Retrovirus-mediated in vivo gene therapy using the herpes simplex virus thymidine kinase gene against carcinomatous peritonitis.
BACKGROUND
Carcinomatous peritonitis is characterized by massive malignant ascites, while peritoneally disseminated carcinomatosis is characterized by a large number of metastatic solid tumors in the peritoneal cavity. Although both are fatal end-stage manifestations of malignancies derived from the digestive system, the former is usually more serious than the latter due to massive malignant ascites. Although the effectiveness of gene therapy against peritoneally disseminated carcinomatosis has been shown in animal experiments, its effectiveness against carcinomatous peritonitis remains to be examined.


METHODS
A carcinomatous peritonitis model was made by inoculating murine hepatocellular carcinoma cells, MH134, into the peritoneal cavity of syngeneic C3H/He mice, resulting in production of massive malignant ascites without development of intraperitoneal solid tumors. Model animals were injected intraperitoneally with retroviruses carrying the herpes simplex virus thymidine kinase (HSV-tk) gene followed by ganciclovir (GCV) treatment.


RESULTS
Retrovirus-mediated in vivo gene therapy with the HSV-tk/GCV system was shown to have a significant impact on survival of animals with carcinomatous peritonitis not only at an early stage, but also at an advanced stage. Furthermore, repeated injections of HSV-tk-carrying retroviruses significantly prolonged the survival of animals with carcinomatous peritonitis compared with a single injection protocol. When intraperitoneal administration of recombinant interleukin-2 (IL-2) was added to the HSV-tk/GCV system, levels of IL-1beta and IL-2 in malignant ascites were significantly increased, resulting in significantly reduced ascite volume and prolonged survival.


CONCLUSIONS
Our results indicate the feasibility of retrovirus-mediated in vivo gene therapy with the HSV-tk/GCV system plus IL-2 treatment against carcinomatous peritonitis.
Toyokawa
Y
Y
Third Dept. of Internal Medicine, Nara Medical University, Kashihara, Japan.
Kuriyama
S
S
Tsujinoue
H
H
Nakatani
T
T
Mitoro
A
A
Yoshiji
H
H
Fukui
H
H
D000818:Animals; D001201:Ascites / Q000209:etiology / Q000378:metabolism / Q000628:therapy*; D006528:Carcinoma, Hepatocellular / Q000150:complications* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D051379:Mice; D008809:Mice, Inbred C3H; D010538:Peritonitis / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D011336:Probability; D012190:Retroviridae / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology* / Q000235:genetics; D018709:Statistics, Nonparametric; D015996:Survival Rate; D013937:Thymidine Kinase / Q000235:genetics*
D016207:Cytokines; D013937:Thymidine Kinase; D015774:Ganciclovir