This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kuball, J. Articles by Schuler, M. Search for Related Content PubMed PubMed Citation Articles by Kuball, J. Articles by Schuler, M. Social Bookmarking                            What's this?

Successful Adenovirus-Mediated Wild-Type p53 Gene Transfer in Patients With Bladder Cancer by Intravesical Vector Instillation

From the Departments of Medicine III and Urology, Johannes Gutenberg University, Mainz, and Department of Pathology, University Herdecke Witten, Germany; Canji Incorporated, San Diego, CA; and Schering-Plough Research Institute, Kenilworth, NJ.

Address reprint requests to Martin Schuler, MD, Department of Medicine III, Johannes Gutenberg University, D-55101 Mainz, Germany; email: m.schuler{at}3-med.klinik.uni-mainz.de

PURPOSE: To study safety, feasibility, and biologic activity of adenovirus-mediated p53 gene transfer in patients with bladder cancer.

PATIENTS AND METHODS: Twelve patients with histologically confirmed bladder cancer scheduled for cystectomy were treated on day 1 with a single intratumoral injection of SCH 58500 (rAd/p53) at cystoscopy at one dose level (7.5 x 10¹¹ particles) or a single intravesical instillation of SCH 58500 with a transduction-enhancing agent (Big CHAP) at three dose levels (7.5 x 10¹¹ to 7.5 x 10¹³ particles). Cystectomies were performed in 11 patients on day 3, and transgene expression, vector distribution, and biologic markers of transgene activity were assessed by molecular and immunohistochemical methods in tumors and normal bladder samples.

RESULTS: Specific transgene expression was detected in tissues from seven of eight assessable patients treated with intravesical instillation of SCH 58500 but in none of three assessable patients treated with intratumoral injection of SCH 58500. Induction of RNA and protein expression of the p53 target gene p21/WAF1 was demonstrated in samples from patients treated with SCH 58500 instillation at higher dose levels. Distribution studies after intravesical instillation of SCH 58500 revealed both high transduction efficacy and vector penetration throughout the whole urothelium and into submucosal tumor cells. No dose-limiting toxicity was observed, and side effects were local and of transient nature.

CONCLUSION: Intravesical instillation of SCH 58500 combined with a transduction-enhancing agent is safe, feasible, and biologically active in patients with bladder cancer. Studies to evaluate the clinical efficacy of this treatment in patients with localized high-risk bladder cancer are warranted.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				J.-j. Pan, S.-w. Zhang, C.-b. Chen, S.-w. Xiao, Y. Sun, C.-q. Liu, X. Su, D.-m. Li, G. Xu, B. Xu, et al. Effect of Recombinant Adenovirus-p53 Combined With Radiotherapy on Long-Term Prognosis of Advanced Nasopharyngeal Carcinoma J. Clin. Oncol., February 10, 2009; 27(5): 799 - 804. [Abstract] [Full Text] [PDF]

				W. Walther, R. Siegel, D. Kobelt, T. Knosel, M. Dietel, A. Bembenek, J. Aumann, M. Schleef, R. Baier, U. Stein, et al. Novel Jet-Injection Technology for Nonviral Intratumoral Gene Transfer in Patients with Melanoma and Breast Cancer Clin. Cancer Res., November 15, 2008; 14(22): 7545 - 7553. [Abstract] [Full Text] [PDF]

				E. Kikuchi, S. Menendez, C. Ozu, M. Ohori, C. Cordon-Cardo, C. R. Logg, N. Kasahara, and B. H. Bochner Highly Efficient Gene Delivery for Bladder Cancers by Intravesically Administered Replication-Competent Retroviral Vectors Clin. Cancer Res., August 1, 2007; 13(15): 4511 - 4518. [Abstract] [Full Text] [PDF]

