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  • Review Article
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Antisense therapy for cancer

Key Points

  • Antisense oligonucleotides (ASOs) offer one approach to target genes involved in cancer progression, particularly those that are not amenable to small-molecule or antibody inhibition.

  • ASOs inhibit translation through a mechanism that involves the formation of an mRNA–ASO duplex, leading to RNase-H-mediated cleavage of the target mRNA.

  • Several useful modifications of ASO backbones have yielded compounds that show good tissue distribution and increased resistance to nuclease digestion.

  • ASO drugs are evolving through improved chemical modifications to prolong in vivo half-life, increase potency and reduce toxicity.

  • The most promising targets for antisense therapy are those that become upregulated during tumorigenesis and several of these, including BCL2, protein kinase Cα, clusterin, X-linked inhibitors of apoptosis and survivin, are currently in or have finished early-phase clinical trials.

  • A disappointing lack of clinical efficacy for some ASOs indicates that challenges remain. However, the advanced chemistry incorporated into the second-generation ASOs has significant promise for the future.

  • A recently completed prostate cancer pre-surgery trial provides proof of concept that the second-generation 2'-MOE OGX-011 can potently suppress the target protein clusterin in humans.

Abstract

Improved understanding of the molecular mechanisms that mediate cancer progression and therapeutic resistance has identified many therapeutic gene targets that regulate apoptosis, proliferation and cell signalling. Antisense oligonucleotides offer one approach to target genes involved in cancer progression, especially those that are not amenable to small-molecule or antibody inhibition. Better chemical modifications of antisense oligonucleotides increase resistance to nuclease digestion, prolong tissue half-lives and improve scheduling. Indeed, recent clinical trials confirm the ability of this class of drugs to significantly suppress target-gene expression. The current status and future directions of several antisense drugs that have potential clinical use in cancer are reviewed.

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Figure 1: Mechanisms of antisense action on target genes.
Figure 2: Immunostaining of OGX-011 antisense oligonucleotide drug distribution in human prostate tissue.

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References

  1. Zamecnik, P. C. & Stephenson, M. L. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc. Natl Acad. Sci. USA 75, 280–284 (1978). First report on the use of antisense oligodeoxy-nucleotides to suppress gene activity in cell culture.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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).

    Article  CAS  PubMed  Google Scholar 

  3. Dean, N. M. & Bennett, C. F. Antisense oligonucleotide-based therapeutics for cancer. Oncogene 22, 9087–9096 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Orr, R. M. & Monia, B. P. Antisense therapy for cancer. Investig. Drugs 1, 199–205 (1998).

    CAS  Google Scholar 

  5. Crooke, S. T. Molecular mechanisms of antisense drugs: RNase H. Antisense Nucleic Acid Drug Dev. 8, 133–134 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Wu, H. et al. Determination of the role of the human RNase H1 in the pharmacology of DNA-like antisense drugs. J. Biol. Chem. 279, 17181–17189 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Galarneau, A., Min, K. L., Mangos, M. M. & Damha, M. J. Assay for evaluating ribonuclease H-mediated degradation of RNA-antisense oligonucleotide duplexes. Methods Mol. Biol. 288, 65–80 (2005).

    CAS  PubMed  Google Scholar 

  8. Carpentier, A. F., Chen, L., Maltonti, F. & Delattre, J. Y. Oligodeoxynucleotides containing CpG motifs can induce rejection of a neuroblastomain mice. Cancer Res. 59, 5429–5432 (1999).

    CAS  PubMed  Google Scholar 

  9. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998). First report on the use of double-stranded siRNA duplexes to suppress gene activity in animal cells.

    Article  CAS  PubMed  Google Scholar 

  10. Matzke, M. A. & Birchler, J. A. RNAi-mediated pathways in the nucleus. Nature Rev. Genet. 6, 24–35 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Soutschek, J. et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432, 173–178 (2004). The first demonstration of siRNA activity in mammals following administration through routes other than the digestive tract.

    Article  CAS  PubMed  Google Scholar 

  12. Monia, B. P. et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as antisense inhibitors of gene expression. J. Biol. Chem. 268, 14514–14522 (1993). This report demonstrates that RNase H is a key terminating mechanism by which antisense drugs exert their effects on gene expression. This report also demonstrates the use of 2′-modified chimeric antisense oligonucleotides in cells.

    Article  CAS  PubMed  Google Scholar 

  13. Shen, L. et al. Evaluation of C-5 propynyl pyrimidine-containing oligonucleotides in vitro and in vivo. Antisense Nucleic Acid Drug Dev. 13, 129–142 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Tsujimoto, Y. & Croce, C. M. Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc. Natl Acad. Sci. USA 83, 5214–5218 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Reed, J. C. Bcl-2 and the regulation of programmed cell death. J. Cell Biol. 124, 1–6 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Miyashita, T. & Reed, J. C. Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood 81, 151–157 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. McDonnell, T. J. et al. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res. 52, 6940–6944 (1992).

    CAS  PubMed  Google Scholar 

  18. Kyprianou, N., King, E. D., Bradbury, D. & Rhee, J. G. bcl-2 over-expression delays radiation-induced apoptosis without affecting the clonogenic survival of human prostate cancer cells. Int. J. Cancer 70, 341–348 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Raffo, A. J. et al. Overexpression of bcl-2 protects prostate cancer cells from apoptosis in vitro and confers resistance to androgen depletion in vivo. Cancer Res. 55, 4438–4445 (1995).

