, 17: 1470–1481, 2003 Tenzer A, Pruschy M: Potentiation of DNA-damageinduced cytotoxicity by G2 checkpoint abrogators. Curr Med Chem Anti-Canc Agents, 3: 35–46, 2003 Tenzer A, Zingg D, Riesterer O, Vuong V, Bodis S, Pruschy M: Signal transduction inhibitors as radiosensitizers. Curr Med Chem Anti-Canc Agents, 2: 727–742, 2002 Zaffaroni N, Daidone MG: Survivin expression and resistance to anticancer treatments: perspectives for new therapeutic interventions. Drug Resist Updat, 5: 65–72, 2002 Zhou BB, Anderson HJ, Roberge M: Targeting DNA checkpoint kinases in cancer therapy. Cancer Biol Ther, 2: S16–22, 2003 Kasid U, Pfeifer A, Brennan T, Beckett M, Weichselbaum RR, Dritschilo A, Mark GE: Effect of antisense c-raf-1 on tumorigenicity and radiation sensitivity of a human squamous carcinoma. Science, 243: 1354–1356, 1989 Gokhale PC, McRae D, Monia BP, Bagg A, Rahman A, Dritschilo A, Kasid U: Antisense raf oligodeoxyribonucleotide is a radiosensitizer in vivo. Antisense Nucleic Acid Drug Dev, 9: 191–201, 1999 Moreira JN, Simoes S: Technology evaluation: LErafAON, NeoPharm. Curr Opin Mol Ther, 5: 547–552, 2003 Zellweger T, Chi K, Miyake H, Adomat H, Kiyama S, Skov K, Gleave ME: Enhanced radiation sensitivity in prostate cancer by inhibition of the cell survival protein clusterin. Clin Cancer Res, 8: 3276–3284, 2002 Zellweger T, Kiyama S, Chi K, Miyake H, Adomat H, Skov K, Gleave ME: Overexpression of the cytoprotective protein clusterin decreases radiosensitivity in the human LNCaP prostate tumor model. BJU Int, 92: 463–469, 2003 Asanuma K, Moriai R, Yajima T, Yagihashi A, Yamada M, Kobayashi D, Watanabe N: Survivin as a radioresistance factor in pancreatic cancer. Jpn J Cancer Res, 91: 1204–1209, 2000 Asanuma K, Kobayashi D, Furuya D, Tsuji N, Yagihashi A, Watanabe N: A role for survivin in radioresistance of pancreatic cancer cells. Jpn J Cancer Res, 93: 1057–1062, 2002 Rodel C, Haas J, Groth A, Grabenbauer GG, Sauer R, Rodel F: Spontaneous and radiation-induced apoptosis in colorectal carcinoma cells with different intrinsic radiosensitivities: survivin as a radioresistance factor. Int J Radiat Oncol Biol Phys, 55: 1341–1347, 2003 Sarela AI, Verbeke CS, Ramsdale J, Davies CL, Markham AF, Guillou PJ: Expression of survivin, a novel inhibitor of apoptosis and cell cycle regulatory protein, in pancreatic adenocarcinoma. Br J Cancer, 86: 886–892, 2002 Pennati M, Binda M, Colella G, Folini M, Citti L, Villa R, Daidone MG, Zaffaroni N: Radiosensitization of human melanoma cells by ribozyme-mediated inhibition of survivin expression. J Invest Dermatol, 120: 648–654, 2003 Scott SL, Higdon R, Beckett L, Shi XB, deVere White RW, Earle JD, Gumerlock PH: BCL2 antisense reduces prostate cancer cell survival following irradiation. Cancer Biother Radiopharm, 17: 647–656, 2002 Greenberger JS, Epperly MW, Gretton J, Jefferson M, Nie S, Bernarding M, Kagan V, Guo HL: Radioprotective gene therapy. Curr Gene Ther, 3: 183–195, 2003 Kuninaka S, Ichinose Y, Koja K, Toh Y: Suppression of manganese superoxide dismutase augments sensitivity to radiation, hyperthermia and doxorubicin in colon cancer cell lines by inducing apoptosis. Br J Cancer, 83: 928–934, 2000 Ueta E, Yoneda K, Kimura T, Tatemoto Y, Doi S, Yamamoto T, Osaki T: Mn-SOD antisense upregulates in vivo apoptosis of squamous cell carcinoma cells by anticancer drugs and gamma-rays regulating expression of the BCL-2 family proteins, COX-2 and p21. Int J Cancer, 94: 545–550, 2001 Choy H, Milas L: Enhancing radiotherapy with cyclooxygenase-2 enzyme inhibitors: a rational advance? J Natl Cancer Inst, 95: 1440–1452, 2003 Krysan K, Merchant FH, Zhu L, Dohadwala M, Luo J, Lin Y, Heuze-Vourc'h N, Pold M, Seligson D, Chia D, Goodglick L, Wang H, Strieter R, Sharma S, Dubinett S: COX-2-dependent stabilization of survivin in non-small cell lung cancer. Faseb J, 3: 3, 2003