Skip to main content

Advertisement

Log in

Antisense oncogene and tumor suppressor gene therapy of cancer

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Rapid advances in cancer gene therapy are driven by an explosive development of gene transfer technology and a strong demand for seeking alternatives to unsatisfactory conventional cancer therapies. Discovery of the genetic basis of cancer has indicated that cancer is a disease of genes. Among a variety of approaches to gene therapy of cancer, antisense oncogene and tumor suppressor gene therapy of cancer are the two strategies that aim at correcting genetic disorders of cancer through suppression of the abnormal expression of the proliferative genes. The potential effectiveness of these approaches is promised by their precise targeting at the mechanisms of the disease. Examples of several preclinical studies of these types of approaches that led to the approval of clinical trials are reviewed. Limitation and future development of these approaches are also discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Harris CC (1992) Molecular basis of multistage carcinogenesis. In: Harris CC, Hirohashi S, Ito N, Pitot HC, Sugimura T, Terada M, Yokota J (eds) Multistage carcinogenesis. Japan Scientific Society, Tokyo/CRC, Boca Raton, 3–19

    Google Scholar 

  2. Weinberg RA Brugge J, Curran T, Harlow ED, McCormick F, (1991) Oncogenes, tumor suppressor genes, and cell transformation: trying to put it all together. In: Brugge J, Curran T, Harlow ED, McCormick F (eds) Origins of human cancer: a comprehensive review. Cold Spring Harbor Laboratory, New York, 1–16

    Google Scholar 

  3. Zhang W-W, Fang X (1995) Gene therapy strategies for cancer. Exp Opin Invest Drugs 4:487–514

    Google Scholar 

  4. Herrmann F (1995) Cancer gene therapy: principles, problems, and perspectives. J Mol Med 73:157–163

    Google Scholar 

  5. Stein CA, Cohen JS (1988) Oligodeoxynucleotides as inhibitors of gene expression: a review. Cancer Res 48, 2659–2668

    Google Scholar 

  6. Hanvey JC, Peffer NJ, Bisi JE, Thompson SA, Cadilla R, Josey JA, Ricca DJ, Hassman CF, Bonham MA, Au KG, Carter SG, Bruckenstein DA, Boyd AL, Noble SA, Babiss LE (1992) Antisense and antigene properties of peptide nucleic acids. Science 258:1481–1485

    Google Scholar 

  7. Choo Y, Sanchez-Garcia I, Klung A (1994) In vivo repression by a site-specific DNA-binding protein designed against an oncogenic sequence. Nature 372:642–645

    Google Scholar 

  8. Mercola D, Cohen JS (1995) Antisense approaches to cancer gene therapy. Cancer Gene Ther 2:47–59

    Google Scholar 

  9. Crooke ST (1993) Oligonucleotide therapeutics: a prospectus. Antisense Res Develop 3:1–2

    Google Scholar 

  10. Wickstrom E (1986) Oligodeoxynucleotide stability in subcellular extracts and culture media. J Biochem Biophys Methods 13:97–102

    Google Scholar 

  11. Helene C (1991) Rational design of sequence-specific oncogene inhibitors based on antisense and antigene oligonucleotides. Eur J Cancer 27:1466–1471

    Google Scholar 

  12. Crooke RM (1991) In vitro toxicology and pharmacokinetics of antisense oligonucleotides. Anti-Cancer Drug Design 6:609–646

    Google Scholar 

  13. Prochownik EV, Erickson RP, Izant JG (1992) Antisense approaches to assessing oncogene signaling pathway. In: Erickson RP, Izant JG (eds) Gene regulation: biology of antisense RNA and DNA, vol 1, Raven, New York, 303–316

    Google Scholar 

  14. Stein CA, Cheng YC (1993) Antisense oligonucleotides as therapeutic agents-is the bullet really magical? Science 261:1004–1012

    Google Scholar 

  15. Szczylik C, Skorski T, Nicolaides NC, Manzella L, Malaguarnera L, Venturelli D, Gewirtz AM, Calabretta B (1991) Selective inhibition of leukemia cell proliferation by BCR-ABL antisense oligodeoxynucleotides. Science 253:562–565

    Google Scholar 

  16. Skorski T, Nieborowskaskorska M, Barletta C, Malaguarnera L, Szczylik C, Chen ST, Lange B, Calabretta B (1993) Highly efficient elimination of Philadelphia leukemic cells by exposure to bcr/abl antosense oligodeoxynucleotides combined with mafosfamide. J Clin Invest 92:194–202