    CAS  PubMed  Google Scholar 

  20. Miyake, H., Tolcher, A. & Gleave, M. E. Antisense Bcl-2 oligodeoxynucleotides inhibit progression to androgen-independence after castration in the Shionogi tumor model. Cancer Res. 59, 4030–4034 (1999).

    CAS  PubMed  Google Scholar 

  21. Gleave, M. et al. Progression to androgen independence is delayed by adjuvant treatment with antisense Bcl-2 oligodeoxynucleotides after castration in the LNCaP prostate tumor model. Clin. Cancer Res. 5, 2891–2898 (1999).

    CAS  PubMed  Google Scholar 

  22. Zangemeister-Wittke, U. et al. A novel bispecific antisense oligonucleotide inhibiting both bcl-2 and bcl-xL expression efficiently induces apoptosis in tumor cells. Clin. Cancer Res. 6, 2547–2555 (2000).

    CAS  PubMed  Google Scholar 

  23. Jansen, B. et al. bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice. Nature Med. 4, 232–234 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Webb, A. et al. BCL-2 antisense therapy in patients with non-Hodgkin lymphoma. Lancet 349, 1137–1141 (1997). This Phase I/IIa trial is the first report of the activity of BCL2 antisense in cancer patients.

    Article  CAS  PubMed  Google Scholar 

  25. Waters, J. S. et al. Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin's lymphoma. J. Clin. Oncol. 18, 1812–1823 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Jansen, B. et al. Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet 356, 1728–1733 (2000). This Phase I/IIa trial was the first to report reduced BCL2 protein levels in serial melanoma biopsies and higher-than-expected response rates using G3139 plus DTIC in a small cohort of patients with metastatic melanoma.

    Article  CAS  PubMed  Google Scholar 

  27. Rai, K. R. & Moore, J. O. Phase 3 randomized trial of fludarabine/cyclophosphamide chemotherapy with or without oblimersen sodium (Bcl-2 antisense; genasense; G3139) for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Blood 104, 100a (2004).

    Article  Google Scholar 

  28. Chanan-Khan, A. Bcl-2 antisense therapy in B-cell malignancies. Blood Rev. 19, 213–221 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Chi, K. N. et al. A phase I dose-finding study of combined treatment with an antisense Bcl-2 oligonucleotide (Genasense) and mitoxantrone in patients with metastatic hormone-refractory prostate cancer. Clin. Cancer Res. 7, 3920–3927 (2001).

    CAS  PubMed  Google Scholar 

  30. De Bono, J. S., Rowinsky, E. K. & Kuhn, J. Phase I pharmacokinetic (PK) and pharmacodynamic (PD) trial of bcl-2 antisense (genasense) and docetaxel (D) in hormone refractory prostate cancer. Proc. Am. Soc. Clin. Oncol. 20, A119 (2001).

    Google Scholar 

  31. Chi, K. N., Murray, R. N. & Gleave, M. E. A phase II study of oblimersen sodium (G3139) and docetaxel (D) in patients (pts) with metastatic hormone-refractory prostate cancer (HRPC). Proc. Am. Soc. Clin. Oncol. 22, 393 (2003).

    Google Scholar 

  32. Han, Z. et al. Isolation and characterization of an apoptosis-resistant variant of human leukemia HL-60 cells that has switched expression from Bcl-2 to Bcl-xL. Cancer Res. 56, 1621–1628 (1996).

    CAS  PubMed  Google Scholar 

  33. Leech, S. H. et al. Induction of apoptosis in lung-cancer cells following bcl-xL anti-sense treatment. Int. J. Cancer 86, 570–576 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Simoes-Wust, A. P. et al. Bcl-xl antisense treatment induces apoptosis in breast carcinoma cells. Int. J. Cancer 87, 582–590 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Lebedeva, I., Rando, R., Ojwang, J., Cossum, P. & Stein, C. A. Bcl-xL in prostate cancer cells: effects of overexpression and down-regulation on chemosensitivity. Cancer Res. 60, 6052–6060 (2000).

    CAS  PubMed  Google Scholar 

  36. Leung, S., Miyake, H., Zellweger, T., Tolcher, A. & Gleave, M. E. Synergistic chemosensitization and inhibition of progression to androgen independence by antisense Bcl-2 oligodeoxynucleotide and paclitaxel in the LNCaP prostate tumor model. Int. J. Cancer 91, 846–850 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Miyake, H., Monia, B. P. & Gleave, M. E. Inhibition of progression to androgen-independence by combined adjuvant treatment with antisense BCL-XL and antisense Bcl-2 oligonucleotides plus taxol after castration in the Shionogi tumor model. Int. J. Cancer 86, 855–862 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Gautschi, O. et al. Activity of a novel bcl-2/bcl-xL-bispecific antisense oligonucleotide against tumors of diverse histologic origins. J. Natl Cancer Inst. 93, 463–471 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Newton, A. C. Regulation of protein kinase C. Curr. Opin. Cell Biol. 9, 161–167 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Liu, B., Maher, R. J., Hannun, Y. A., Porter, A. T. & Honn, K. V. 12(S)-HETE enhancement of prostate tumor cell invasion: selective role of PKCα. J. Natl Cancer Inst. 86, 1145–1151 (1994).