				A. P. Mitra, R. H. Datar, and R. J. Cote Molecular Pathways in Invasive Bladder Cancer: New Insights Into Mechanisms, Progression, and Target Identification J. Clin. Oncol., December 10, 2006; 24(35): 5552 - 5564. [Abstract] [Full Text] [PDF]

				G.-S. Shieh, A.-L. Shiau, Y.-T. Yo, P.-R. Lin, C.-C. Chang, T.-S. Tzai, and C.-L. Wu Low-Dose Etoposide Enhances Telomerase-Dependent Adenovirus-Mediated Cytosine Deaminase Gene Therapy through Augmentation of Adenoviral Infection and Transgene Expression in a Syngeneic Bladder Tumor Model. Cancer Res., October 15, 2006; 66(20): 9957 - 9966. [Abstract] [Full Text] [PDF]

				T. Fujiwara, N. Tanaka, S. Kanazawa, S. Ohtani, Y. Saijo, T. Nukiwa, K. Yoshimura, T. Sato, Y. Eto, S. Chada, et al. Multicenter Phase I Study of Repeated Intratumoral Delivery of Adenoviral p53 in Patients With Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol., April 10, 2006; 24(11): 1689 - 1699. [Abstract] [Full Text] [PDF]

				S. J. Antonia, N. Mirza, I. Fricke, A. Chiappori, P. Thompson, N. Williams, G. Bepler, G. Simon, W. Janssen, J.-H. Lee, et al. Combination of p53 Cancer Vaccine with Chemotherapy in Patients with Extensive Stage Small Cell Lung Cancer Clin. Cancer Res., February 1, 2006; 12(3): 878 - 887. [Abstract] [Full Text] [PDF]

				N. Ramesh, Y. Ge, D. L. Ennist, M. Zhu, M. Mina, S. Ganesh, P. S. Reddy, and D.-C. Yu CG0070, a Conditionally Replicating Granulocyte Macrophage Colony-Stimulating Factor-Armed Oncolytic Adenovirus for the Treatment of Bladder Cancer Clin. Cancer Res., January 1, 2006; 12(1): 305 - 313. [Abstract] [Full Text] [PDF]

				A. Vecchione, C. Sevignani, E. Giarnieri, N. Zanesi, H. Ishii, R. Cesari, L. Y. Y. Fong, L. G. Gomella, C. M. Croce, and R. Baffa Inactivation of the FHIT Gene Favors Bladder Cancer Development Clin. Cancer Res., November 15, 2004; 10(22): 7607 - 7612. [Abstract] [Full Text] [PDF]

				E. Casado, J. De Castro, C. Belda-Iniesta, J. Feliu, M. Gonzalez-Baron, and W. Arafat Doomed Trials for Promising Adenoviruses: A Rationale for Success J. Clin. Oncol., March 15, 2004; 22(6): 1162 - 1163. [Full Text] [PDF]

				L. Barzon, M. Boscaro, and G. Palu Endocrine Aspects of Cancer Gene Therapy Endocr. Rev., February 1, 2004; 25(1): 1 - 44. [Abstract] [Full Text] [PDF]

				P. Sweeney, T. Karashima, H. Ishikura, S. Wiehle, M. Yamashita, W. F. Benedict, R. J. Cristiano, and C. P. N. Dinney Efficient Therapeutic Gene Delivery after Systemic Administration of a Novel Polyethylenimine/DNA Vector in an Orthotopic Bladder Cancer Model Cancer Res., July 15, 2003; 63(14): 4017 - 4020. [Abstract] [Full Text] [PDF]

				L. C. Pagliaro, A. Keyhani, D. Williams, D. Woods, B. Liu, P. Perrotte, J. W. Slaton, J. A. Merritt, H. B. Grossman, and C. P. Dinney Repeated Intravesical Instillations of an Adenoviral Vector in Patients With Locally Advanced Bladder Cancer: A Phase I Study of p53 Gene Therapy J. Clin. Oncol., June 15, 2003; 21(12): 2247 - 2253. [Abstract] [Full Text] [PDF]