    Google Scholar 

  17. Akhtar S, Ivinson AJ (1993) Therapies that make sense. Nature Genet 4:215–217

    Google Scholar 

  18. Bayever E, Iversen P, Smith L, Spinolo J, Zon G (1992) Guest editorial: systemic human antisense therapy begins. Antisense Res Dev 2:109–110

    Google Scholar 

  19. Smith LJ, McCulloch EA, Benchimol S (1986) Expression of the p53 oncogene in acute myeloblastic leukemia. J Exp Med 164:71–76

    Google Scholar 

  20. Maher LJ, Dolnick BJ (1987) Specific hybridization arrest of dihydrofolate reductase mRNA in vitro using anti-sense RNA or anti-sense oligonucleotides. Arch Biochem Biophys 253:214–220

    Google Scholar 

  21. Walder RY, Walder JA (1988) Role of RNase H in hybrid-arrested translation by antisense oligonucleotides. Proc Natl Acad Sci USA 85:5011–5015

    Google Scholar 

  22. Loke SL, Stein C, Zhang XH, Mori K, Nakanishi M, Subasinghe C, Cohen JS, Neckers LM (1989) Characterization of oligonucleotide transport into living cells. Proc Natl Acad Sci USA 86:3474–3478

    Google Scholar 

  23. Yakubov LA, Deeva EA, Zarytova VF, Ivanova EM, Ryte AS, Yurchenko LV, Vlassov VV (1989) Mechanism of oligonucleotide uptake by cells: involvement of receptors? Proc Natl Acad Sci USA 86:6454–6458

    Google Scholar 

  24. Stein CA, Tonkinson JL, Zhang LM, Yakubov L, Gervasoni J, Taub R, Rosenberg SA (1993) Dynamics of the internalization of phosphodiester oligodeoxynucleotides in HL60 cells. Biochemistry 32:4855–4861

    Google Scholar 

  25. Akhtar S, Shoji Y, Juliano RL (1992) Pharmaceutical aspects of the biological stability and membrane transport characteristics of antisense. In: Erickson RP, Izant JG (eds) Gene regulation: biology of antisense RNA and DNA, vol 1. Raven, New York, 133–145

    Google Scholar 

  26. Shaw JP, Kent K, Bird J, Fishback J, Froehler B (1991) Modified deoxyoligonucleotides stable to exonuclease degradation in serum. Nucleic Acids Res 19:747–750

    CAS  PubMed  Google Scholar 

  27. Letsinger RL, Zhang G, Sun DK, Ikeuchi T, Sarin PS (1989) Cholesteryl-conjugated oligonucleotides: synthesis, properties and activity as inhibitors of replication of human immunodeficiency virus in culture. Proc Natl Acad Sci USA 86:6553–6556

    Google Scholar 

  28. Clarence JP, Degols G, Leonetti JP, Milhaud P, Lebleu B (1993) Delivery of antisense oligonucleotides by poly (l-lysine) conjugation and liposome encapsulation. Anti-Cancer Drug Design 8:81–94

    Google Scholar 

  29. Leonetti JP, Machy, P, Degols G, Lebleu B, Leserman L (1990) Antibody-targeted liposomes containing oligdeoxyonu-cleotides complementary to viral RNA selectively inhibit viral replication. Proc Natl Acad Sci USA 87:2448–2451

    Google Scholar 

  30. Milligan JF, Jones RJ, Froehler BC, Matteucci MD (1994) Development of antisense therapeutics: implications for cancer gene therapy. Ann NY Acad Sci 716:228–241

    Google Scholar 

  31. Eguchi Y, Itoh T, Tomizawa J (1991) Antisense RNA. Annu Rev Biochem 60:631–652

    Google Scholar 

  32. Krystal GW (1992) Regulation of eukaryotic gene expression by naturally occurring antisense RNA. In: Erickson RP, Izant JG (eds) Gene regulation: biology of antisense RNA and DNA, vol 1. Raven, New York, 11–20