    Article  CAS  PubMed  Google Scholar 

  41. Ways, D. K. et al. MCF-7 breast cancer cells transfected with protein kinase C-α exhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype. J. Clin. Invest. 95, 1906–1915 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gill, P. K., Gescher, A. & Gant, T. W. Regulation of MDR1 promoter activity in human breast carcinoma cells by protein kinase C isozymes α and τ. Eur. J. Biochem. 268, 4151–4157 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Swannie, H. C. & Kaye, S. B. Protein kinase C inhibitors. Curr. Oncol. Rep. 4, 37–46 (2002).

    Article  PubMed  Google Scholar 

  44. Isonishi, S., Ohkawa, K., Tanaka, T. & Howell, S. B. Depletion of protein kinase C (PKC) by 12-O-tetradecanoylphorbol-13-acetate (TPA) enhances platinum drug sensitivity in human ovarian carcinoma cells. Br. J. Cancer 82, 34–38 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Shen, L., Dean, N. M. & Glazer, R. I. Induction of p53-dependent, insulin-like growth factor-binding protein-3-mediated apoptosis in glioblastoma multiforme cells by a protein kinase Cα antisense oligonucleotide. Mol. Pharmacol. 55, 396–402 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Wang, X. Y., Repasky, E. & Liu, H. T. Antisense inhibition of protein kinase Cα reverses the transformed phenotype in human lung carcinoma cells. Exp. Cell Res. 250, 253–263 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Dean, N. M. & McKay, R. Inhibition of protein kinase Cα expression in mice after systemic administration of phosphorothioate antisense oligodeoxynucleotides. Proc. Natl Acad. Sci. USA 91, 11762–11766 (1994). Demonstrated for the first time that antisense oligonucleotides can inhibit gene expression in a highly specific manner when administered parenterally to normal mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yazaki, T. et al. Treatment of glioblastoma U-87 by systemic administration of an antisense protein kinase C-α phosphorothioate oligodeoxynucleotide. Mol. Pharmacol. 50, 236–242 (1996).

    CAS  PubMed  Google Scholar 

  49. Geiger, T., Muller, M., Dean, N. M. & Fabbro, D. Antitumor activity of a PKC-α antisense oligonucleotide in combination with standard chemotherapeutic agents against various human tumors transplanted into nude mice. Anticancer Drug Des. 13, 35–45 (1998).

    CAS  PubMed  Google Scholar 

  50. Dennis, J. U. et al. Human melanoma metastasis is inhibited following ex vivo treatment with an antisense oligonucleotide to protein kinase C-α. Cancer Lett. 128, 65–70 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Nemunaitis, J. et al. Phase I evaluation of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C-α, in patients with advanced cancer. J. Clin. Oncol. 17, 3586–3595 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Yuen, A. R. et al. Phase I study of an antisense oligonucleotide to protein kinase C-α (ISIS 3521/CGP 64128A) in patients with cancer. Clin. Cancer Res. 5, 3357–3363 (1999).

    CAS  PubMed  Google Scholar 

  53. Cunningham, C. C. et al. A phase I trial of c-Raf kinase antisense oligonucleotide ISIS 5132 administered as a continuous intravenous infusion in patients with advanced cancer. Clin. Cancer Res. 6, 1626–1631 (2000).

    CAS  PubMed  Google Scholar 

  54. Tolcher, A. W. et al. A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer. Clin. Cancer Res. 8, 2530–2535 (2002).

    CAS  PubMed  Google Scholar 

  55. Yuen, A. R. et al. Phase I/II trial of ISIS 3521, an antisense inhibitor of PKC-α, with carboplatin and paclitaxel in non-small cell lung cancer. Proc. Am. Soc. Clin. Oncol. A1234 (2001).

  56. Ritch, P. et al. Phase I/II trial of ISIS 3521/LY900003, an antisense inhibitor of PKC-α, with cisplatin and gemcitabine in advanced non-small cell lung cancer. Proc. Am. Soc. Clin. Oncol. 21, 309a (2002).

    Google Scholar 

  57. Cervellera, M. et al. Direct transactivation of the anti-apoptotic gene apolipoprotein J (clusterin) by B-MYB. J. Biol. Chem. 275, 21055–21060 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Wellmann, A. et al. Detection of differentially expressed genes in lymphomas using cDNA arrays: identification of clusterin as a new diagnostic marker for anaplastic large-cell lymphomas. Blood 96, 398–404 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Steinberg, J. et al. Intracellular levels of SGP-2 (Clusterin) correlate with tumor grade in prostate cancer. Clin. Cancer Res. 3, 1707–1711 (1997).

    CAS  PubMed  Google Scholar 

  60. Redondo, M. et al. Overexpression of clusterin in human breast carcinoma. Am. J. Pathol. 157, 393–399 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Miyake, H., Gleave, M., Kamidono, S. & Hara, I. Overexpression of clusterin in transitional cell carcinoma of the bladder is related to disease progression and recurrence. Urology 59, 150–154 (2002).

