title: Repeated intravesical instillations of an adenoviral vector in patients with locally advanced bladder cancer: a phase I study of p53 gene therapy.
abstract: OBJECTIVE
  We investigated the feasibility, safety, and biologic activity of adenovirus-mediated p53 gene transfer in patients with locally advanced bladder cancer.
  
  
  METHODS
  Patients with measurable, locally advanced transitional-cell carcinoma of the bladder who were not candidates for cystectomy were eligible. On a 28-day cycle, intravesical instillations of INGN 201 (Ad5CMV-p53) were administered on days 1 and 4 at three dose levels (10(10) particles to 10(12) particles) or on either 4 or 8 consecutive days at a single dose level (10(12) particles).
  
  
  RESULTS
  Thirteen patients received a total of 22 courses without dose-limiting toxicity. Specific transgene expression was detected by reverse transcriptase polymerase chain reaction in bladder biopsy tissue from two of seven assessable patients. There were no changes in p53, p21waf1/cip1, or bax protein levels in bladder epithelium evident from immunohistochemical analysis of 11 assessable patients. Outpatient administration of multiple courses was feasible and well tolerated. A patient with advanced superficial bladder cancer showed evidence of tumor response.
  
  
  CONCLUSIONS
  Intravesical instillation of Ad5CMV-p53 is safe, feasible, and biologically active when administered in multiple doses to patients with bladder cancer. Observations from this study indicate that this treatment has an antitumor effect in superficial transitional-cell carcinoma. Improvements in the efficiency of gene transfer and the levels of gene expression are required to develop more effective gene therapy for bladder cancer.
authors.affiliation: Department of Genitourinary Medical Oncology, Box 427, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA. lpagliar@mdanderson.org
authors.forename: Lance C
authors.initials: LC
authors.lastname: Pagliaro
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Keyhani
authors.forename: Dallas
authors.initials: D
authors.lastname: Williams
authors.forename: Denise
authors.initials: D
authors.lastname: Woods
authors.forename: Baoshun
authors.initials: B
authors.lastname: Liu
authors.forename: Paul
authors.initials: P
authors.lastname: Perrotte
authors.forename: Joel W
authors.initials: JW
authors.lastname: Slaton
authors.forename: James A
authors.initials: JA
authors.lastname: Merritt
authors.forename: H Barton
authors.initials: HB
authors.lastname: Grossman
authors.forename: Colin P
authors.initials: CP
authors.lastname: Dinney
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000283:Administration, Intravesical; D000368:Aged; D000369:Aged, 80 and over; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005260:Female; D018014:Gene Transfer Techniques; D016158:Genes, p53 / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*