Assessment of p53 gene transfer and biological activities in a clinical study of adenovirus-p53 gene therapy for recurrent ovarian cancer.
A cohort study was designed to evaluate the efficiency of gene transfer and whether biological activity from the expressed therapeutic gene resulted after administration of a recombinant adenovirus containing the human wild-type p53 (p53(wt)) gene (rAd-p53 SCH 58500). The cohort study was conducted in five trial subjects with recurrent ovarian cancer. Each trial subject received multiple cycles of rAd-p53 SCH 58500, each cycle comprised of doses of 7.5 x 10(13) particles on each of five consecutive days. Subjects were treated with rAd-p53 SCH 58500 alone during Cycle 1 and in combination with gemcitabine during the subsequent cycles. Both tumor biopsies and peritoneal aspirates were collected and evaluated for gene transfer and evidence of the biological activities of the expressed p53(wt) gene. Using quantitative PCR and RT-PCR, and in situ PCR, gene transfer and expression were documented in tumor biopsies (four of five patients) collected from Cycle 1. Furthermore, upregulation of p21/WAF1, bax and mdm-2, and downregulation of survivin were observed in these same tumor biopsy samples, suggesting that intraperitoneal administration of rAd-p53 SCH 58500 leads to detectable p53 biological activity in target tumor tissue. In addition, gene transfer and its expression were observed in cells obtained from peritoneal aspirates. These fluids were mainly comprised of polymorphonuclear neutrophils, indicating that successful gene transfer can be achieved by multiple cycle intraperitoneal administration of recombinant adenovirus.
Wen
Shu Fen
SF
Canji, Inc., San Diego, California 92121, USA. shufen.wen@canji.com
Mahavni
Vikas
V
Quijano
Erlinda
E
Shinoda
Jeremy
J
Grace
Michael
M
Musco-Hobkinson
Mary Lynn
ML
Yang
Tong-Yuan
TY
Chen
Yuetian
Y
Runnenbaum
Ingo
I
Horowitz
JoAnn
J
Maneval
Dan
D
Hutchins
Beth
B
Buller
Richard
R
D000256:Adenoviridae / Q000235:genetics* / Q000254:growth & development; D017209:Apoptosis; D001202:Ascitic Fluid / Q000378:metabolism / Q000473:pathology; D001706:Biopsy; D015331:Cohort Studies; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D016158:Genes, p53 / Q000235:genetics*; D005822:Genetic Vectors; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014771:Virion / Q000254:growth & development
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53