Effects of tumor selective replication-competent herpes viruses in combination with gemcitabine on pancreatic cancer

Purpose Pancreatic cancer still has a poor prognosis, even if aggressive therapy is pursued. Currently, new modalities of oncolytic virus therapy are being tested against this cancer. The combination of one of two representative mutant herpes simplex viruses (R3616: γ 1 34.5 inactivated, hrR3: UL39...

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Published in:Cancer chemotherapy and pharmacology 2008-04, Vol.61 (5), p.875-882
Main Authors: Watanabe, Izuru, Kasuya, Hideki, Nomura, Naohiro, Shikano, Toshio, Shirota, Takashi, Kanazumi, Naohito, Takeda, Shin, Nomoto, Shuji, Sugimoto, Hiroyuki, Nakao, Akimasa
Format: Article
Language:English
Subjects:
Animals
Antimetabolites, Antineoplastic - pharmacology
Antineoplastic agents
Biological and medical sciences
Blotting, Western
Cancer Research
Cell Line, Tumor
Combined Modality Therapy
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacology
Disease Models, Animal
Drug Screening Assays, Antitumor
Female
Gastroenterology. Liver. Pancreas. Abdomen
Human viral diseases
Humans
Infectious diseases
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Medical sciences
Medicine
Medicine & Public Health
Mice
Mice, Inbred BALB C
Mice, Nude
Mutation
Oncology
Oncolytic Viruses
Original Article
Pancreatic cancer
Pancreatic Neoplasms - therapy
Pharmacology. Drug treatments
Pharmacology/Toxicology
Simplexvirus - genetics
Tumors
Viral diseases
Viral diseases with cutaneous or mucosal lesions and viral diseases of the eye
Virus Replication - drug effects
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Summary:Purpose Pancreatic cancer still has a poor prognosis, even if aggressive therapy is pursued. Currently, new modalities of oncolytic virus therapy are being tested against this cancer. The combination of one of two representative mutant herpes simplex viruses (R3616: γ 1 34.5 inactivated, hrR3: UL39 inactivated) with a standard anti-pancreatic cancer chemotherapy drug (gemcitabine), was investigated in this study. Experimental design The intracellular concentration of ribonucleotide reductase was estimated by Western blotting. The effect of gemcitabine on viral replication and the total cytotoxic effect of the combination therapy were investigated on pancreatic cancer cell lines. We compared the results of two oncolytic viruses, R3616 and hrR3. A mouse model of pancreatic cancer with peritoneal dissemination was used to evaluate the in vivo effect of the combination therapy. Results Although the replication of both viruses was inhibited by gemcitabine, the combination caused more tumor cell cytotoxicity than did virus alone in vitro. The results with R3616 were more striking. Although the difference was not statistically significant, R3616 with gemcitabine had a greater effect than did R3616 alone, while hrR3 with gemcitabine had a weaker effect than did hrR3 alone in vivo experiments. Conclusion The combination of oncolytic virus with gemcitabine is a promising new strategy against advanced pancreatic cancer. Each virus has different functional characteristics, and can affect the results of the combination of viruses and chemotherapy drugs. The results indicate that there is a complicated interaction among viruses, cells, and chemotherapy drugs and that the best combination of oncolytic virus and chemotherapeutic agents should be studied more extensively before embarking on a clinical trial.
ISSN:0344-5704
1432-0843
DOI:10.1007/s00280-007-0567-8