Preclinical Study of a "Tailor-Made" Combination of NK4-expressing Gene Therapy and Gefitinib (ZD1839, Iressa) for Disseminated Peritoneal Scirrhous Gastric Cancer

Int J Cancer. 2006 Mar 15;118(6):1545-55. doi: 10.1002/ijc.21531.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma, Scirrhous / genetics
  • Adenocarcinoma, Scirrhous / pathology
  • Adenocarcinoma, Scirrhous / therapy*
  • Administration, Oral
  • Adult
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • ErbB Receptors / metabolism
  • Gefitinib
  • Genetic Therapy / methods*
  • Hepatocyte Growth Factor / genetics*
  • Hepatocyte Growth Factor / metabolism
  • Hepatocyte Growth Factor / pharmacology
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Peritoneum / metabolism
  • Peritoneum / pathology
  • Quinazolines / administration & dosage
  • Quinazolines / pharmacology*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / pathology
  • Stomach Neoplasms / therapy*
  • Survival Analysis
  • Treatment Outcome
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Cytokines
  • HGF protein, human
  • Quinazolines
  • Hepatocyte Growth Factor
  • ErbB Receptors
  • Gefitinib