Skip to main content

Antisense cancer therapy: The state of the science

Current Oncology Reports volume 2, pages 23–30 (2000)Cite this article

Abstract

Over the last few years, antisense technology has emerged as an exciting and promising strategy in the fight against cancer. The antisense concept is to selectively bind short, modified DNA or RNA molecules to messenger RNA in cells and prevent the synthesis of the encoded protein. As anticancer agents, these molecules can be targeted against a myriad of genes involved in cell transformation, cell survival, metastasis, and angiogenesis. Indeed, the list of possible antisense targets increases as the knowledge of the genetic basis of oncogenesis expands. One aim of this review is to focus on those antisense cancer drugs that have entered human clinical trials. At least four of these compounds are currently in phase II trials, including those targeting protein kinase C-α, bcl-2, c-raf, and the R1-α subunit of protein kinase A. A new development in antisense chemistry (peptide nucleic acids) is discussed, along with alternative antisense-related strategies (ribozymes and 2-5A-antisense) designed to overcome some of the challenges of this already encouraging technology.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References and Recommended Reading

  1. WickstromE:Prospects for Antisense Nucleic Acid Therapy of Cancer and AIDS. New York: Wiley-Liss; 1991.

    Google Scholar 

  2. PersidisA: Antisense therapeutics. Nat Biotechnol 1999, 17:403–404.

    PubMed  Article  CAS  Google Scholar 

  3. Zamecnik PC, Stephenson ML: Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci USA 1978, 75:280–284.

    PubMed  Article  CAS  Google Scholar 

  4. Stephenson ML, Zamecnik PC: Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc Natl Acad Sci U S A 1978, 75:285–288.

    PubMed  Article  CAS  Google Scholar 

  5. Ho PTC, Parkinson DR: Antisense oligonucleotides as therapeutics for malignant diseases. Semin Oncol 1997, 24:187–202.

    PubMed  CAS  Google Scholar 

  6. FlanaganWM: Antisense comes of age. Cancer and Metastasis Rev 1998, 17:169–176.

    Article  CAS  Google Scholar 

  7. Benimetskaya L, Takle GB, Vilenchik M, et al.: Cationic porphyrins: novel delivery vehicles for antisense oligodeoxynucleotides. Nucleic Acids Res 1998, 26:5310–5317.

    PubMed  Article  CAS  Google Scholar 

  8. Kondo S, Kondo Y, Li G, et al.: Targeted therapy of human malignant glioma in a mouse model by 2–5A antisense directed against telomerase RNA. Oncogene 1998, 16:3323–3330.

    PubMed  Article  CAS  Google Scholar 

  9. Monia BP, Johnston JF, Geiger T, et al.: Antitumor activity of a phosphorothioate antisense oligodeoxynucleotide targeted against C-raf kinase. Nature Med 1996, 2:668–675.

    PubMed  Article  CAS  Google Scholar 

  10. Dean NM, McKay R: Inhibition of protein kinase C-a expression in mice after systemic administration of phosphorothioate antisense oligodeoxynucleotides. Proc Natl Acad Sci U S A 1994, 91:11762–11766.

    PubMed  Article  CAS  Google Scholar 

  11. NishizukaY: Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 1992, 258:607–614.

    PubMed  Article  CAS  Google Scholar 

  12. NewtonAC: Protein kinase C: Structure, function and regulation. J Biol Chem 1995, 270:28495–28498.

    PubMed  Article  CAS  Google Scholar 

  13. McGraw K, McKay R, Miraglia L, et al.: Antisense oligonucleotide inhibitors of isozymes of protein kinase C: in vitro and in vivo activity, and clinical development as anti-cancer therapeutics. Anti-cancer Drug Des 1997, 12:315–327.

    CAS  Google Scholar 

  14. Dean NM, McKay R, Condon TP, et al.: Inhibition of protein kinase C-a expression in human A549 cells by antisense oligonucleotides inhibits induction of intercellular adhesion molecule 1 (ICAM-1) mRNA by phorbol esters. J Biol Chem 1994, 269:16416–16424.