    Article  PubMed  Google Scholar 

  62. Parczyk, K., Pilarsky, C., Rachel, U. & Koch-Brandt, C. Gp80 (clusterin; TRPM-2) mRNA level is enhanced in human renal clear cell carcinomas. J. Cancer Res. Clin. Oncol. 120, 186–188 (1994).

    Article  CAS  PubMed  Google Scholar 

  63. Calero, M. et al. Apolipoprotein J (clusterin) and Alzheimer's disease. Microsc. Res. Tech. 50, 305–315 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Rosenberg, M. E. & Silkensen, J. Clusterin and the kidney. Exp. Nephrol. 3, 9–14 (1995).

    CAS  PubMed  Google Scholar 

  65. Montpetit, M. L., Lawless, K. R. & Tenniswood, M. Androgen-repressed messages in the rat ventral prostate. Prostate 8, 25–36 (1986).

    Article  CAS  PubMed  Google Scholar 

  66. Miyake, H., Nelson, C., Rennie, P. S. & Gleave, M. E. Testosterone-repressed prostate message-2 is an antiapoptotic gene involved in progression to androgen independence in prostate cancer. Cancer Res. 60, 170–176 (2000). Reported that increased levels of clusterin after hormone therapy conferred therapeutic resistance, identifying clusterin for the first time as a cytoprotective protein and therapeutic target.

    CAS  PubMed  Google Scholar 

  67. Kyprianou, N., English, H. F. & Isaacs, J. T. Programmed cell death during regression of PC-82 human prostate cancer following androgen ablation. Cancer Res. 50, 3748–3753 (1990).

    CAS  PubMed  Google Scholar 

  68. Bubendorf, L. et al. Hormone therapy failure in human prostate cancer: analysis by complementary DNA and tissue microarrays. J. Natl Cancer Inst. 91, 1758–1764 (1999).

    Article  CAS  PubMed  Google Scholar 

  69. July, L. V. et al. Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy. Prostate 50, 179–188 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Koch-Brandt, C. & Morgans, C. Clusterin: a role in cell survival in the face of apoptosis? Prog. Mol. Subcell. Biol. 16, 130–149 (1996).

    Article  CAS  PubMed  Google Scholar 

  71. Wilson, M. R. & Easterbrook-Smith, S. B. Clusterin is a secreted mammalian chaperone. Trends Biochem. Sci. 25, 95–98 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Michel, D., Chatelain, G., North, S. & Brun, G. Stress-induced transcription of the clusterin/apoJ gene. Biochem. J. 328, 45–50 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Humphreys, D. T., Carver, J. A., Easterbrook-Smith, S. B. & Wilson, M. R. Clusterin has chaperone-like activity similar to that of small heat shock proteins. J. Biol. Chem. 274, 6875–6881 (1999).

    Article  CAS  PubMed  Google Scholar 

  74. Sensibar, J. A. et al. Prevention of cell death induced by tumor necrosis factor alpha in LNCaP cells by overexpression of sulfated glycoprotein-2 (clusterin). Cancer Res. 55, 2431–2437 (1995).

    CAS  PubMed  Google Scholar 

  75. Zellweger, T. et al. Enhanced radiation sensitivity in prostate cancer by inhibition of the cell survival protein clusterin. Clin. Cancer Res. 8, 3276–3284 (2002).

    CAS  PubMed  Google Scholar 

  76. Miyake, H., Chi, K. N. & Gleave, M. E. Antisense TRPM-2 oligodeoxynucleotides chemosensitize human androgen-independent PC-3 prostate cancer cells both in vitro and in vivo. Clin. Cancer Res. 6, 1655–1663 (2000).

    CAS  PubMed  Google Scholar 

  77. Zellweger, T. et al. Antitumor activity of antisense clusterin oligonucleotides is improved in vitro and in vivo by incorporation of 2′-O-(2-methoxy)ethyl chemistry. J. Pharmacol. Exp. Ther. 298, 934–940 (2001). A preclinical pharmacology paper that demonstrated that tissue half-life and target suppression was superior using a second-generation 2'-MOE OGX-011 compared to unmodified phosphorthioate ASO. These data provided the preclinical proof of principle to proceed into human trials using OGX-011.

    CAS  PubMed  Google Scholar 

  78. July, L. V. et al. Nucleotide-based therapies targeting clusterin chemosensitize human lung adenocarcinoma cells both in vitro and in vivo. Mol. Cancer Ther. 3, 223–232 (2004).

    CAS  PubMed  Google Scholar 

  79. Zellweger, T. et al. Chemosensitization of human renal cell cancer using antisense oligonucleotides targeting the antiapoptotic gene clusterin. Neoplasia 3, 360–367 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Miyake, H., Hara, I., Kamidono, S. & Gleave, M. E. Synergistic chemsensitization and inhibition of tumor growth and metastasis by the antisense oligodeoxynucleotide targeting clusterin gene in a human bladder cancer model. Clin. Cancer Res. 7, 4245–4252 (2001).

    CAS  PubMed  Google Scholar 

  81. Biroccio, A., D'Angelo, C., Gleave, M. & Gonos, E. S. Antisense clusterin oligodeoxynucleotides increase the response of HER-2 gene amplified breast cancer cells to trastuzumab. J. Cell Physiol. 31 Jan 2005 (10.1002/jcp.20295).

