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.