    PubMed  CAS  Google Scholar 

  15. Yazaki T, Ahmad S, Chahlavi A, et al.: Treatment of glioblastoma U-87 by systemic administration of an antisense protein kinase C-a phosphorothioate oligodeoxynucleotide. Mol Pharm 1997, 50:236–242.

    Google Scholar 

  16. Dean N, McKay R, Miraglia L, et al.: Inhibition of growth of human tumor cell lines in nude mice by an antisense oligonucleotide inhibitor of protein kinase C-a expression. Cancer Res 1996, 56:3499–3507.

    PubMed  CAS  Google Scholar 

  17. Dennis JU, Dean NM, Bennett CF, et al.: Human melanoma metastasis is inhibited following ex vivo treatment with an antisense oligonucleotide to protein kinase C-a. Cancer Lett 1998, 128:65–70.

    PubMed  Article  CAS  Google Scholar 

  18. Sikic BI, Yuen AR, Advani R, et al.: Antisense oligonucleotide therapy targeted to protein kinase C-a (ISIS 3521/CGP 64128A) by 21 day infusion: Results of the phase I trial and activity in ovarian carcinomas [abstract]. Proc ASCO 1998, 17:1654A.

    Google Scholar 

  19. Nemunaitis J, Van Hoff DD, Holmund J, et al.: Phase I/pharmacokinetic trial of a protein kinase C-a antisense oligonucleotide, ISIS 3521, administered thrice weekly [abstract]. Proc ASCO 1998, 17:812A.

    Google Scholar 

  20. Advani R, Fisher GA, Grant P, et al.: A Phase I trial of an antisense oligonucleotide targeted to protein kinase C-a (ISIS 3521/ISI641A) delivered as a 24-hour continuous infusion [abstract]. Proc ASCO 1999, 18:609A.

    Google Scholar 

  21. Sikic BI, Yuen A, Advani R, et al.: A Phase I trial of ISIS 3521 (ISI 641A), an antisense inhibitor of protein kinase C-a, combined with carboplatin and paclitaxel in patients with cancer [abstract]. Proc ASCO 1999, 18:1718A.

    Google Scholar 

  22. Mani S, Shulman K, Kunkel K, et al.: A phase I trial of protein kinase C-a antisense oligonucleotide (ISIS 3521; ISI 641A) with 5-fluorouracil and leucovorin in patients with advanced cancer [abstract]. Proc ASCO 1999, 18:608A.

    Google Scholar 

  23. DorrFA: Antisense oligonucleotides in the treatment of cancer. Antisense Nucleic Acid Drug Dev 1999, 9:391–396.

    CAS  Google Scholar 

  24. CowsertLM: In vitro and in vivo activity of antisense inhibitors of ras: Potential for clinical development. Anti-cancer Drug Des 1997, 12:359–371.

    CAS  Google Scholar 

  25. Monia BP, Johnston JF, Ecker DJ, et al.: Selective inhibition of mutant Ha-ras mRNA expression by antisense oligonucleotides. J Biol Chem 1992, 267:19954–19962.

    PubMed  CAS  Google Scholar 

  26. Dorr A, Bruce J, Monia B, et al.: Phase I and pharmacokinetic trial of ISIS 2503, a 20-mer antisense oligonucleotide against H-ras, by 14-day continuous infusion in patients with advanced cancer [abstract]. Proc ASCO 1999, 18:603A.

    Google Scholar 

  27. Gordon MS, Sandler AB, Holmlund JT, et al.: A phase I trial of ISIS 2503, an antisense inhibitor of H-ras, administered by a 24-hour weekly infusion to patients with advanced cancer [abstract]. Proc ASCO 1999, 18:604A.

    Google Scholar 

  28. MoniaBP: First- and second-generation antisense inhibitors targeted to human c-raf kinase: in vitro and in vivo studies. Anti-cancer Drug Des 1997, 12:327–341.

