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

Abstract

We evaluated the effect of a ''tailor-made'' chemo-gene therapy in scirrhous gastric cancer (SGC)-bearing nude mice. For this tailormade 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 5 8), 11.9; treated (n 5 8), 17.3; p 5 0.0014) and the numbers of mice in good condition (control, 2; treated, 8; p 5 0.0012) were significantly greater, and the abdominal girth (mm) (control, 81.1; treated, 70.3; p 5 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.

FGFR2-Amplified Gastric Cancer Cell Lines Require FGFR2 and Erbb3 Signaling for Growth and Survival

“…S4), and combination treatment of PD173074 and gefitinib did not improve the potency of either compound treatment alone (data not shown). Gefitinib function was confirmed by inhibition of the NUGC4 cell line at an IC 50 of 125 nmol/L (data not shown), similar to previously reported inhibition (36). Regarding chemotherapeutic compounds, paclitaxel and 5-fluorouracil had relatively similar potency against FGFR2-amplified cells in comparison with non-FGFR2-amplified cells (Supplementary Fig.…”

“…Finally, the NUGC4 (EGFR/Erbb3 activated; Fig. 6) and Her2-amplified N87 cell lines (39) are selectively inhibited by EGFR inhibitors or Herceptin, respectively (36,40). It remains to be tested whether gastric cancers harboring these genetic alterations will be similarly responsive in a clinical setting.…”

Single-Agent and Combination Therapeutic Strategies to Inhibit Hepatocyte Growth Factor/MET Signaling in Cancer

“…This effect was presumably due to stromal production of HGF. The combination of gefitinib and NK4 was significantly more effective in this model than either agent alone (57).…”

“…The combination of the EGFR inhibitor gefitinib and the HGF antagonist NK4 has also been tested in a preclinical model of gastric cancer (57). In vitro, NUGC-4 gastric cancer cells were sensitive to gefitinib, but in vivo, NUGC-4 cells were resistant to gefitinib treatment when co-injected with gastric fibroblasts.…”

Effect of Bevacizumab, a Humanized Monoclonal Antibody to Vascular Endothelial Growth Factor, on Peritoneal Metastasis of MNK-45P Human Gastric Cancer in Mice

“…All mice were killed on day 18 after tumor inoculation, and the maximum abdominal circumference and ascites volume were measured [23]. The maximum abdominal circumference was measured with a measuring tape by two investigators who were blinded as to which group the animal had been assigned [24]. Because mice had only a small amount of ascites, 1 mL of PBS was intraperitoneally injected and the peritoneal fluid was totally recovered [25].…”