Intraperitoneal delivery of hrR3 and ganciclovir prolongs survival in mice with disseminated pancreatic cancer.
BACKGROUND AND OBJECTIVES; Intraperitoneal dissemination of pancreatic cancer is associated with a poor prognosis. Surgical resection does not prolong survival. Here we describe a novel approach to this difficult clinical problem consisting of intraperitoneal delivery of the herpes simplex virus (HSV) vector (hrR3) to mice with peritoneal dissemination of the pancreatic cancer cells.


METHODS
The human pancreatic cancer cell line (SW1990) was implanted into the abdominal cavity of nude mice. Fifteen days later, the abdominal neoplasm was treated by intraperitoneal injection of the replication-conditional HSV vector (hrR3). The mutant lacks the ribonucleotide reductase gene, but contains an intact HSV-tk gene. Beginning 5 days after vector injection, mice were treated with a 14-day course of ganciclovir.


RESULTS
Long-term survival (150 days) was seen in 70% of mice receiving hrR3 and ganciclovir, 40% of mice receiving hrR3 alone, and 0% of untreated mice. No vector-related mortality was observed. X-Gal tissue staining revealed blue-stained cells only in tumor nodules, not in normal organs.


CONCLUSIONS
Intraperitoneal delivery of hrR3 and ganciclovir improves survival in this murine model of peritoneal dissemination of pancreatic cancer. The ability of hrR3 to replicate only in rapidly dividing cells makes this virus an attractive vector for gene therapy of cancer.
Kasuya
H
H
Department of Surgery II, Research Institute for Disease Mechanism and Control, University School of Medicine, Nagoya, Japan.
Nishiyama
Y
Y
Nomoto
S
S
Hosono
J
J
Takeda
S
S
Nakao
A
A
D000818:Animals; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000401:mortality / Q000628:therapy*; D012264:Ribonucleotide Reductases / Q000235:genetics; D018139:Simplexvirus / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics; D014183:Transplantation, Heterologous
D012264:Ribonucleotide Reductases; D013937:Thymidine Kinase; D015774:Ganciclovir