title: Effective gene therapy of biliary tract cancers by a conditionally replicative adenovirus expressing uracil phosphoribosyltransferase: significance of timing of 5-fluorouracil administration.
abstract: In order to enhance the efficacy of conditionally replicating adenoviruses (CRAd) in the treatment of cancers of the biliary tract, we studied the efficacy in vitro and in vivo of AxE1CAUP, a CRAd vector that carries a gene for uracil phosphoribosyltransferase (UPRT), which converts 5-fluorouracil (5-FU) directly to 5-fluorouridine monophosphate and greatly enhances the cytotoxicity of 5-FU. AxE1CAUP replicated and induced an increased UPRT expression in biliary cancer cells more efficiently than AxCAUP, a nonreplicative adenovirus carrying the UPRT gene. Whereas AxCAUP and AxE1AdB, a CRAd without the UPRT gene, modestly increased the sensitivity of BC cells to 5-FU, AxE1CAUP markedly increased the sensitivity, especially when the timing of 5-FU administration was appropriately chosen. AxE1CAUP replicated much less efficiently in normal WI-38 fibroblasts without any change in the sensitivity to 5-FU. In nude mice with s.c. biliary cancer xenografts, i.t. AxE1CAUP/5-FU therapy inhibited tumor growth significantly more strongly than AxCAUP/5-FU or AxE1AdB/5-FU therapy. Furthermore, in mice with peritoneally disseminated biliary cancer, i.p. AxE1CAUP efficiently proliferated in the tumors, decreased the tumor burden, and prolonged the survival of the mice when 5-FU was started 10 or 15 days after the vector inoculation, whereas earlier initiation of 5-FU resulted in early eradication of the vector and no survival benefit. The present study shows that the CRAd expressing UPRT was a more potent sensitizer of biliary cancer to 5-FU, than was a nonreplicative UPRT-encoding vector or a CRAd without UPRT gene, even at a lower dose of the vector, and that timing of 5-FU administration was a key factor to maximize the efficacy. This gene therapy with appropriately timed administration of 5-FU should be useful in overcoming the resistance of biliary cancers to 5-FU.
authors.affiliation: Division of Gastroenterology and Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Seo
authors.forename: Masato
authors.initials: M
authors.lastname: Abei
authors.forename: Mariko
authors.initials: M
authors.lastname: Wakayama
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Fukuda
authors.forename: Hideyo
authors.initials: H
authors.lastname: Ugai
authors.forename: Takehide
authors.initials: T
authors.lastname: Murata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Todoroki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuzaki
authors.forename: Naomi
authors.initials: N
authors.lastname: Tanaka
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hamada
authors.forename: Kazunari K
authors.initials: KK
authors.lastname: Yokoyama
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000818:Animals; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005706:Gallbladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010430:Pentosyltransferases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014161:Transduction, Genetic; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D005472:Fluorouracil