1. Therapeutic Cell-Cycle-Decoy Efficacy of a Telomerase-Dependent Adenovirus in an Orthotopic Model of Chemotherapy-Resistant Human Stomach Carcinomatosis Peritonitis Visualized With FUCCI Imaging.
- Author
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Yano S, Takehara K, Tazawa H, Kishimoto H, Urata Y, Kagawa S, Fujiwara T, and Hoffman RM
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma pathology, Animals, G2 Phase genetics, Humans, Mice, Nude, Neoplasm Proteins genetics, Neoplasms, Experimental genetics, Neoplasms, Experimental pathology, Peritoneal Neoplasms genetics, Peritoneal Neoplasms pathology, S Phase genetics, Stomach Neoplasms genetics, Stomach Neoplasms pathology, Telomerase genetics, Adenocarcinoma enzymology, Adenoviridae, Neoplasm Proteins metabolism, Neoplasms, Experimental enzymology, Peritoneal Neoplasms enzymology, Stomach Neoplasms enzymology, Telomerase metabolism
- Abstract
We have established an orthotopic nude-mouse model of gastric cancer carcinomatosis peritonitis, a recalcitrant disease in human patients. Human MKN45 poorly-differentiated human gastric cancer cells developed carcinomatosis peritonitis upon orthotopic transplantation in nude mice. The MKN45 cells expressed the fluorescent ubiquitination-based cell cycle indicator (FUCCI) that color codes the phases of the cell cycle. The intra-peritoneal tumors and ascites contained mostly quiescent G
1 /Go cancer cells visualized as red by FUCCI imaging. Cisplatinum (CDDP) treatment did not reduce bloody ascites, and larger tumors formed in the peritoneal cavity after CDDP treatment in an early-stage carcinomatosis peritonitis orthotopic mouse model. Paclitaxel-treated mice had reduced ascites, but also had large tumor masses in the peritonium after treatment with cancer cells mostly in G0 /G1 , visualized by FUCCI red. In contrast, OBP-301 telomerase-dependent adenovirus-treated mice had no ascites and only small tumor nodules consisting of cancer cells mostly in S/G2 phases in the early-stage carcinomatosis peritonitis model, visualized by FUCCI green. Furthermore, OBP-301 significantly reduced the size of tumors (P < 0.01) and ascites even in a late-stage carcinomatosis peritonitis model. These results suggest that quiescent peritoneally-disseminated gastric cancer cells are resistant to conventional chemotherapy, but OBP-301 significantly reduced the weight of the tumors and increased survival, suggesting clinical potential. J. Cell. Biochem. 118: 3635-3642, 2017. © 2016 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)- Published
- 2017
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