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Molecular therapy for peritoneal dissemination of xenotransplanted human MKN-45 gastric cancer cells with adenovirus mediated Bax gene transfer
  1. Y Tsunemitsu1,
  2. S Kagawa2,
  3. N Tokunaga1,
  4. S Otani1,
  5. T Umeoka1,
  6. J A Roth3,
  7. B Fang3,
  8. N Tanaka1,
  9. T Fujiwara2
  1. 1Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan
  2. 2Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan, and Centre for Gene and Cell Therapy, Okayama University Hospital, Okayama 700-8558, Japan
  3. 3Department of Thoracic and Cardiovascular Surgery, University of Texas MD. Anderson Cancer Center, Houston, TX 77030, USA
  1. Correspondence to:
    Dr T Fujiwara
    Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan; toshi_fmd.okayama-u.ac.jp

Abstract

Background: Gene therapy is an innovative therapeutic approach for cancer. An adenoviral vector expressing the tumour suppressor p53 gene (Ad/p53) is currently under clinical evaluation for various cancers. We recently developed a binary adenoviral vector system that can express the strong proapoptotic gene Bax (Ad/PGK-GV16+Ad/GT-Bax: Ad/Bax).

Aims: To evaluate the potential of Bax gene therapy for gastric cancer, we assessed its antitumour effect in comparison with that of p53.

Methods: The human gastric cancer cell lines MKN-1, MKN-7, MKN-28, and MKN-45 were treated with Ad/Bax or Ad/p53, and cell viability, transgene expression, and caspase activation were assessed in vitro. To compare the antitumour effects of Ad/Bax and Ad/p53 treatment in vivo, subcutaneous tumours and peritoneal dissemination of MKN-45 cells were generated in nude mice. Each mouse underwent intratumoral or intraperitoneal administration of viruses and the growth of implanted tumours was observed after treatment.

Results: Treatment with Ad/Bax and Ad/p53 resulted in marked Bax and p53 protein expression and effective apoptosis induction in MKN-1, MKN-7, and MKN-28 cells in vitro. In contrast, MKN-45 cells showed resistance to Ad/p53 and only treatment with Ad/Bax resulted in activation of caspase 3 expression and massive apoptosis. Ad/Bax treatment was more effective in suppressing both subcutaneous and peritoneally disseminated MKN-45 tumours compared with Ad/p53 treatment.

Conclusion: Ad/Bax treatment significantly inhibited the growth of even p53 resistant gastric cancer in vitro and in vivo. Therefore, adenovirus mediated Bax gene transfer may be useful in gene therapy for gastric cancers.

  • gastric cancer
  • gene therapy
  • Bax
  • p53
  • adenovirus
  • GT, GAL4/TATA
  • GV16, GAL4/VP16 fusion protein
  • PGK, 3-phosphoglycerate kinase
  • CMV, cytomegalovirus
  • vp, viral particles
  • pfu, plaque forming units
  • MOI, multiplicity of infection
  • X-gal, 5-bromo-4-chloro-3-indolyl-β-D-galactopyranoside
  • XTT, 2,3-bis-(2-methoxy-4-nitro-5-sulphenyl)-(2H)-tetrazolium-5-carboxanilide
  • PBS, phosphate buffered saline
  • SDS, sodium dodecyl sulphate
  • PAGE, polyacrylamide gel electrophoresis
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