Gene therapy for intraperitoneally disseminated pancreatic cancers by Escherichia coli uracil phosphoribosiltransferase (UPRT) gene mediated by restricted replication-competent adenoviral vectors

Masaru Oonuma, Makoto Sunamura, Fuyuhiko Motoi, Shouji Fukuyama, Hiromune Shimamura, Jun Ichiro Yamauchi, Kazuhiko Shibuya, Shin Ichi Egawa, Hirofumi Hamada, Kazunori Takeda, Seiki Matsuno

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Although patients with unresectable pancreatic tumors have been treated with 5-fluorouracil (5FU)-based combination chemotherapy, the drug resistance of cancer cells presents a crucial therapeutic problem. It was reported that UPRT overcomes 5FU resistance. UPRT catalyzes the synthesis of 5-fluorouridine monophosphate (FUMP) from Uracil and phosphoribosylpyrophosphate (PRPP). The antitumor effect of 5FU is enhanced by augmenting 5-fluorodeoxyuridine monophosphate (FdUMP) converted from FUMP, which inhibits thymidylate synthetase (TS). We first demonstrated that injecting an El-deficient adenoviral vector (Adv) expressing UPRT (AxCAUPRT) followed by 5-FU treatment resulted in a volume reduction of xenotransplanted human tumors. In examining the therapeutic effect of AxCAUPRT/5-FU against peritoneal dissemination, we found that non-selective gene transduction of AxCAUPRT caused severe adverse effects arising from the increase of F-dUMP in normal intestine. Because the therapeutic gene delivered by a restricted replication-competent Adv lacking 55 kDa EIB protein (AxE1AdB) is speculated to be expressed selectively in tumors, mice with established tumors were injected with AxElAdB and El-deleted Adv expressing the lacZ reporter gene (AxCA1acZ). The expression of the reporter gene (lacZ) was selectively enhanced in disseminated tumors. The therapeutic advantage of restricted replication competent Adv that expresses UPRT (AxE1AdB-UPRT) was evaluated in an intraperitoneal disseminated tumor model. To study the anti-tumor effect of AxE1AdB-UPRT/5FU, mice with disseminated AsPC-1 tumors were administered the Adv, followed by the 5FU treatment. It was shown that the treatment with AxE1AdB-UPRT/5FU caused a dramatic reduction of the disseminated tumor burden without toxicity in normal tissues. Our results showed that the AxE1AdB-UPRT/5FU system is a promising tool for intraperitoneal disseminated pancreatic cancer.

Original languageEnglish
Pages (from-to)51-59
Number of pages9
JournalInternational Journal of Cancer
Volume102
Issue number1
DOIs
Publication statusPublished - 2002 Nov 1

Keywords

  • Gene therapy
  • Pancreatic cancer
  • Peritoneal dissemination
  • Replicating adenovirus
  • UPRT

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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