    CAS  Google Scholar 

  29. O’Dwyer PJ, Stevenson JP Gallagher, M et al.: Phase I/ pharmacokinetic/ pharmacodynamic trial of raf-1 antisense ODN (ISIS 5132, CGP 69846A) [abstract]. Proc ASCO 1998, 17:810A.

    Google Scholar 

  30. Holmlund J, Nemunaitis J, Schiller J, et al.: Phase I trial of c-raf antisense oligonucleotide ISIS 5132 by 21-day continuous intravenous infusion in patients with advanced cancer [abstract]. Proc ASCO 1998, 17:811A.

    Google Scholar 

  31. Holmlund JT, Rudin CM, Mani S, et al.: Phase I trial of ISIS 5132/ODN 698A, a 20-mer phosphorothioate antisense oligonucleotide inhibitor of c-raf kinase, administered by a 24-hour weekly intravenous infusion to patients with advanced cancer [abstract]. Proc ASCO 1999, 18:605A.

    Google Scholar 

  32. Reed JC: Double identity for proteins of the Bcl-2 family. Nature, 387:773–776.

  33. ReedJC: Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistance. Curr Opin Oncol 1995, 7:541–546.

    PubMed  CAS  Google Scholar 

  34. Miyashita T, Reed JC: Bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res 1992, 52:5407–5411.

    PubMed  CAS  Google Scholar 

  35. Jansen B, Schlagbauer-Wadl H, Brown BD, et al.: Bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice. Nature Med 1998, 4:232–234.

    PubMed  Article  CAS  Google Scholar 

  36. Webb A, Cunningham D, Cotter R, et al.: BCL-2 antisense therapy in patients with non-Hodgkin lymphoma. Lancet 1997, 349:1137–1141. This is one of the first antisense clinical cancer trials to be published in a peer-review journal. A phase I escalating-dose trial is described in this report. No treatment-related toxicities were observed.

    PubMed  Article  CAS  Google Scholar 

  37. Chi KN, Gleave M, Klasa R, et al.:A phase I/II trial of G3139 (antisense oligodeoxynuclotides to BCL-2) and mitoxantrone in metastatic hormone refractory prostate cancer [abstract]. Proc Canadian Assoc Med Oncol 1999, in press.

  38. Waters JS, Webb A, Cunningham D, et al.: Results of a phase I clinical trial of BCL-2 antisense molecule G3139 in patients with non-Hodgkin’s lymphoma [abstract]. Proc ASCO 1999, 18:11A.

    Google Scholar 

  39. Morris MJ, Tong W, Osman I, et al.: A phase I/IIA dose-escalating trial of BCL-2 antisense (G3139) treatment by 14-day continuous intravenous infusion for patients with androgenindependent prostate cancer or other advanced solid tumor malignancies [abstract]. Proc ASCO 1999, 18:1243A.

    Google Scholar 

  40. Jansen B, Wacheck V, Heere-Ress E, et al.: A phase I/II study with dacarbazine and BCL-2 antisense oligonucleotide G3139 (GENTA) as a chemosensitizer in patients with advanced malignant melanoma [abstract]. Proc ASCO 1999, 18:2049A.

    Google Scholar 

  41. Imamura J, Miyoshi I, Koeffler JP: p53 in hematologic malignancies. Blood 1994, 84:2412–2421.

    PubMed  CAS  Google Scholar 

  42. Bayever E, Haines KM, Iversen PL, et al.: Selective cytotoxicity to human leukemic myeloblasts produced by oligodeoxyribonucleotide phosphorothioates complementary to p53 nucleotide sequences. Leuk Lymphoma 1994, 12:223–231.

    PubMed  CAS  Google Scholar 

  43. Spinolo J, Bayever E, Iversen P, et al.: Toxicity of human p53 antisense oligonucleotide infusions in Rhesis macacca [abstract]. Proc Am Assoc Cancer Res 1992, 33:523.

    Google Scholar 

  44. Bishop MR, Iversen PL, Bayever E, et al.: Phase I trial of an antisense oligonucleotide OL(1)p53 in hematologic malignancies. J Clin Oncol 1996, 14:1320–1326.

