Featured Article Evidence That Transfer of Functional p53 Protein Results in Increased Apoptosis in Prostate Cancer Louis L. Pisters, 1 Curtis A. Pettaway, 1 Patricia Troncoso, 3 Timothy J. McDonnell, 2 L. Clifton Stephens, 4 Christopher G. Wood, 1 Kim-Anh Do, 5 Shawn M. Brisbay, 2 Xuemei Wang, 5 Elizabeth A. Hossan, 6 Robert B. Evans, 1 Cindy Soto, 3 Marc G. Jacobson, 7 Karen Parker, 9 James A. Merritt, 9 Mitchell S. Steiner, 8 and Christopher J. Logothetis 6 Departments of 1 Urology, 2 Molecular Pathology, 3 Pathology, 4 Veterinary Medicine and Surgery, 5 Biostatistics, 6 Genitourinary Medical Oncology, and 7 Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 8 University of Tennessee Department of Urology, Memphis, Tennessee; and 9 Introgen Therapeutics, Inc., Houston, Texas ABSTRACT Purpose: INGN 201 (Ad-p53) is a replication-defective adenoviral vector that encodes a wild-type p53 gene driven by the cytomegalovirus promoter. INGN 201 has been shown to have antitumoral activity against human prostate cancer cell lines. This study was undertaken to determine the safety of INGN 201 in patients with locally advanced prostate cancer, to assess transgene expression, and to eval- uate antitumoral activity. Experimental Design: Our study included patients with clinical stage T3, T1c-T2a with Gleason score 8 –10 disease, or T2a-T2b with Gleason score 7 disease and a prostate- specific antigen level >10 ng/ml. INGN 201 was adminis- tered by intraprostatic injection under ultrasonographic guidance. One course of INGN 201 was defined as three separate INGN 201 administrations 2 weeks apart. Biopsies at baseline and 24 h after the first administration were assessed for p53 protein by immunohistochemical staining and for apoptosis by terminal deoxynucleotidyl transferase- mediated nick end labeling assay. Results: A total of 38 courses of INGN 201 gene therapy were administered to 30 patients, of whom 26 underwent radical prostatectomy. There were no grade 3 or 4 adverse events related to INGN 201 administration. Of the 11 pa- tients with negative baseline immunostaining for p53 pro- tein, 10 had positive p53 immunostaining after the first administration of INGN 201, and 8 had an increase in apoptotic cells by terminal deoxynucleotidyl transferase- mediated nick end labeling staining. All 26 of the patients who underwent radical prostatectomy had significant resid- ual viable prostate cancer, and 12 have experienced bio- chemical failure (median follow-up, 42 months). Conclusion: Intraprostatic INGN 201 gene therapy is safe and can reliably result in p53 protein production and apoptosis. INTRODUCTION Approximately 10% of patients diagnosed with prostate cancer have locally advanced disease and are at high risk of disease progression despite local therapy with radical prostatec- tomy or radiation therapy. These patients can be accurately identified based on their clinical stage, tumor grade, and initial prostate-specific antigen (PSA) level, but the optimal treatment for this group remains controversial. Because external beam radiation therapy and radical prostatectomy used alone have significant limitations in their ability to eradicate locally ad- vanced prostate cancer, interest has shifted toward the use of multimodality therapy. In the development of multimodality approaches involving radical prostatectomy, to date, there has been no evidence of any improvement in biochemical outcome for patients treated with hormonal therapy plus surgery when compared with surgery alone. Because standard therapies have poor results, we believe that patients with locally advanced prostate cancer are excellent candidates for experimental thera- pies including gene therapy. The p53 gene has been extensively studied and is known to play a critical role in cell cycle regulation and control of apo- ptosis (1). The p53 protein is a multifunctional protein that can act as a transcriptional activator or repressor, is induced by DNA damage, and interacts with proteins involved in DNA replication and repair (2). The p53 gene appears to have an important role in sensing and repairing DNA damage, inhibiting the cell cycle to allow DNA repair, and inducing apoptosis to eliminate se- verely damaged cells (2). Alterations in the p53 gene play an important role in the progression of human prostate cancer (3). Overexpression of the p53 protein has been shown to be an independent predictor of disease-free and overall survival after surgery (4, 5) or radiation therapy (6, 7) in patients with prostate cancer. Most studies have reported a low frequency (4 –20%) of p53 alterations in primary prostate tumors (8, 9). In contrast, when samples of metastatic tumors are included, particularly samples of bone metastases, the frequency of p53 alterations increases to 50 –79% (10 –12). Both Navone et al. (13) and Stapleton et al. (3) have demonstrated clonal expansion of p53 mutations from the primary tumor to metastases in paired sam- Received 10/10/03; revised 11/21/03; accepted 12/4/03. Grant support: American Cancer Society Grants RPG96-036-04-CDD and RSGCDD-10154, the Assisi Foundation, Hyde Family Foundation, NIH Prostate Specialized Programs of Research Excellence P50 CA90270, and CapCure Grant 80095069. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Louis L. Pisters, Department of Urology, Unit 446, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-3250; Fax: (713) 794-4824; E-mail: lpisters@mdanderson.org. 2587 Vol. 10, 2587–2593, April 15, 2004 Clinical Cancer Research Downloaded from http://aacrjournals.org/clincancerres/article-pdf/10/8/2587/1955553/zdf00804002587.pdf by guest on 25 April 2023