  82. Trougakos, I. P., So, A., Jansen, B., Gleave, M. E. & Gonos, E. S. Silencing expression of the clusterin/apolipoprotein J gene in human cancer cells using small interfering RNA induces spontaneous apoptosis, reduced growth ability, and cell sensitization to genotoxic and oxidative stress. Cancer Res. 64, 1834–1842 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Chi, K. et al. A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of OGX–011, a 2′methoxyethyl phosphorothioate antisense to clusterin, in patients with prostate cancer prior to radical prostatectomy. J. Clin. Oncol. 22, 3033 (2004).

    Article  Google Scholar 

  84. Li, F. et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 396, 580–584 (1998).

    Article  CAS  PubMed  Google Scholar 

  85. Schimmer, A. D. Inhibitor of apoptosis proteins: translating basic knowledge into clinical practice. Cancer Res. 64, 7183–7190 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Okada, H. & Mak, T. W. Pathways of apoptotic and non-apoptotic death in tumour cells. Nature Rev. Cancer 4, 592–603 (2004).

    Article  CAS  Google Scholar 

  87. LaCasse, E. C., Baird, S., Korneluk, R. G. & MacKenzie, A. E. The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene 17, 3247–3259 (1998).

    Article  PubMed  Google Scholar 

  88. Ambrosini, G., Adida, C. & Altieri, D. C. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nature Med. 3, 917–921 (1997).

    Article  CAS  PubMed  Google Scholar 

  89. Tamm, I. et al. IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res. 58, 5315–5320 (1998).

    CAS  PubMed  Google Scholar 

  90. Lu, C. D., Altieri, D. C. & Tanigawa, N. Expression of a novel antiapoptosis gene, survivin, correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomas. Cancer Res. 58, 1808–1812 (1998).

    CAS  PubMed  Google Scholar 

  91. Lal, A. et al. A public database for gene expression in human cancers. Cancer Res. 59, 5403–5407 (1999).

    CAS  PubMed  Google Scholar 

  92. Altieri, D. C. Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene 22, 8581–8589 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Li, F. et al. Pleiotropic cell-division defects and apoptosis induced by interference with survivin function. Nature Cell Biol. 1, 461–466 (1999).

    Article  CAS  PubMed  Google Scholar 

  94. Chen, J. et al. Down-regulation of survivin by antisense oligonucleotides increases apoptosis, inhibits cytokinesis and anchorage-independent growth. Neoplasia 2, 235–241 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ansell, S. M. et al. Inhibition of survivin expression suppresses the growth of aggressive non-Hodgkin's lymphoma. Leukemia 18, 616–623 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Deveraux, Q. L., Takahashi, R., Salvesen, G. S. & Reed, J. C. X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388, 300–304 (1997).

    Article  CAS  PubMed  Google Scholar 

  97. Silke, J. et al. The anti-apoptotic activity of XIAP is retained upon mutation of both the caspase 3- and caspase 9-interacting sites. J. Cell Biol. 157, 115–124 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Salvesen, G. S. & Duckett, C. S. IAP proteins: blocking the road to death's door. Nature Rev. Mol. Cell Biol. 3, 401–410 (2002).

    Article  CAS  Google Scholar 

  99. Hu, Y. et al. Antisense oligonucleotides targeting XIAP induce apoptosis and enhance chemotherapeutic activity against human lung cancer cells in vitro and in vivo. Clin. Cancer Res. 9, 2826–2836 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  101. Darnell, J. E. Jr., Kerr, I. M. & Stark, G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415–1421 (1994).

    Article  CAS  PubMed  Google Scholar 

  102. Yu, C. L. et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 269, 81–83 (1995).

    Article  CAS  PubMed  Google Scholar 

  103. Yu, H. & Jove, R. The STATs of cancer — new molecular targets come of age. Nature Rev. Cancer 4, 97–105 (2004).

    Article  CAS  Google Scholar 

  104. Buettner, R., Mora, L. B. & Jove, R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin. Cancer Res. 8, 945–954 (2002).

    CAS  PubMed  Google Scholar 

  105. Mora, L. B. et al. Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Res. 62, 6659–6666 (2002).

    CAS  PubMed  Google Scholar 

  106. Cheng, F. et al. A critical role for Stat3 signaling in immune tolerance. Immunity 19, 425–436 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Epling-Burnette, P. K. et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J. Clin. Invest. 107, 351–362 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Turkson, J. & Jove, R. STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 19, 6613–6626 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Garrido, C. et al. HSP27 and HSP70: potentially oncogenic apoptosis inhibitors. Cell Cycle 2, 579–584 (2003).

    Article  CAS  PubMed  Google Scholar 

  110. Concannon, C. G., Gorman, A. M. & Samali, A. On the role of Hsp27 in regulating apoptosis. Apoptosis 8, 61–70 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. Ciocca, D. R., Oesterreich, S., Chamness, G. C., McGuire, W. L. & Fuqua, S. A. Biological and clinical implications of heat shock protein 27,000 (Hsp27): a review. J. Natl Cancer Inst. 85, 1558–1570 (1993).

    Article  CAS  PubMed  Google Scholar 

  112. Neckers, L., Schulte, T. W. & Mimnaugh, E. Geldanamycin as a potential anti-cancer agent: its molecular target and biochemical activity. Invest. New Drugs 17, 361–373 (1999).

