title: Phase I/II adenoviral p53 gene therapy for chemoradiation resistant advanced esophageal squamous cell carcinoma.
abstract: We investigated the feasibility, safety, biological activity and therapeutic efficacy of adenovirus-mediated p53 gene transfer in patients with chemoradiation resistant advanced esophageal carcinoma. Eligible patients were not surgical candidates and had measurable, advanced squamous cell carcinoma of the esophagus that was resistant to chemoradiation therapy. On a 28-day cycle, intratumoral injections of Ad5CMV-p53 (INGN 201; ADVEXIN) were administered on days 1 and 3 at four dose levels (10 x 10(11) particles to 25 x 10(11) particles) and treated for up to five cycles. Ten patients received a total of 26 cycles with no dose-limiting toxicity. Administration of multiple courses was feasible and well-tolerated. Local tumor responses revealed stable disease in nine cases and progressive disease in one case. The overall responses were stable in six and progressive in four cases. Using polymerase chain reaction (PCR) analyses, gene transfer and p53 specific transgene expression were detected in tumor biopsy tissue from all patients. mRNA levels of p53, p21 and MDM2 increased in all but one case. Three patients showed absence of disease upon repeat biopsies. Substantial improvement in swallowing was observed in one patient with stenotic lesions. Intratumoral injection of Ad5CMV-p53 is safe, feasible and biologically active when administered in multiple doses to patients with esophageal cancer. Observations from this study indicate that this treatment results in local antitumor effects in chemoradiation resistant esophageal squamous cell carcinoma.
authors.affiliation: Department of Frontier Surgery, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chiba, 260-8670, Japan. hshimada@faculty.chiba-u.jp
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shimada
authors.forename: Hisahiro
authors.initials: H
authors.lastname: Matsubara
authors.forename: Tooru
authors.initials: T
authors.lastname: Shiratori
authors.forename: Takanori
authors.initials: T
authors.lastname: Shimizu
authors.forename: Shinichi
authors.initials: S
authors.lastname: Miyazaki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Okazumi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nabeya
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Shuto
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayashi
authors.forename: Tooru
authors.initials: T
authors.lastname: Tanizawa
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nakatani
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakasa
authors.forename: Mitsukazu
authors.initials: M
authors.lastname: Kitada
authors.forename: Takenori
authors.initials: T
authors.lastname: Ochiai
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000368:Aged; D000369:Aged, 80 and over; D000914:Antibodies, Viral / Q000097:blood; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000473:pathology / Q000628:therapy*; D005260:Female; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D011836:Radiation Tolerance; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes
chemical_list: D000914:Antibodies, Viral; D012333:RNA, Messenger