    Google Scholar 

  33. Inouye M (1988) Antisense RNA its function and applications in gene regulation — a review. Gene 72:25–34

    Google Scholar 

  34. Weintraub HM (1990) Antisense RNA and DNA. Sci Am 262:40–48

    Google Scholar 

  35. Ledwith BJ, Manam S, Kraynak AR, Nichols WW, Bradley MO (1990) Antisense-fos RNA causes partial reversion of the transformation phenotypes induced by the c-Ha-ras oncogene. Mol Cell Biol 10:1545–1555

    Google Scholar 

  36. Sklar MD, Thompson E, Welsh MJ, Liebert M, Harney J, Grossman HB, Smith M, Prochownik EV (1991) Depletion of c-myc with specific antisense sequences reverses the transformed phenotype in ras oncogene-transformed NIH 3T3 cells. Mol Cell Biol 11:3699–3710

    Google Scholar 

  37. Mukhopadhyay T, Tainsky M, Cavender AC, Roth JA (1991) Specific inhibition of K-ras expression and tumorigenicity of lung cancer cells by antisense RNA. Cancer Res 51:1744–1748

    Google Scholar 

  38. Skotzko M, Wu L, Anderson WF, Gordon EM, Hall FL (1995) Retroviral vector-mediated gene transfer of antisense cyclin G1 (CYCG1) inhibits proliferation of human osteogenic sarcoma cells. Cancer Res 55:5493–5498

    Google Scholar 

  39. Kibler-Herzog L, Kell B, Zon G, Shinozuka K, Miizan S, Wilson WD (1990) Sequence-dependent effects in methylphosphonate deoxyribonucleotide double and triple helical complexes. Nucleic Acids Res 18:3545–3555

    Google Scholar 

  40. Maher LJ, Wold B, Dervan PB (1989) Inhibition of DNA binding proteins by oligonucleotide-directed triple helix formation. Science 245:725–730

    Google Scholar 

  41. Hanvey JC, Shimizu M, Wells RD (1990) Site-specific inhibition of Eco-RI restriction/modification enzymes by a DNA triple helix. Nucleic Acids Res 18:157–161

    Google Scholar 

  42. Cooney M, Czernuszewicz G, Postel EH, Flint SJ, Hogan ME (1988) Site-specific oligonucleotide binding represses transcription of the human c-myc gene in vitro. Science 241:456–459

    Google Scholar 

  43. Orson FM, Thomas DW, McShan WM, Kessler DJ, Hogan ME (1991) Oligonucleotide inhibition of IL2Ra RNA transcription by promoter region collinear triplex formation in lymphocytes. Nucleic Acids Res 19:3435–3441

    Google Scholar 

  44. Gee JE, Miller DM (1992) Structure and applications of inter-molecular DNA triplexes. Am J Med Sci 304:366–372

    Google Scholar 

  45. Ono A, Ts′o OP, Kan LS (1991) Triplex formation of oligonucleotides containing 2′-O-methylpseudo-isocytidine in substitution for 2′-deoxycidine. J Am Chem Soc 113:4032–4033

    Google Scholar 

  46. Gagnor C, Bertrand JR, Thenet S, Lemaitre M, Morvan F, Rayner B, Malvy C, Lebleu B, Imbach JL, Paoletti C (1987) Comparative study of α and β anomeric oligdeoxy-ribonucleotides in hybridization to mRNA and in cell-free translation inhibition. Nucleic Acids Res 15:10507–10521

    Google Scholar 

  47. Helene C (1992) Control of gene expression by antisense and antigene oligonucleotide-intercalator conjugates. In: Erickson RP, Izant JG (eds) Gene regulation: biology of antisense RNA and DNA, vol 1. Raven, New York, 109–118

    Google Scholar 

  48. Kim SH, Cech TR (1987) Three-dimensional model of the active site of the self-splicing rRNA precursor of tetrahymena. Proc Natl Acad Sci USA 84, 8788–8792

    Google Scholar 

  49. Cech TR (1988) Ribozymes and their medical implications. JAMA 260:3030–3034

    Article  CAS  PubMed  Google Scholar 

  50. von Ahsen U, Schroeder R (1993) RNA as a catalyst: natural and designed ribozymes. Bioessays 15:299–307

    Google Scholar 

  51. Kashani-Sabet M, Funato T, Tone T, Jiao L, Wang W, Yoshida E, Kashfinn BI, Shitara T, Wu AM, Moreno JG, Traweek ST, Ahlering TE, Scanlon KJ (1992) Reversal of the malignant phenotype by an anti-ras ribozyme. Antisense Res Dev 2:3–15