    Article  CAS  PubMed  Google Scholar 

  113. Ramanathan, R. K., Trump, D. L. & Eiseman, J. L. A phase I pharmacokinetic (PK) and pharmacodynamic (PD) trial of weekly 17-allylamino-17 demethoxygeldanamycin (17AAG, NSC–704057) in patients with advanced tumors. J. Clin. Oncol. 22, 3031 (2004).

    Article  Google Scholar 

  114. Liang, P. & MacRae, T. H. Molecular chaperones and the cytoskeleton. J. Cell Sci. 110, 1431–1440 (1997).

    Article  CAS  PubMed  Google Scholar 

  115. Parcellier, A., Gurbuxani, S., Schmitt, E., Solary, E. & Garrido, C. Heat shock proteins, cellular chaperones that modulate mitochondrial cell death pathways. Biochem. Biophys. Res. Commun. 304, 505–512 (2003).

    Article  CAS  PubMed  Google Scholar 

  116. Conroy, S. E. & Latchman, D. S. Do heat shock proteins have a role in breast cancer? Br. J. Cancer 74, 717–721 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Arts, H. J. et al. Heat-shock-protein-27 (hsp27) expression in ovarian carcinoma: relation in response to chemotherapy and prognosis. Int. J. Cancer 84, 234–238 (1999).

    Article  CAS  PubMed  Google Scholar 

  118. Zhang, R., Tremblay, T. L., McDermid, A., Thibault, P. & Stanimirovic, D. Identification of differentially expressed proteins in human glioblastoma cell lines and tumors. Glia 42, 194–208 (2003).

    Article  PubMed  Google Scholar 

  119. Cornford, P. A. et al. Heat shock protein expression independently predicts clinical outcome in prostate cancer. Cancer Res. 60, 7099–7105 (2000).

    CAS  PubMed  Google Scholar 

  120. Bruey, J. M. et al. Differential regulation of HSP27 oligomerization in tumor cells grown in vitro and in vivo. Oncogene 19, 4855–4863 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Rocchi, P. et al. Heat shock protein 27 increases after androgen ablation and plays a cytoprotective role in hormone-refractory prostate cancer. Cancer Res. 64, 6595–6602 (2004).

    Article  CAS  PubMed  Google Scholar 

  122. Garrido, C. et al. HSP27 as a mediator of confluence-dependent resistance to cell death induced by anticancer drugs. Cancer Res. 57, 2661–2667 (1997).

    CAS  PubMed  Google Scholar 

  123. Vargas-Roig, L. M., Gago, F. E., Tello, O., Aznar, J. C. & Ciocca, D. R. Heat shock protein expression and drug resistance in breast cancer patients treated with induction chemotherapy. Int. J. Cancer 79, 468–475 (1998).

    Article  CAS  PubMed  Google Scholar 

  124. Garrido, C. et al. HSP27 inhibits cytochrome c-dependent activation of procaspase-9. FASEB J. 13, 2061–2070 (1999).

    Article  CAS  PubMed  Google Scholar 

  125. Paul, C. et al. Hsp27 as a negative regulator of cytochrome C release. Mol. Cell. Biol. 22, 816–834 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Concannon, C. G., Orrenius, S. & Samali, A. Hsp27 inhibits cytochrome c-mediated caspase activation by sequestering both pro-caspase-3 and cytochrome c. Gene Expr. 9, 195–201 (2001).

    Article  CAS  PubMed  Google Scholar 

  127. Ho, S. P. et al. Mapping of RNA accessible sites for antisense experiments with oligonucleotide libraries. Nature Biotechnol. 16, 59–63 (1998).

    Article  CAS  Google Scholar 

  128. Matveeva, O., Felden, B., Audlin, S., Gesteland, R. F. & Atkins, J. F. A rapid in vitro method for obtaining RNA accessibility patterns for complementary DNA probes: correlation with an intracellular pattern and known RNA structures. Nucleic Acids Res. 25, 5010–5016 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Stull, R. A., Taylor, L. A. & Szoka, F. C. Jr. Predicting antisense oligonucleotide inhibitory efficacy: a computational approach using histograms and thermodynamic indices. Nucleic Acids Res. 20, 3501–3508 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Butler, M. et al. Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice. Diabetes 51, 1028–1034 (2002).

    Article  CAS  PubMed  Google Scholar 

  131. Geary, R. S. et al. Pharmacokinetic properties of 2′-O-(2-methoxyethyl)-modified oligonucleotide analogs in rats. J. Pharmacol. Exp. Ther. 296, 890–897 (2001). Describes the pharmacokinetic attributes of second-generation 2'-MOE antisense oligonucleotides in animals.

    CAS  PubMed  Google Scholar 

  132. Henry, S. P., Geary, R. S., Yu, R. & Levin, A. A. Drug properties of second-generation antisense oligonucleotides: how do they measure up to their predecessors? Curr. Opin. Investig. Drugs 2, 1444–1449 (2001).

    CAS  PubMed  Google Scholar 

  133. Henry, S. P., Monteith, D., Bennett, F. & Levin, A. A. Toxicological and pharmacokinetic properties of chemically modified antisense oligonucleotide inhibitors of PKC-α and C-raf kinase. Anticancer Drug Des. 12, 409–420 (1997).

