Adenoviral p53 Gene Therapy Strategies in Nonsmall-Cell Lung Cancer

  • Stephen G. Swisher
  • Jack A. Roth
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Lung cancer is a worldwide problem. In the United States, less than 15% of people presenting with lung cancer survive 5 yr. Early-stage lung cancer (Stage I and II) is curable with surgery. Unfortunately, the majority of patients present with locoregionally advanced (Stage III) or metastatic (Stage IV) lung cancer, which is seldom curable with surgery alone. Multimodality approaches with conventional therapies have been developed combining surgery, chemotherapy, and radiation therapy to improve survival. Unfortunately, despite these strategies, the 3-yr survival rates for patients with Stage III disease are still only 20% dropping to less than 5% for Stage IV patients. Additionally, many of the lung cancer patients now in treatment have failed currently available multimodality strategies, often because their tumors have proven remarkably resistant to the effects of radiation or chemotherapy. Although some progress has been made in combining conventional therapies, the increased toxicity is often unacceptable and median survival of nonsmall-cell lung cancer (NSCLC) patients has not markedly improved (1). The identification of novel, less toxic cancer therapy strategies is therefore critical to improve on current treatment strategies, and it is becoming increasingly clear that rational development of these new therapies will depend on our understanding of the molecular biology of tumors.