    Google Scholar 

  52. Koizumi M, Kamiya H, Ohtsuka E (1992) Ribozymes designed to inhibit transformation of NIH3T3 cells by the activated c-Ha-ras gene. Gene 117:179–184

    Google Scholar 

  53. Sioud M, Natvig JB, Forre O (1992) Preformed ribozyme destroys tumour necrosis factor mRNA in human cells. J Mol Biol 223:831–835

    Google Scholar 

  54. Weerasinghe M, Liem SE, Asad S, Read SE, Joshi S (1991) Resistance to human immunodeficiency virus type 1 (HIV-1) infection in human CD4+ lymphocyte-derived cell lines conferred by using retroviral vectors expressing an HIV-1 RNA-specific ribozyme. J Virol 65:5531–5534

    Google Scholar 

  55. Lu D, Chtterjee S, Brar D, Wong KK, Jr (1994) Ribozymemediated in vitro cleavage of transcripts arising from the major transforming genes of human papillomavirus type 16. Cancer Gene Ther 1267–277

  56. Zhang Y, Mukhopadhyay T, Donehower LA, Georges RN, Roth JA (1993) Retroviral vector-mediated transduction of K-ras antisense RNA into human lung cancer cells inhibits expression of the malignant phenotype. Human Gene Ther 4:451–460

    Google Scholar 

  57. Georges RN, Mukhopadhyay T, Zhang Y, Yen N, Roth JAL (1993) Prevention of orthotopic human lung cancer growth by intratracheal instillation of a retroviral antisense K-ras construct. Cancer Res 53:1743–1746

    Google Scholar 

  58. McLemore TL, Liu MC, Blacker PC, Gregg M, Alley MC, Abbott BJ, Shoemaker RH, Bohlman ME, Litterst CC, Hubbard WC, Brennan RH, McMahon JB, Fine DL, Eggleston JC, Mayo JG, Boyd MR (1987) Novel intrapulmonary model for orthotopic propagation of human lung cancers in athymic nude mice. Cancer Res 47:5132–5140

    Google Scholar 

  59. Alemany R, Ruan S, Koch PE, Mukhopadhyay T, Roth JA, Zhang W-W (1996) Growth inhibitory effect of anti-K-ras adenovirus on lung cancer cells. Cancer Gene Ther (in press)

  60. Harris H (1993) How tumor suppressor genes were discovered. FASEB J 7:978–979

    Google Scholar 

  61. Anderson MJ, Stanbridge EJ (1993) Tumor suppressor genes studied by cell hybridization and chromosome transfer. FASEB J 7:826–833

    Google Scholar 

  62. Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA, Butel JS, Bradley A (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature 356:215–221

    Google Scholar 

  63. Duan DR, Pause A, Burgess WH, Aso T, Chen DYT, Garrett KP, Conaway RC, Conaway JW, Linehan WM, Klausner RD (1995) Inhibition of transcription elongationby the VHL tumor suppressor protein. Science 269:1402–1406

    Google Scholar 

  64. Wiman KG (1993) The retinoblastoma gene: role in cell-cycle control and cell differentiation. FASEB J 7:841–845

    Google Scholar 

  65. Huang HJS, Yee JK, Shew JY, Chen PL, Bookstein R, Friedmann T, Lee EYHP, Lee WH (1988) Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells. Science 242:1563–1566

    Google Scholar 

  66. Bookstein R, Shew JY, Chen PL, Scully P, Lee WH (1990) Suppression of tumorigenicity of human prostate carcinoma cells by replacing a mutated RB gene. Science 247:712–715

    Google Scholar 

  67. Montenarh M (1992) Biochemical, immunological, and functional aspects of the growth-suppressor/oncoprotein p53. Crit Rev Oncogene 3:233–256

    Google Scholar 

  68. Tominaga O, Hamelin R, Remvikos Y, Salmon RJ, Thomas G (1992) p53 from basic research to clinical applications. Crit Rev Oncogene 3:257–282

    Google Scholar 

  69. Mercer WE (1992) Cell-cycle regulation and the p53 tumor suppressor protein. Crit Rev Eukaryot Gene Expr 2:251–263

    Google Scholar 

  70. Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB (1992) Wild-type p53 is a cell-cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA 89:7491–7495