    CAS  PubMed  Google Scholar 

  134. Levin, A. A. A review of the issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochim. Biophys. Acta 1489, 69–84 (1999).

    Article  CAS  PubMed  Google Scholar 

  135. Henry, S. P., Monteith, D. & Levin, A. A. Antisense oligonucleotide inhibitors for the treatment of cancer: 2. Toxicological properties of phosphorothioate oligodeoxynucleotides. Anticancer Drug Des. 12, 395–408 (1997).

    CAS  PubMed  Google Scholar 

  136. Geary, R. S. et al. Pharmacokinetics of a tumor necrosis factor-α phosphorothioate 2′-O-(2-methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab. Dispos. 31, 1419–1428 (2003).

    Article  CAS  PubMed  Google Scholar 

  137. Cook, P. Second generation antisense oligonucleotides: 2′–modifications. Annu. Rep. Med. Chem. 33, 313 (1998).

    CAS  Google Scholar 

  138. Vester, B. & Wengel, J. LNA (locked nucleic acid): high-affinity targeting of complementary RNA and DNA. Biochemistry 43, 13233–13241 (2004).

    Article  CAS  PubMed  Google Scholar 

  139. Pollak, M. N., Schernhammer, E. S. & Hankinson, S. E. Insulin-like growth factors and neoplasia. Nature Rev. Cancer 4, 505–518 (2004). Excellent contemporary review on the IGF1 axis in cancer.

    Article  CAS  Google Scholar 

  140. Jones, J. I. & Clemmons, D. R. Insulin-like growth factors and their binding proteins: biological actions. Endocr. Rev. 16, 3–34 (1995).

    CAS  PubMed  Google Scholar 

  141. Miyake, H., Nelson, C., Rennie, P. S. & Gleave, M. E. Overexpression of insulin-like growth factor binding protein-5 helps accelerate progression to androgen-independence in the human prostate LNCaP tumor model through activation of phosphatidylinositol 3′-kinase pathway. Endocrinology 141, 2257–2265 (2000).

    Article  CAS  PubMed  Google Scholar 

  142. Miyake, H., Pollak, M. & Gleave, M. E. Castration-induced up-regulation of insulin-like growth factor binding protein-5 potentiates insulin-like growth factor-I activity and accelerates progression to androgen independence in prostate cancer models. Cancer Res. 60, 3058–3064 (2000).

    CAS  PubMed  Google Scholar 

  143. Kiyama, S. et al. Castration-induced increases in insulin-like growth factor-binding protein 2 promotes proliferation of androgen-independent human prostate LNCaP tumors. Cancer Res. 63, 3575–3584 (2003).

    CAS  PubMed  Google Scholar 

  144. Bae, J., Leo, C. P., Hsu, S. Y. & Hsueh, A. J. MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain. J. Biol. Chem. 275, 25255–25261 (2000).

    Article  CAS  PubMed  Google Scholar 

  145. Akgul, C., Turner, P. C., White, M. R. & Edwards, S. W. Functional analysis of the human MCL-1 gene. Cell Mol. Life Sci. 57, 684–691 (2000).

    Article  CAS  PubMed  Google Scholar 

  146. Derenne, S. et al. Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-xL is an essential survival protein of human myeloma cells. Blood 100, 194–199 (2002).

    Article  CAS  PubMed  Google Scholar 

  147. Zhou, P., Qian, L., Kozopas, K. M. & Craig, R. W. Mcl-1, a Bcl-2 family member, delays the death of hematopoietic cells under a variety of apoptosis-inducing conditions. Blood 89, 630–643 (1997).

    Article  CAS  PubMed  Google Scholar 

  148. Miyamoto, Y. et al. Immunohistochemical analysis of Bcl-2, Bax, Bcl-X, and Mcl-1 expression in pancreatic cancers. Oncology 56, 73–82 (1999).

    Article  CAS  PubMed  Google Scholar 

  149. Chung, T. K. et al. Expression of apoptotic regulators and their significance in cervical cancer. Cancer Lett. 180, 63–68 (2002).

    Article  CAS  PubMed  Google Scholar 

  150. Cho-Vega, J. H. et al. MCL-1 expression in B-cell non-Hodgkin's lymphomas. Hum. Pathol. 35, 1095–1100 (2004)

    Article  CAS  PubMed  Google Scholar 

  151. Heere-Ress, E. et al. Bcl-X(L) is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy. Int. J. Cancer 99, 29–34 (2002).

    Article  CAS  PubMed  Google Scholar 

  152. Thallinger, C. et al. Mcl-1 is a novel therapeutic target for human sarcoma: synergistic inhibition of human sarcoma xenotransplants by a combination of mcl-1 antisense oligonucleotides with low-dose cyclophosphamide. Clin. Cancer Res. 10, 4185–4191 (2004).

    Article  CAS  PubMed  Google Scholar 

  153. Wacheck, V. et al. Bcl-xL antisense oligonucleotides radiosensitise colon cancer cells. Br. J. Cancer 89, 1352–1357 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Sigalas, I., Calvert, A. H., Anderson, J. J., Neal, D. E. & Lunec, J. Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer. Nature Med. 2, 912–917 (1996).

