Preclinical study of a “tailor-made” combination of NK4-expressing gene therapy and gefitinib (ZD1839, Iressa™) for disseminated peritoneal scirrhous gastric cancer


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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.

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