title: Evidence that transfer of functional p53 protein results in increased apoptosis in prostate cancer.
abstract: OBJECTIVE
  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 evaluate antitumoral activity.
  
  
  METHODS
  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 administered 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 patients with negative baseline immunostaining for p53 protein, 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 residual viable prostate cancer, and 12 have experienced biochemical failure (median follow-up, 42 months).
  
  
  CONCLUSIONS
  Intraprostatic INGN 201 gene therapy is safe and can reliably result in p53 protein production and apoptosis.
authors.affiliation: Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. lpisters@mdanderson.org
authors.forename: Louis L
authors.initials: LL
authors.lastname: Pisters
authors.forename: Curtis A
authors.initials: CA
authors.lastname: Pettaway
authors.forename: Patricia
authors.initials: P
authors.lastname: Troncoso
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: McDonnell
authors.forename: L Clifton
authors.initials: LC
authors.lastname: Stephens
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Wood
authors.forename: Kim-Anh
authors.initials: KA
authors.lastname: Do
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Brisbay
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wang
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hossan
authors.forename: Robert B
authors.initials: RB
authors.lastname: Evans
authors.forename: Cindy
authors.initials: C
authors.lastname: Soto
authors.forename: Marc G
authors.initials: MG
authors.lastname: Jacobson
authors.forename: Karen
authors.initials: K
authors.lastname: Parker
authors.forename: James A
authors.initials: JA
authors.lastname: Merritt
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Steiner
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000368:Aged; D017209:Apoptosis; D053938:DNA Fragmentation; D018450:Disease Progression; D018572:Disease-Free Survival; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D019076:Transgenes; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53