Enhanced efficacy of conditionally replicating herpes simplex virus (G207) combined with 5-fluorouracil and surgical resection in peritoneal cancer dissemination models.
BACKGROUND
The therapeutic efficacy of G207, a replication-competent herpes simplex virus, for malignancies is increased when combined with certain chemotherapies, but the mechanism is unclear and the interaction between G207 and surgical resection has not been extensively studied. The goals of the current study were to examine the performance of combination treatments for peritoneal disseminated cancers and to explore the mechanism of effective combinations.


METHODS
Hamsters and SCID and BALB/c mice harboring peritoneal dissemination of gallbladder, gastric or colon cancer cells were treated with G207, 5-fluorouracil (5FU), or surgical resection alone, or G207 combined with 5FU or surgery. Animal survival, antiviral immunity, intratumoral ribonucleotide reductase activity, and viral spread were compared between the groups.


RESULTS
The combination of G207 and 5FU prolonged the survival of hamsters bearing peritoneal dissemination of gallbladder cancer compared with the controls, G207 alone and 5FU alone. 5FU did not suppress the production of neutralizing antibodies against G207, but increased ribonucleotide reductase activity and viral spread in subcutaneous gallbladder tumors. The enhanced efficacy of the combination treatment was also observed in immunodeficient mice with disseminated gastric cancer. Although surgical resection did not significantly prolong animal survival or increase the intratumoral activity of ribonucleotide reductase, long-term survivors emerged from groups of animals treated with surgical resection and G207 for gallbladder and colon disseminated cancers.


CONCLUSIONS
These results indicate that the increased activity of ribonucleotide reductase in tumors mediated by 5FU and the decreased tumor burden resulting from surgical resection may enhance the therapeutic efficacy of oncolytic herpes virus for peritoneal disseminated cancer.
Nakano
Kenji
K
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ken10@pitt.edu
Todo
Tomoki
T
Zhao
Gang
G
Yamaguchi
Koji
K
Kuroki
Syoji
S
Cohen
Justus B
JB
Glorioso
Joseph C
JC
Tanaka
Masao
M
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000276:immunology / Q000601:surgery / Q000628:therapy; D003131:Combined Modality Therapy; D006224:Cricetinae; D003673:Defective Viruses; D004195:Disease Models, Animal; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D005706:Gallbladder Neoplasms / Q000276:immunology / Q000628:therapy; D018014:Gene Transfer Techniques; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010534:Peritoneal Neoplasms / Q000556:secondary / Q000601:surgery / Q000628:therapy*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018139:Simplexvirus / Q000235:genetics*; D013274:Stomach Neoplasms / Q000276:immunology / Q000601:surgery / Q000628:therapy; D015996:Survival Rate; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D014764:Viral Proteins / Q000187:drug effects; D014779:Virus Replication
D000914:Antibodies, Viral; D000964:Antimetabolites, Antineoplastic; D014764:Viral Proteins; D012264:Ribonucleotide Reductases; D005472:Fluorouracil