Abstracts
1999 Digestive Disease Week

# 3468 GENE THERAPY FOR PANCREATIC CANCER USING A MUTANT ADENOVIRUS CAPABLE OF PREFERENTIALLY DESTROYING CANCER CELLS
Makoto Sunamura, Tohoku Univ Sch of Medicine, Sendai Japan; Hirofumi Hamada, Fuyuhiko Motoi, Cancer Chemotherapy Ctr, Cancer Instute, Tokyo Japan; Lianghao Ding, Tadaaki Yokoyama, Toshimasa Yatsuoka, Syoji Fukuyama, Shin-ichi Egawa, Masao Kobari, Akira Horii, Seiki Matsuno, Tohoku Univ Sch of Medicine, Sendai Japan

Introduction: The adenovirus E1B gene encodes a 55KD protein that is known to bind and inactivate p53, allowing viral replication without p53-mediated growth arrest or apoptosis. We constructed a mutant adenovirus (AxE1AdB), which can replicate in cells lacking normal p53 functionality, by inserting a stop codon in the E1B region encoding for a 55KD protein in the type 5 adenoviral genome. The cytopathic effect of AxE1AdB on pancreatic cancer was studied. Methods and Results: AxE1AdB replicated 50- to 3600-fold in p53 defective pancreatic cancer cells with abnormal p53 function (i.e, Panc.1, MIAPaCa.2, Su.86.86. and BxPC3) for one week. In contrast, AxE1AdB replication was significantly impaired in normal cell or tumor cell with functional p53. AxE1AdB showed potent cytocital effect in all cell lines(>90%). However, glioma cell line U87 retaining expressing p53 constitutionally was not killed by AxE1AdB. Coinfection of E1-deficient vector AxCAlacZ with AxE1AdB resulted in the replication of both viruses documented by the marked LacZ expression in Panc.1 cells. Coinfected Panc.1 cells showed about 110 fold increase in IL-2 production compared with single infection of AxCAhIL-2, adenovirus vector containing IL-2 gene. In vivo, we have shown that AxE1AdB injected daily intratumoraly for 5 days starting one week after subcutaneous inoculation of 1x107 Panc1 cells in SCID mice suppressed tumor growth by 86% at the end of a four week observation period (P=0.0035). However, these tumors begun to grow after five weeks, eventually causing the death of SCID mice. Moreover, when AxE1AdB was administered along with AxCAhIL-2 tumor regrowth was not observed in half of mice receiving combined therapy. Discussion: Genetic alterations studies showed that inactivation of p53 mutation is supposed to be involved in the development of pancreatic cancer accompanied with inactivation of MTS1 and/or SMAD4 and activation of K-ras. Mutant adenovirus may treat efficiently p53 deficient cancers including pancreatic cancer and be a prove to be a useful partner for other adenoviral vectors in cancer gene therapy.

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