    PubMed  CAS  Google Scholar 

  45. Bishop MR, Jackson JD Tarantolo SR, et al.: Ex Vivo treatment of bone marrow with phosphorothioate oligonucleotide OL(1)p53 for autologous transplantation in acute myelogenous leukemia and myelodysplastic syndrome. J Hematother 1997, 6:441–446.

    PubMed  CAS  Google Scholar 

  46. Bayever E, Iversen PL, Bishop MR, et al.: Systemic administration of a phosphorothioate oligonucleotide with a sequence complementary to p53 for acute myelogenous leukemia and myelodysplastic syndrome: Initial results of a phase I trial. Antisense Res Dev 1993, 3:383–390.

    PubMed  CAS  Google Scholar 

  47. MartinRR: Clinical experience with GEM231, a secondgeneration antisense oligonucleotide targeting protein kinase A. Antisense Nucleic Acid Drug Dev 1999, 9:389–390.

    CAS  Google Scholar 

  48. Chen H, Ness E, Marshall J, et al.: Phase I trial of a secondgeneration oligonucleotide (GEM 231) targeted at type I protein kinase A in patients with refractory solid tumors [abstract]. Proc ASCO 1999, 18:610A.

    Google Scholar 

  49. Calabretta B, Nicolaides NC: c-myb and growth control. Crit Rev Eukaryotic Gene Exp 1992, 2:225–235.

    CAS  Google Scholar 

  50. Lyon J, Robinson C, Watson R: The role of myb proteins in normal and neoplastic cell proliferation. Crit Rev Oncog 1994, 5:373–388.

    PubMed  CAS  Google Scholar 

  51. Ratajczak MZ, Kant JA, Luger SM, et al.: In vivo treatment of human leukemia in a SCID mouse model with c-myb antisense oligodeoxynucleotides. Proc Natl Acad Sci U S A 1992, 89:11823–11827.

    PubMed  Article  CAS  Google Scholar 

  52. Del Bufalo D, Cucco C, Leonetti C, et al.: Effect of cisplatin and c-myb antisense phosphorothioate oligodeoxynucleotides combination on a human colon carcinoma cell line in vitro and in vivo. Br J Cancer 1996, 74:387–393.

    Google Scholar 

  53. Luger S, Sokol D, Gowdin E, et al.: Oligodeoxynucleotide therapeutics for human myelogenous leukemia: Interim results. Proc Am Soc Hematol, 1999, in press.

  54. Daley GQ, Van EttenRA, Baltimore D: Induction of chronic myelogenous leukemia in mice by the p210bcr/abl gene of the Philadelphia chromosome. Science 1990, 247:824–830.

    PubMed  Article  CAS  Google Scholar 

  55. Szcylik C, Skorski T, Nicolaides NC, et al.: Selective inhibition of leukemia cell proliferation by bcr-abl antisense oligodeoxynucleotides. Science 1991, 253:562–565.

    Article  Google Scholar 

  56. Skorski T, Neiborowska-Skorska M, Nicolaides NC, et al.: Suppression of Philadelphia 1 leukemia cell growth in mice by bcr-abl antisense oligodeoxynucleotide. Proc Natl Acad Sci U S A 1994, 91:4504–4508.

    PubMed  Article  CAS  Google Scholar 

  57. de FabritiisP, Amadori S, Petti MC, et al.: In vitro purging with BCR-ABL antisense oligodeoxynucleotides does not prevent haematologic reconstitution after autologous bone marrow transplantation. Leukemia 1995, 9:662–664.

    Google Scholar 

  58. de Fabritiis P, Petti MC, Montefusso E, et al.: BCR-ABL antisense oligodeoxynucleotide in vitro purging and autologous bone marrow transplantation for patients with chronic myelogenous leukemia in advanced phase. Blood 1998, 3156–3162. This paper describes the first series of patients who underwent ex vivo bone marrow purging with bcr-abl antisense. Overall, the protocol had low toxicity, and all patients experienced hematologic reconstitution. A complete karyotypic response was seen in two patients.

