Evidence that transfer of functional p53 protein results in increased apoptosis in prostate cancer.
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.
Pisters
Louis L
LL
Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. lpisters@mdanderson.org
Pettaway
Curtis A
CA
Troncoso
Patricia
P
McDonnell
Timothy J
TJ
Stephens
L Clifton
LC
Wood
Christopher G
CG
Do
Kim-Anh
KA
Brisbay
Shawn M
SM
Wang
Xuemei
X
Hossan
Elizabeth A
EA
Evans
Robert B
RB
Soto
Cindy
C
Jacobson
Marc G
MG
Parker
Karen
K
Merritt
James A
JA
Steiner
Mitchell S
MS
Logothetis
Christopher J
CJ
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*
D016159:Tumor Suppressor Protein p53