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- Title
Preclinical study of a 'tailor-made' combination of NK4-expressing gene therapy and gefitinib (ZD1839, Iressa™) for disseminated peritoneal scirrhous gastric cancer.
- Authors
Namiki, Yoshihisa; Namiki, Tamami; Yoshida, Hiroshi; Date, Masataka; Yashiro, Masakazu; Matsumoto, Kunio; Nakamura, Toshikazu; Yanagihara, Kazuyoshi; Tada, Norio; Satoi, Jujin; Fujise, Kiyotaka
- Abstract
We evaluated the effect of a 'tailor-made' chemo-gene therapy in scirrhous gastric cancer (SGC)-bearing nude mice. For this tailor-made approach, we first selected gefitinib (epidermal growth factor receptor-tyrosine kinase inhibitor)-sensitive SGC cell lines, and 5/8 cell lines demonstrated various degrees of gefitinib-sensitivity. In the highly gefitinib-sensitive NUGC-4, the biological response to NK4 (HGF antagonist/angiogenesis inhibitor) was examined. Subsequently, the composition of an NK4-expressing ternary complex (cationic lipid/nucleic acid/HMG-1, 2 protein) was optimized for maximum transfection activity in NUGC-4. Finally, mice were peritoneally coinoculated with NUGC-4 and scirrhous-associated gastric fibroblasts, NF22, on day 0. Animal models were orally administrated gefitinib (50 mg/kg/day, on days 7-28), and peritoneally NK4-expressing ternary complex (on days 14, 21 and 28). NK4-expression suppressed the gefitinib-resistance induced by the interaction between fibroblasts and SGC, and eventually, this tailor-made combination synergistically decelerated the disease progression by inhibiting proliferative, angiogenic and antiapoptotic effects in tumor tissues. On day 28, both the hemoglobin concentration (g/dl) (control ( n = 8), 11.9; treated ( n = 8), 17.3; p = 0.0014) and the numbers of mice in good condition (control, 2; treated, 8; p = 0.0012) were significantly greater, and the abdominal girth (mm) (control, 81.1; treated, 70.3; p = 0.0036) was significantly reduced. The median points of bloody ascite-free survival time (days) (control, 22; treated, 44; p < 0.0001) and time to euthanasia (days) (control, 36.5; treated, 56; p < 0.0001) were also significantly prolonged. This combination is a potentially useful approach to the treatment of peritoneal gefitinib-sensitive SGC dissemination. © 2005 Wiley-Liss, Inc.
- Publication
International Journal of Cancer, 2006, Vol 118, Issue 6, p1545
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.21531