    CAS  PubMed  Google Scholar 

  71. Fields S, Jang SJ (1990) Presence of a potent transcription-activating sequence in the p53 protein. Science 249:1046–1049

    Google Scholar 

  72. Mietz JA, Unger T, Huibregtse JM, Howley PM (1992) The transcriptional transactivation function of wild-type p53 is inhibited by SV40 large T-antigen and by HPV-16 E6 oncoprotein. EMBOJ 11:5013–5020

    Google Scholar 

  73. Wilcock D, Lane DP (1991) Localization of p53, retinoblastoma, and host replication proteins at sites of viral replication in herpes-infected cells. Nature 349:429–431

    Google Scholar 

  74. Bargonetti J, Friedmann PN, Kern SE, Vogelstein B, Prives C (1991) Wild-type but not mutant p53 immunopurified proteins bind to sequences adjacent to the SV40 origin of replication. Cell 65:1083–1091

    Google Scholar 

  75. Yonish-Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M (1991) Wild-type p53 induces apoptosis of myeloid leukemic cells that is inhibited by interleukin-6. Nature 352:345–347

    Google Scholar 

  76. Shaw P, Bovey R, Tardy S, Sahli R, Sordat B, Costa J (1992) Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line. Proc. Natl. Acad. Sci. USA 89:4495–4499

    Google Scholar 

  77. Ryan JJ, Danih R, Gottlieb CA, Clarke, M (1993) Cell-cycle analysis of p53-induced cell death in murine erythroleukemia cells. Mol Cell Biol 13:711–719

    Google Scholar 

  78. Finlay CA, Hinds PW, Levine AJ (1989) The p53 proto-oncogene can act as a suppressor of transformation. Cell 57:1083–1093

    Google Scholar 

  79. Baker SJ, Markowitz S, Fearson ER, Villson JKV, Vogelstein B (1990) Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249:912–915

    Google Scholar 

  80. Cheng J, Yee JK, Yeargin J, Friedmann T, Haas M (1992) Suppression of acute lymphoblastic leukemia by the human wild-type p53 gene. Cancer Res 52:222–226

    Google Scholar 

  81. Takahashi T, Carbone D, Takahashi T, Nau MM, Hida T, Linnoila I, Ueda R, Minna JD (1992) Wild-type but not mutant p53 suppresses the growth of human lung cancer cells bearing multiple genetic lesions. Cancer Res 52:2340–2343

    Google Scholar 

  82. Quinlan DC, Davidson AG, Summers CL, Warden HE, Doshi HM (1992) Accumulation of p53 protein correlates with a poor prognosis in human lung cancer. Cancer Res 52:4828–4831

    Google Scholar 

  83. Horio Y, Takahashi T, Kuroishi T, Hibi K, Suyama M, Niimi T (1993) Prognostic significance of p53 mutations and 3P deletions in primary resected non-small cell lung cancer. Cancer Res 53:1–4

    Google Scholar 

  84. Shrivastova S, Zou A, Pirollo K, Blattner S, Chang E (1990) Germline transmission of a mutated p53 gene in a cancer prone family with Li-Fraumeni syndrome. Nature 348:747–749

    Google Scholar 

  85. Harper JW, Adam GR, Wei N, Keyomarsi K, Elledge SJ (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinase. Cell 75:805–816

    Google Scholar 

  86. El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzier KW, Vogelstein B (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75:817–825

    Google Scholar 

  87. Roemer K, Friedmann T (1994) Mechanisms of action of the p53 tumor suppressor and prospects for cancer gene therapy by reconstitution of p53 function. Ann NY Acad Sci 716:265–280

    Google Scholar 

  88. Goyette MC, Cho K, Fasching CL, Levy DB, Kinzler KW, Paraskeva C, Vogelstein B, Stanbridge EJ (1992) Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer. Mol Cell Biol 12:1387–1395

    Google Scholar 

  89. Leone A, Flatow U, King CR, Sandeen MA, Margulies MK, Liotta LA, Steeg PS (1991) Reduced tumor incidence, metastatic potential, and cytokine responsiveness of nm23-transfected melanoma cells. Cell 65:25–35

    Google Scholar 

  90. Florenes VA, Aamdal S, Myklebost O, Maelandsmo GM, Bruland OS, Fodstad O (1992) Levels of nm23 messenger RNA in metastatic melanomas inverse correlation to disease prognosis. Cancer Res 52:6088–6091

