Total vascular exclusion of the liver enhances the efficacy of retroviral-mediated associated thymidine kinase and interleukin-2 genes transfer against multiple hepatic tumors in rats.
BACKGROUND
Recent advances in gene transfer technology render gene therapy an attractive treatment of disseminated liver metastases for which other treatments remain disappointing. In this setting, total vascular exclusion of the liver could improve gene transfer to cancer cells and prevent extrahepatic vector spreading during portal infusion of therapeutic genes. We evaluate the efficiency of combined herpes simplex virus type-1 thymidine kinase (HSV1-TK) and interleukin-2 retrovirus-mediated gene transfer through the portal vein, under total vascular exclusion of the liver, in a model of macroscopic multiple liver metastases in rats.


METHODS
Multifocal liver metastases were established in BDIX rats with intraportal injection of DHDK12 colon cancer cells. On randomization, rats received either vector-producing cells or saline solution under total vascular exclusion of the liver. Vector-producing cells released retroviral vectors encoding Lac-Z in marking studies or HSV1-TK or interleukin-2 in therapeutic studies. Rats were either killed for pathologic studies, or followed for survival.


RESULTS
Total vascular exclusion of the liver markedly improved gene transfer efficacy in marking studies. In therapeutic studies we observed a significant reduction in tumor volume of treated rats compared with untreated controls (2170 +/- 310 mm(3)). Although singular HSV1-TK or interleukin-2 gene transfer showed significant efficacy, the greatest tumor volume regression was observed in rats treated with combined HSV1-TK + interleukin-2 gene therapy (145 +/- 60 mm(3); P =.0001 vs control). This translated into an increased median survival rate compared with either control rats (P =.006) or rats treated with single gene therapy.


CONCLUSIONS
In a rat model, a significant antitumoral effect against macroscopic multifocal liver metastases can be observed after retrovirus-mediated HSV1-TK and interleukin-2 gene transfer through the portal vein under total vascular exclusion of the liver, followed by ganciclovir administration. We believe that this well-tolerated and efficient therapeutic approach deserves clinical evaluation in patients with disseminated colorectal liver metastases.
Alves
Arnaud
A
Laboratoire de Biologie et Thérapeutique des Pathologies Immunitaires, Centre National de la Recherche Scientifique, Hôpital de la Pitié-Salpétrière, Paris, France.
Charre
Lionel
L
Panis
Yves
Y
Cardoso
Jorge
J
Fabre
Monique
M
Brisson
Edith
E
Houssin
Didier
D
Soubrane
Olivier
O
Klatzmann
David
D
D000818:Animals; D018014:Gene Transfer Techniques; D005819:Genetic Markers; D015316:Genetic Therapy; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D007376:Interleukin-2 / Q000235:genetics*; D008099:Liver / Q000098:blood supply*; D008114:Liver Neoplasms, Experimental / Q000628:therapy*; D008297:Male; D051381:Rats; D012190:Retroviridae / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured
D005819:Genetic Markers; D007376:Interleukin-2; D013937:Thymidine Kinase