Oncolytic virotherapy as a novel strategy for pancreatic cancer.

Abstract

We have developed a novel gene therapy that targets genetic alterations in pancreatic cancer using oncolytic replication-selective adenoviruses in tumor cells. E1B-55kDa-deleted adenovirus (AxE1AdB) can selectively replicate in TP53-deficient human cancer cells but not cells with functional TP53. Consecutive injection with AxE1AdB markedly inhibited the growth of human pancreatic tumors in severe combined immunodeficiency disease mice. Furthermore, AxE1AdB displayed the ability to enhance gene expression as a virus vector. It is reported that uracil phosphoribosyl transferase (UPRT) overcomes 5-FU resistance. The therapeutic advantage of a replication-selective adenovirus that expresses UPRT (AxE1AdB-UPRT) was thus evaluated in an intraperitoneum-disseminated tumor model. Combined treatment with 5-FU and AxE1AdB-UPRT dramatically reduced the disseminated tumor burden without causing toxicity in normal tissues. We also clarified the process of AxE1AdB-inhibited tumor angiogenesis through the preserved E1A region: an adenoviral E1A protein binds to pRB, forcing the quiescent cell into the S phase. We constructed a double-mutant, replication-selective adenovirus (AxdAdB-3) containing a mutation in the RB-binding motif of the E1A region and a deletion of large E1B-55kDa. AxdAdB-3 swiftly induced cancer cell death in vitro and showed a potent antitumor effect in vivo. These results strongly suggest that AxdAdB-3 possesses a wider therapeutic potential than previously believed, given that most pancreatic cancers have abnormalities in both the TP53 and RB pathways.

• Authors: Makoto Sunamura, Hirofumi Hamada, Fuyuhiko Motoi, Masaru Oonuma, Hisashi Abe, Yukoh Saitoh, Toru Hoshida, Shigeru Ottomo, Noriyuki Omura, Seiki Matsuno
• Journal: Pancreas (Pancreas) Vol. 28 Issue 3 Pg. 326-9 (Apr 2004) ISSN: 1536-4828 [Electronic] United States
• PMID: 15084981 (Publication Type: Journal Article)

Chemical References

• Adenovirus E1B Proteins

Topics

• Adenoviridae (genetics, physiology)
• Adenovirus E1B Proteins (genetics)
• Animals
• Genes, p53
• Genetic Therapy
• Genetic Vectors
• Humans
• Mice
• Mice, SCID
• Mutation
• Neovascularization, Pathologic (therapy)
• Pancreatic Neoplasms (blood supply, genetics, therapy)
• Virus Replication