2005 Fiscal Year Final Research Report Summary
Research for novel therapeutic approach against pancreatic cancer using oncolytic reovirus
| Project/Area Number |
16591331
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Oita University |
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Principal Investigator |
NISHIZONO Akira Oita University, Faculty of Medicine, Professor, 医学部, 教授 (70218155)
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| Co-Investigator(Kenkyū-buntansha) |
KITANO Seigo Oita University, Faculty of Medicine, Professor, 医学部, 教授 (90169871)
OHTA Masayuki Oita University, Faculty of Medicine, Assistant Professor, 医学部, 講師 (80271104)
ETOH Tsuyoshi Oita University, Faculty of Medicine, Instructor, 医学部, 助手 (00404369)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Reovirus / Pancreatic cancer / Liver metastasis / Peritoneal dissemination |
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| Research Abstract |
Pancreatic cancer has a poor prognosis and few effective therapies are available. The primary reason for such poor prognosis is that most patients with pancreatic cancer have locally advances and/or metastatic disease at the time of diagnosis. Recently, tumor-targeted replication-competent viruses have been developed as cancer therapy with an activated Ras signaling pathway. Pancreatic cancer may be a candidate target for reovirus because K-ras mutation is frequently found in pancreatic cancer. In this study, we examined the feasibility of using reovirus as an antihuman pancreatic cancer agent and that of the efficacy against liver metastasis from pancreatic cancer in immunocompetent models.
1.Oncolytic effect of reovirus against human pancreatic cancer cells
Reovirus was able to infect five human pancreatic cancer cell lines (Panc1, MIApaca-2, PK1, PK9, and BxPC1) in vitro. The Ras activity in these cell lines was elevated compared with that in the normal cell line (NIH3T3) and that sus
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ceptibility to reovirus was closely associated with the activated Ras pathway. In a unilatetral murine xenograft model using Panc1 and BxPC3 cell lines, each tumor growth was suppressed by intratumoral injection of reovirus. Local injection of reovirus also had systemic antitumor effects in a bilateral xenograft model using Panc1 cell line. Immunohistochemical examination revealed that reovirus replication was observed within the tumorbut not in the surrounding normal tissue.
2.Effect of oncolytic reovirus against liver metastasis in immunocompetent model
Three hamster pancreatic cancer cell lines (HPD1NR, HPD2NR, and HaP-T1) was susceptible to reovirus determined by in vitro oncolysis and de novo synthesis of viral specific protein. Similarly, Reovirus infected all cell lines and propagated via an activated Ras signaling pathway in vitro. In syngeneic hamster models using the HPD2NR cell line, intraportal administration of reovirus significantly decreased the number and size of treated tumors in comparison with non-treated tumors. Immunohistochemical study revealed that reovirus replication within the tumor cells but not found in the surrounding normal tissue and organs. There were no reovirus-related toxicities and deaths.
Our results indicate that reovirus can be considered for novel therapeutic candidate against pancreatic cancer with poor clinically prognosis and systemic administration (intraportal route) of reovirus can be effective and safe in immunocompetent host with liver metastasis from pancreatic cancer. In future, we will try to adapt clinical use of oncolysis therapy using reovirus for human patients with pancreatic cancer. Less
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