title: Interaction of endothelial progenitor cells expressing cytosine deaminase in tumor tissues and 5-fluorocytosine administration suppresses growth of 5-fluorouracil-sensitive liver cancer in mice.
abstract: The drug delivery system to tumors is a critical factor in upregulating the effect of anticancer drugs and reducing adverse events. Recent studies indicated selective migration of bone marrow-derived endothelial progenitor cells (EPC) into tumor tissues. Cytosine deaminase (CD) transforms nontoxic 5-fluorocytosine (5-FC) into the highly toxic 5-fluorouracil (5-FU). We investigated the antitumor effect of a new CD/5-FC system with CD cDNA transfected EPC for hepatocellular carcinoma (HCC) in mice. We used human hepatoma cell lines (HuH-7, HLF, HAK1-B, KYN-2, KIM-1) and a rat EPC cell line (TR-BME-2). Escherichia coli CD cDNA was transfected into TR-BME-2 (CD-TR-BME). The inhibitory effect of 5-FU on the proliferation of hepatoma cell lines and the inhibitory effect of 5-FU secreted by CD-TR-BME and 5-FC on the proliferation of co-cultured hepatoma cells were evaluated by a tetrazolium-based assay. In mouse subcutaneous xenograft models of KYN-2 and HuH-7, CD-TR-BME was transplanted intravenously followed by 5-FC injection intraperitoneally. HuH-7 cells were the most sensitive to 5-FU and KYN-2 cells were the most resistant. CD-TR-BME secreted 5-FU and inhibited HuH-7 proliferation in a 5-FC dose-dependent manner. CD-TR-BME were recruited into the tumor tissues and some were incorporated into tumor vessels. Tumor growth of HuH-7 was significantly suppressed during 5-FC administration. No bodyweight loss, ALT abnormality or bone marrow suppression was observed. These findings suggest that our new CD/5-FC system with CD cDNA transfected EPC could be an effective and safe treatment for suppression of 5-FU-sensitive HCC growth.
authors.affiliation: Liver Cancer Division, Research Center for Innovative Cancer Therapy and Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan. tori@med.kurume-u.ac.jp
authors.forename: Takuji
authors.initials: T
authors.lastname: Torimura
authors.forename: Takato
authors.initials: T
authors.lastname: Ueno
authors.forename: Eitaro
authors.initials: E
authors.lastname: Taniguchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Masuda
authors.forename: Hideki
authors.initials: H
authors.lastname: Iwamoto
authors.forename: Toru
authors.initials: T
authors.lastname: Nakamura
authors.forename: Kinya
authors.initials: K
authors.lastname: Inoue
authors.forename: Osamu
authors.initials: O
authors.lastname: Hashimoto
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Abe
authors.forename: Hironori
authors.initials: H
authors.lastname: Koga
authors.forename: Vincenza
authors.initials: V
authors.lastname: Barresi
authors.forename: Emi
authors.initials: E
authors.lastname: Nakashima
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Yano
authors.forename: Michio
authors.initials: M
authors.lastname: Sata
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002465:Cell Movement; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000637:transplantation*; D005437:Flucytosine / Q000008:administration & dosage*; D005472:Fluorouracil / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008113:Liver Neoplasms / Q000628:therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D011355:Prodrugs / Q000008:administration & dosage; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D005437:Flucytosine; D043525:Cytosine Deaminase; D005472:Fluorouracil