    Google Scholar 

  91. Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS III, Johnson BE, Skolnick MH (1994) A cell cycle regulator potentially involved in genesis of many tumor types. Science 264:436–440

    Google Scholar 

  92. Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA (1994) Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368:753–756

    Google Scholar 

  93. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, Bell R, Rosenthal J, Hussey C, Tran T, McClure M, Frye C, Hattier T, Phelps R, Haugen-Strano A, Katcher H, Yakumo K, Gholami Z, Shaffer D, Stone S, Bayer S, Wray C, Bogden R, Dayananth P, Ward J, Tonin P, Narod S, Bristow PK, Norris FH, Helvering L, Morrison P, Rosteck P, Lai M, Barrett JC, Lewis C, Neuhausen S, Cannon-Albright L, Goldgar D, Wiseman R, Kamb A, Skolnick MH (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71

    Google Scholar 

  94. Hannon G, Beach D (1994) p15INK4B is a potential effector of TGF-induced cell cycle arrest. Nature 371:257–261

    Google Scholar 

  95. Marx J (1994) A challenge to p16 gene as a major tumor suppressor. Science 264, 1846

    Google Scholar 

  96. Zhang S-Y, Klein-Szanto AJP, Sauter ER, Shafarenko M, Mitsunaga S, Nobori T, Carson DA, Ridge JA, Goodrow TL (1994) Higher frequency of alternations in the p16/CDKN2 gene in squamous cell carcinoma cell lines than in primary tumors of the head and neck. Cancer Res 54:5050–5053

    Google Scholar 

  97. Jen J, Harper W, Bigner SH, Bigner DD, Papadopoulos N, Markowitz S, Willson JKV, Kinzler KW, Vogelstein B (1994) Deletion of p16 and p15 genes in brain tumors. Cancer Res 54:6353–6358

    Google Scholar 

  98. Washimi, O, Nagatake, M, Osada, H, Ueda, R, Koshikawa, T, Seki, T, Takahashi, T, Takahashi, T (1995) In vivo occurrence of p16 (MTS1) and p15 (MTS2) alterations preferentially in non-small cell lung cancers. Cancer Res 55:514–517

    Google Scholar 

  99. Hussussian CJ, Struewing JP, Goldstein AM, Higgins PAT, Ally DS, Sheahan MD, Clark WH Jr, Tucker MA, Dracopoli NC (1994) Germline p16 mutation in familial melanoma. Nature Genet 8:15–21

    Google Scholar 

  100. Cai DW, Mukhopadhyay T, Liu Y, Fujiwara T, Roth JA (1993) Stable expression of the wild-type p53 gene in human lung cancer cells after retrovirus-mediated gene transfer. Hum Gene Ther 4:617–624

    Google Scholar 

  101. Fujiwara T, Grimm EA, Mukhopadhyay T, Cai DW, Owen-Schaub LB, Roth JA (1993) A retroviral wild-type p53 expression vector penetrates human lung cancer spheroids and inhibits growth by inducing apoptosis. Cancer Res 53:4129–4133

    Google Scholar 

  102. Casson AG, Mukhopadhyay T, Cleary KR, Ro JY, Levine B, Roth JA (1991) p53 mutations in Barrett's epithelium and esophageal cancer. Cancer Res 51:4495–4499

    Google Scholar 

  103. Chung KY, Mukhopadhyay T, Kim J, Casson A, Ro JY, Goepfert H, Hong WK, Roth JA (1993) Discordant p53 gene mutations in primary head and neck cancers and corresponding second primary cancers of the aerodigestive tract. Cancer Res 53:1676–1683

    Google Scholar 

  104. Zhang W-W, Fang X, Branch CD, Mazur W, French BA, Roth JA (1993) Generation and identification of recombinant adenovirus by liposome-mediated transfection and PCR analysis. Biotechniques 15:868–872

    Google Scholar 

  105. Zhang W-W, Fang X, Mazur W, French BA, Georges RN, Roth JA (1994) High-efficiency gene transfer and high-level expression of wild-type p53 in human lung cancer cells mediated by recombinant adenovirus. Cancer Gene Ther 1:5–13