    Article  CAS  PubMed  Google Scholar 

  155. Wang, H., Yu, D., Agrawal, S. & Zhang, R. Experimental therapy of human prostate cancer by inhibiting MDM2 expression with novel mixed-backbone antisense oligonucleotides: in vitro and in vivo activities and mechanisms. Prostate 54, 194–205 (2003).

    Article  CAS  PubMed  Google Scholar 

  156. Zhang, Z., Li, M., Wang, H., Agrawal, S. & Zhang, R. Antisense therapy targeting MDM2 oncogene in prostate cancer: effects on proliferation, apoptosis, multiple gene expression, and chemotherapy. Proc. Natl Acad. Sci. USA 100, 11636–11641 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Adjei, A. A. et al. A phase I trial of ISIS 2503, an antisense inhibitor of H-ras, in combination with gemcitabine in patients with advanced cancer. Clin. Cancer Res. 9, 115–123 (2003).

    CAS  PubMed  Google Scholar 

  158. Davis, A. J. et al. Phase I and pharmacologic study of the human DNA methyltransferase antisense oligodeoxynucleotide MG98 given as a 21-day continuous infusion every 4 weeks. Invest. New Drugs 21, 85–97 (2003).

    Article  CAS  PubMed  Google Scholar 

  159. de Fabritiis, P. et al. BCR–ABL antisense oligodeoxynucleotide in vitro purging and autologous bone marrow transplantation for patients with chronic myelogenous leukemia in advanced phase. Blood 91, 3156–3162 (1998).

    Article  CAS  PubMed  Google Scholar 

  160. Nylandsted, J. et al. Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2. Proc. Natl Acad. Sci. USA 97, 7871–7876 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Ratajczak, M. Z. et al. Acute- and chronic-phase chronic myelogenous leukemia colony-forming units are highly sensitive to the growth inhibitory effects of c-myb antisense oligodeoxynucleotides. Blood 79, 1956–1961 (1992).

    Article  CAS  PubMed  Google Scholar 

  162. Tortora, G. et al. Oral antisense that targets protein kinase A cooperates with taxol and inhibits tumor growth, angiogenesis, and growth factor production. Clin. Cancer Res. 6, 2506–2512 (2000).

    CAS  PubMed  Google Scholar 

  163. Monia, B. P., Johnston, J. F., Geiger, T., Muller, M. & Fabbro, D. Antitumor activity of a osphorothioate antisense oligodeoxynucleotide targeted against C-raf kinase. Nature Med. 2, 668–675 (1996).

    Article  CAS  PubMed  Google Scholar 

  164. Stevenson, J. P. et al. Phase I clinical/pharmacokinetic and pharmacodynamic trial of the c-raf-1 antisense oligonucleotide ISIS 5132 (CGP 69846A). J. Clin. Oncol. 17, 2227–2236 (1999).

    Article  CAS  PubMed  Google Scholar 

  165. Bishop, M. R. et al. Phase I trial of an antisense oligonucleotide OL(1)p53 in hematologic malignancies. J. Clin. Oncol. 14, 1320–1326 (1996).

    Article  CAS  PubMed  Google Scholar 

  166. Eder, I. E. et al. Inhibition of LNCaP prostate tumor growth in vivo by an antisense oligonucleotide directed against the human androgen receptor. Cancer Gene Ther. 9, 117–125 (2002).

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Martin E. Gleave.

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DATABASES

Entrez Gene

BCL2

BCL-XL

caspase-3

CLU

HSP27

PKCα

STAT3

XIAP

National Cancer Institute

chronic lymphocytic leukaemia

melanoma

multiple myeloma

non-Hodgkin's lymphoma

non-small-cell lung cancer

prostate cancer

FURTHER INFORMATION

Genta

ISIS Pharmaceuticals

OncoGenex Technologies

Glossary

PHOSPHOROTHIOATE BACKBONE

The non-bridging phosphoryl oxygen of each nucleotide in an oligomer is replaced with sulphur, which increases resistance to nuclease digestion and prolongs tissue half-life.

OFF TARGET

A non-specific effect of a drug or antisense oligonucleotide that is different from its characterized specific effect on its known target molecule.

APOPTOTIC RHEOSTAT

Describes the dynamic interactions between pro-survival and pro-death signals within a cell that regulate programmed cell death.

THROMBOCYTOPAENIA

Low circulating platelet count (<125 × 109/L), which leads to a reduction in the clotting efficiency of the blood.

INTENT-TO-TREAT ANALYSIS

Patients are analysed according to the treatment group they were randomized to, as opposed to the treatment actually received.

PER-PROTOCOL ANALYSIS

A priori planned analysis of results.

2′-O-METHOXYETHYL MODIFICATIONS

Modifications of the ribose at the 2′-position with an electronegative substitute such as 2′-O-methyl or 2′-O-methoxy-ethyl group (illustrated in Box 2).

LEUKOPAENIA

Low circulating total white blood cell count, often associated with anticancer drugs, which can predispose the host to infections.

NEUTROPAENIA

Low circulating neutrophil cell count (<2 × 109/L), which is often associated with anticancer drugs and can predispose the host to infections.

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Gleave, M., Monia, B. Antisense therapy for cancer. Nat Rev Cancer 5, 468–479 (2005). https://doi.org/10.1038/nrc1631

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