  59. James HA, Gibson I: The therapeutic potential of ribozymes. Blood 1998, 91:371–382. This article describes what is known about the structure and mechanism of action of ribozymes. It reviews the many applications of these molecules in overcoming drug resistance, viral disease including HIV, and cancer.

    PubMed  CAS  Google Scholar 

  60. SioudM: Application of preformed hammerhead ribozymes in the gene therapy of cancer [review]. Int J Mol Med 1999, 3:381–384.

    PubMed  CAS  Google Scholar 

  61. Wong-Staal F, Wong-Staal F, Poeschla EM, Looney D: 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 1998, 2407–2425.

  62. Nielsen PE, Egholm M, Berg RH, et al.: Sequence-selective recognition of DNA by strand displacement with a thyminesubstituted polyamide. Science 1991, 254:1497–1500.

    PubMed  Article  CAS  Google Scholar 

  63. Zhou A, Hassel BA, Silverman RH, et al.: Expression cloning of 2–5 A-dependent RNase-a uniquely regulated mediator of interferon action. Cell 1993, 72:753–765.

    PubMed  Article  CAS  Google Scholar 

  64. Torrence PF, Maitra RK, Lesiak K, et al.: Targeting RNA for degradation with a (2′-5′)oligoadenylate-antisense chimera. Proc Natl Acad Sci U S A 1993, 90:1300–1304.

    PubMed  Article  CAS  Google Scholar 

  65. Leaman DW, Cramer H: Controlling gene expression with 2–5A antisense. Methods 1999, 18:252–265.

    PubMed  Article  CAS  Google Scholar 

  66. Maran A, Waller CF, Paranjape JM, et al.: 2′5′ Oligoadenylateantisense chimeras cause RNase L to selectively degrade bcr/abl mRNA in chronic myelogenous leukemia cells. Blood 1998, 92:4336–4343.

    PubMed  CAS  Google Scholar 

  67. Verheijen JC, van der Marel GA, van BoomJH, et al.: 2,5-oligoadenylate-peptide nucleic acids (2-5A-PNAs) activate RNase L. Bioorg Med Chem 1999, 7:449–455.

    PubMed  Article  CAS  Google Scholar 

  68. Cramer H, Player MR, Torrence PF: Discrimination between ribonuclease H- and ribonuclease L-mediated RNA degradation by 2′-O-methylated 2–5A-antisense oligonucleotides. Bioorg Med Chem Lett 1999, 9:1049–1054.

    PubMed  Article  CAS  Google Scholar 

  69. Gerwitz AM, Sokol DL, Ratajczak MZ: Nucleic acid therapeutics: state of the art and future prospects. Blood 1998, 92:712–736. This paper is an excellent and exhaustive review of nucleic acid-based therapies with a strong emphasis on antisense therapy. The authors cover the theoretic and practical considerations necessary to create active genetic therapies and provides a brief review of such progress in regards to clinical hematology.

    Google Scholar 

  70. CookeST: An overview of progress in antisense therapeutics. Antisense Nucleic Acid Drug Dev 1998, 8:115–122. This review focuses on the pharmacokinetic and toxicologic properties of antisense therapy. The authors discuss some of the controversies in this field including interpretation of specific experiments.

    Google Scholar 

Download references

Author information

Affiliations

  1. Department of Cancer Biology, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, NB40, 44195, Cleveland, OH, USA

    Robert H. Silverman PhD

  2. Department of Gynecology and Obstetrics, The Cleveland Clinic Foundation, USA

    David M. Kushner MD

Authors
  1. David M. Kushner MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert H. Silverman PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kushner, D.M., Silverman, R.H. Antisense cancer therapy: The state of the science. Curr Oncol Rep 2, 23–30 (2000). https://doi.org/10.1007/s11912-000-0007-y

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-000-0007-y

Keywords

  • Chronic Myelogenous Leukemia
  • Antisense Oligonucleotide
  • Peptide Nucleic Acid
  • Phosphorothioate
  • Proc ASCO