    Google Scholar 

  106. Fujiwara T, Grimm EA, Mukhopadhyay T, Zhang WW, Owen-Schaub LB, Roth JA (1994) Induction of chemosensitivity in human lung cancer cells in vivo by adenovirus-mediated transfer of the wild-type p53 gene. Cancer Res 54:2287–2291

    Google Scholar 

  107. Wang J, Bucana CD, Roth JA, Zhang W-W (1995) Apoptosis induced in human osteosarcoma cells is one of the mechanisms for the cytocidal effect of Ad5CMV-p53. Cancer Gene Ther 1:9–17

    Google Scholar 

  108. Wills KN, Maneval DC, Menzel P, Harris MP, Sutjipto S, Vaillancourt M-T, Huang W-M, Johnson DE, Anderson SC, Wen SF, Bookstein R, Shepard HM, Gregory RJ (1994) Development and characterization of recombinant adenoviruses encoding human p53 for gene therapy of cancer. Hum Gene Ther 5:1079–1088

    Google Scholar 

  109. Liu TJ, Zhang W-W, Taylor DL, Roth JA, Goepfert H, Clayman GL (1994) Growth suppression of human head and neck cancer cells by the introduction of a wild-type p53 gene via a recombinant adenovirus. Cancer Res 54:3662–3667

    CAS  PubMed  Google Scholar 

  110. Dulic V, Kaufman, WK, Wilson S, Tisty TD, Lees E, Harper JW, Elledge SJ, Reed SI (1994) p53-dependent inhibition of cyclin dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell 76:1013–1023

    Google Scholar 

  111. Sherr CJ, Roberts JM (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 9:1149–1163

    CAS  PubMed  Google Scholar 

  112. El-Diery WS, Harper JW, Oconnor PM, Velculesca VE, Canman CE, Jackman J, Pietenpol J, Burrell M, Hill DE, Mercer WE, Kastan MB, Kohn KW, Elledge SJ, Kinzler KW, Vogelstein B (1994) WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 54:1169–1174

    Google Scholar 

  113. Harper JW, Elledge SJ, Keyomarsi K, Dynlacht B, Tsai L-H, Zhang P, Dobrowolski S, Bai C, Connell-Crowley L, Swindell E, Fox MP, Wei N (1995) Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell 6:387–400

    Google Scholar 

  114. Deng C, Zhang P, Harper JW, Elledge SJ, Leder P (1995) Mice deficient in p21 develop normally but have defects in G1 checkpoint function. Cell 82:675–684

    Google Scholar 

  115. Gossen M, Bujard H (1992) Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 89:5547–5551

    CAS  PubMed  Google Scholar 

  116. Chen TQ, Cipriano SC, Arenkiel JM, Miller FR (1995) Tumor suppression by p21WAF1. Cancer Res 55:4536–4539

    Google Scholar 

  117. Katayose D, Wersto R, Cowan KH, Seth P (1995) Effects of a recombinant adenovirus expressing WAF1/Cip1 on cell growth, cell cycle, and apoptosis. Cell Growth Diff 6:1207–1212

    Google Scholar 

  118. Eastham JA, Hall SJ, Sehgal I, Wang J, Timme TL, Yang G, Connell-Crowley L, Elledge SJ, Zhang W-W, Harper JW, Thompson TC (1995) In vivo gene therapy with p53 or p21 adenovirus for prostate cancer. Cancer Res 55:5151–5155

    Google Scholar 

  119. Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature (Lond) 366:704–707

    Google Scholar 

  120. Serrano M, Gomez-Lahoz E, Depinho RA, Beach D, BarSagi D (1995) Inhibition of ras-induced proliferation and cellular transformation by p16INK14. Science 267:249–252

    Google Scholar 

  121. Caldas C, Hahn SA, Dacosta LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE (1994) Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nature Genet 8:27–32

    Google Scholar 

  122. Cheng JQ, Jhanwar SC, Llein WM, Bell DW, Lee W, Altomare DA, Nobori T, Olopade OI, Buckler AJ, Testa JR (1994) p16 alterations and deletion mapping of 9p21-p22 in malignant mesothelioma. Cancer Res 54:5547–5551

    Google Scholar 

  123. Kamb A, Shattuck-Eidens D, Liu Q, Gruis NA, Ding W, Hussey C, Tran T, Miki Y, Weaver-Felkhous J, McClure M, Atiken JF, Anderson DE, Hergman W, Frants R, Goldgar DE, Green A, MacLennan R, Martin NG, Meyer LJ, Youl P, Zone JJ, Skolnick MH, Cannon-Albright LA (1994) Analysis of the p16 gene (CDKN2) as a candidate from chromosome 9p melanoma susceptifility locus. Nature Genet 8:22–26

