Intraperitoneal injection of adenovirus-mediated NK4 gene suppresses peritoneal dissemination of pancreatic cancer cell line AsPC-1 in nude mice.
NK4, composed of the N-terminal hairpin and subsequent four-kringle domains of hepatocyte growth factor (HGF), acts not only as a competitive antagonist for HGF but also as a potent angiogenesis inhibitor. This study was designed to assess a therapeutic potential of adenovirus-mediated NK4 gene transfer for disseminated pancreatic cancer cells in the peritoneal lavage of nude mice. We constructed a recombinant adenovirus NK4 (Ad-NK4), which encodes a secretable form of human NK4. In vitro migration of AsPC-1 (human pancreatic cancer cell line) was stimulated by HGF, and it was completely inhibited by Ad-NK4 transfection. Weekly intraperitoneal injections of Ad-NK4 could suppress the development of tumor nodules in a nude mouse peritoneal dissemination model. NK4 expression was detected in the disseminated nodules, liver, pancreas, spleen, and mesenterium. Immunohistochemical study of the disseminated tumors showed a remarkable decrease in microvessel density and an increase in number of apoptotic tumor cells in the Ad-NK4-treated mice. Survival of the Ad-NK4-treated mice was significantly improved. This study indicates that the intraperitoneal transduction of adenovirus-mediated NK4 gene may be a useful therapeutic modality to prevent the development of peritoneal dissemination of pancreatic cancer.
Saimura
Michiyo
M
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Fukuoka, Japan.
Nagai
Eishi
E
Mizumoto
Kazuhiro
K
Maehara
Naoki
N
Okino
Hidenobu
H
Katano
Mitsuo
M
Matsumoto
Kunio
K
Nakamura
Toshikazu
T
Narumi
Kou
K
Nukiwa
Toshihiro
T
Tanaka
Masao
M
D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D007274:Injections, Intraperitoneal; D007763:Lac Operon; D008099:Liver / Q000378:metabolism; D008643:Mesentery / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008934:Mitogens; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D013154:Spleen / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D001616:beta-Galactosidase / Q000378:metabolism
C066855:HGF protein, human; D008934:Mitogens; D017228:Hepatocyte Growth Factor; D001616:beta-Galactosidase