Advanced NSCLC Human Lung Cancer Cell Compute Tomography Guidance Gene Therapy Strategy Gene Therapy Trial 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1997. CA Cancer J Clin 1997; 47: 5–27.PubMedCrossRefGoogle Scholar
  2. 2.
    Mukhopadhyay T, Maxwell SA, Roth JA. p53 Suppressor Gene. Austin, TX: R.G. Landes Co., 1995.Google Scholar
  3. 3.
    Rampino N, Yamamoto H, Ionov Y, et al. Somatic frameshift mutations in the Bax gene in colon cancers of the microsatellite mutator phenotype. Science 1997; 275: 967–969.PubMedCrossRefGoogle Scholar
  4. 4.
    Seewaldt VL, Mrozek K, Dietze EC, Parker M, Caldwell LE. Human papillomavirus type 16 E6 inactivation of p53 in normal human mammary epithelial cells promotes tamoxifen-mediated apoptosis. Cancer Res 2001; 61: 616–624.PubMedGoogle Scholar
  5. 5.
    Li Z, Rakkar A, Katayose Y, et al. Efficacy of multiple administrations of a recombinant adenovirus expressing wild-type p53 in an immune-competent mouse tumor model. Gene Ther 1998; 5: 605–613.PubMedCrossRefGoogle Scholar
  6. 6.
    Dai Y, Schwarz EM, Gu D, Zhang WW, Sarvetnick N, Verma IM. Cellular and humoral immune responses to adenoviral vectors containing factor IX gene: tolerization of factor IX and vector antigens allows for long-term expression. Proc Natl Acad Sci USA 1995; 92: 1401–1405.PubMedCrossRefGoogle Scholar
  7. 7.
    Fujiwara T, Cai DW, Georges RN, Mukhopadhyay T, Grimm EA, Roth JA. Therapeutic effect of a retroviral wild-type p53 expression vector in an orthotopic lung cancer model. J Natl Cancer Inst 1994; 86: 1458–1462.PubMedCrossRefGoogle Scholar
  8. 8.
    Zhang WW, Fang X, Mazur W, French BA, Georges RN, Roth JA. High-efficiency gene transfer and high-level expression of wild-type p53 in human lung cancer cells mediated by recombinant adenovirus. Cancer Gene Ther 1994; 1: 5–13.PubMedGoogle Scholar
  9. 9.
    Takahashi T, Carbone D, Nau MM, et al. Wild-type but not mutant p53 suppresses the growth of human lung cancer cells bearing multiple genetic lesions. Cancer Res 1992; 52: 2340–2343.PubMedGoogle Scholar
  10. 10.
    Pearson AS, Spitz FR, Swisher SG, et al. Up-regulation of the proapoptotic mediators Bax and Bak after adenovirus-mediated p53 gene transfer in lung cancer cells. Clin Cancer Res 2000; 6: 887–890.PubMedGoogle Scholar
  11. 11.
    El-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993; 75: 817–825.PubMedCrossRefGoogle Scholar
  12. 12.
    Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of human Bax gene. Cell 1995; 80: 293–299.PubMedCrossRefGoogle Scholar
  13. 13.
    Owen-Schaub LB, Zhang W, Cusack JC, et al. Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol 1995; 15: 3032–3040.PubMedGoogle Scholar
  14. 14.
    Roth JA, Nguyen D, Lawrence DD, et al. Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer. Nat Med 1996; 2: 985–991.PubMedCrossRefGoogle Scholar
  15. 15.
    Swisher SG, Roth JA, Nemunaitis J, et al. Adenovirus-mediated p53 gene transfer in advanced non-small cell lung cancer. J Natl Cancer Inst 1999; 91: 763–771.PubMedCrossRefGoogle Scholar
  16. 16.
    Yen N, Ioannides CG, Xu K, et al. Cellular and humoral immune responses to adenovirus and p53 protein antigens in patients following intratumor injection of an adenovirus vector expressing wild-type p53 (Ad-p53). Cancer Gene Ther 2000; 7: 530–536.PubMedCrossRefGoogle Scholar
  17. 17.
    Roth JA, Swisher SG, Merritt JA, et al. Gene therapy for non-small cell lung cancer: a preliminary report of a phase I trial of adenoviral p53 gene replacement. Semin Oncol 1998; 25: 33–37.PubMedGoogle Scholar
  18. 18.
    Schuler M, Rochlitz C, Horowitz JA, et al. A phase I study of adenovirus-mediated wild-type p53 gene transfer in patients with advanced non-small cell lung cancer. Human Gene Therapy 1998; 9: 2075–2082.PubMedCrossRefGoogle Scholar
  19. 19.
    Lebedeva S, Bagdasarova S, Tyler T, Mu X, Wilson DR, Gjerset RA. Tumor Suppression and Therapy Sensitization of Localized and Metastatic Breast Cancer by Adenovirus p53. Hum Gene Ther 2001; 12: 763–772.PubMedCrossRefGoogle Scholar
  20. 20.
    Seth P, Katayose D, Li Z, et al. A recombinant adenovirus expressing wild type p53 induces apoptosis in drug-resistant human breast cancer cells: a gene therapy approach for drug-resistant cancers. Cancer Gene Ther 1997; 4: 383–390.PubMedGoogle Scholar
  21. 21.
    Osaki S, Nakanishi Y, Takayama K, Pei XH, Ueno H, Hara N. Alteration of drug chemosensitivity caused by the adenovirus-mediated transfer of the wild-type p53 gene in human lung cancer cells. Cancer Gene Ther 2000; 7: 300–307.PubMedCrossRefGoogle Scholar
  22. 22.
    Nielsen LL, Lipari P, Dell J, Gurnani M, Hajian G. Adenovirus-mediated p53 gene therapy and paclitaxel have synergistic efficacy in models of human head and neck. Clin Cancer Res 1998; 4: 835–846.PubMedGoogle Scholar
  23. 23.
    Nemunaitis J, Swisher SG, Timmons T, et al. Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small cell lung cancer. J Clin Oncol 2000; 18: 609–622.PubMedGoogle Scholar
  24. 24.
    Schuler M, Herrmann R, De Greve JL, et al. Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multicenter phase II study. J Clin Oncol 2001; 19: 1750–1758.PubMedGoogle Scholar
  25. 25.
    Le Chevalier T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst 1991; 83: 417–423.PubMedCrossRefGoogle Scholar
  26. 26.
    Bouvet M, Bold RJ, Lee J, et al. Adenovirus-mediated wild-type p53 tumor suppressor gene therapy induces apoptosis and suppresses growth of human pancreatic cancer. Ann Surg Oncol 1998; 5: 681–688.PubMedCrossRefGoogle Scholar
  27. 27.
    Jung M, Notarlo V, Dritschilo A. Mutations in the p53 gene in radiation-sensitive and -resistant human squamous carcinoma cells. Cancer Res 1992; 52: 6390–6393.PubMedGoogle Scholar
  28. 28.
    Pardo FS, Su M, Borek C, et al. Transfection of rat embryo cells with mutant p53 increases the intrinsic radiation resistance. Radiat Res 1994; 140: 180–185.PubMedCrossRefGoogle Scholar
  29. 29.
    Lee JM, Bernstein A. p53 mutations increase resistance to ionizing radiation. Proc Natl Acad Sci USA 1993; 90: 5742–5746.PubMedCrossRefGoogle Scholar
  30. 30.
    Swisher S, Roth JA, Komaki R, et al. A phase II trial of adenoviral mediated p53 gene transfer (RPR/ INGN 201) in conjunction with radiation therapy in patients with localized non-small cell lung cancer (NSCLC). Am Soc Clin Oncol 2000; 19:46la (abstract).Google Scholar
  31. 31.
    Swisher SG, Roth JA, Komaki R, et al. Induction of pro-apoptotic mediators and tumor regression following intratumoral delivery of adenoviral p53 (RTR/INGN 201) and radiation therapy in patients with non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001; 20: 257a.Google Scholar
  32. 32.
    Saunders M, Dische BA, Harvey A, Gibson D, Parmar M. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. Lancet 1997; 350: 161–165.PubMedCrossRefGoogle Scholar
  33. 33.
    Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. N Engl J Med 1992; 326: 524–530.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Stephen G. Swisher
  • Jack A. Roth

There are no affiliations available

Personalised recommendations