    Google Scholar 

  124. Mori T, Miura K, Aoki T, Nishihira T, Mori S, Nakamura Y (1994) Frequent somatic mutation of the MTS1/CDK41 (multiple tumor suppressor/cyclin-dependent kinase 4 inhibitor) gene in esophageal squamous cell carcinoma. Cancer Res 54:3396–3397

    Google Scholar 

  125. Okamoto A, Demetrick DJ, Spillare EA, Higiwara K, Hussain SP, Bennett WP, Forrester K, Gerwin B, Serrano M, Beach DH, Harris CC (1994) Mutations and altered expression pf p16(INK4) in human cancer. Proc Natl Acad Sci USA 91:11045–11049

    Google Scholar 

  126. Orlow I, Lianes P, Lacombe L, Dalbagni G, Reuter VE, Cardon-Cardo C (1994) Chromosome 9 allelic losses and microsatellite alterations in human bladder tumors. Cancer Res 54:2848–2851

    Google Scholar 

  127. Arap W, Nishikawa R, Furnari FB, Cavenee WK, Huang HS (1995) Replacement of the p16/CDKN2 gene suppresses human glioma cell growth. Cancer Res 55:1351–1354

    Google Scholar 

  128. Jin X, Nguyen D, Zhang W-W, Kyritsis AP, Roth JA (1995) Cell cycle arrest and inhibition of tumor cell proliferation by the p16 INK4 gene mediated by an adenovirus vector. Cancer Res 55:3250–3253

    Google Scholar 

  129. Takahashi T, Nau MM, Chiba I, Birrer MJ, Rosenberg RK, Vinocour M, Levitt M, Pass H, Gazdar AF, Minna JD (1989) p53: a frequent target for genetic abnormalitits in lung cancer. Science 246:491–494

    Google Scholar 

  130. Harbour JW, Lai S, Whang-Peng J, Gazdar AF, Minna JD, Kaye FJ (1988) Abnormalities instructure and expression of the human retinoblastoma gene in SCLC. Science 241:353–357

    Google Scholar 

  131. Mitsudomi T, Steinberg SM, Nau MM, Carbone D, DÕAmico D, Bodner S, Oie HD, Linnoila RI, Mulshine JL, Minna JD, Gazdar AF (1992) p53 gene mutations in non-small-cell lung cancer cell lines and their correlation with the presence of ras mutations and clinical features. Oncogene 7:171–180

    Google Scholar 

  132. Fujiwara T, Cai DW, Georges RN, Mukhopadhay T, Grimm EA, Roth JA (1994) Therapeutic effect of a retroviral wildtype p53 expression vector in an orthotopic lung cancer model. J Natl Cancer Inst 86:1458–1462

    Google Scholar 

  133. Culver KW, Ram Z, Wallbridge S, Ishii H, Oldfield EH, Blaese, RM (1992) Vector-producer cells for treatment of experimental brain tumors. Science 256:1550–1552

    Google Scholar 

  134. Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T (1993) p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362:847–849

    Google Scholar 

  135. Hu G, Liu W, Hanania EG, Fu S, Wang T, Deisseroth AB (1995) Suppression of tumorigenesis by transcription units expressing the antisense E6 and E7 messenger RNA (mRNA) for the transforming proteins of human papilloma virus and the sense mRNA for the retinoblastoma gene in cervical carcinoma cells. Cancer Gene Ther 2:19–32

    Google Scholar 

  136. Castleden S, Helson JA, Chong H, Hart I, Vile RG (1995) The use of combination gene therapies for the treatment of cancer. J Cell Biochem 21 [Suppl A]:418

    Google Scholar 

  137. Chen SH, Chen XH, Kosail KI, Wang Y, Finegold MJ, Rich SS, Woo SLC (1995) Combination suicide and cytokine gene therapy for metastatic colon carcinoma in vivo. J Cell Biochem 21 [Suppl A]:419

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, W.W. Antisense oncogene and tumor suppressor gene therapy of cancer. J Mol Med 74, 191–204 (1996). https://doi.org/10.1007/BF00204749

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00204749

Key words

Navigation