Hepatic intra-arterial delivery of a retroviral vector expressing the cytosine deaminase gene, controlled by the CEA promoter and intraperitoneal treatment with 5-fluorocytosine suppresses growth of colorectal liver metastases.
Targeting of colorectal liver metastases by regional gene therapy was tested in a clinically relevant syngeneic model. First, the CEA-CD-113 retroviral vector containing the cytosine deaminase gene controlled by the CEA specific tumour cell promoter, was shown in vitro to convert 5-fluorocytosine to 5-fluorouracil, resulting in cancer cell killing with a large bystander effect. Second, 10 days after the establishment of liver metastases, retroviral vectors were delivered to the liver by hepatic artery injection. After 5-fluorocytosine administration for 7 days, most surface metastases disappeared and tumour volumes were suppressed up to 8.2-fold. The results support the development of this approach for patient treatment.
Humphreys
M J
MJ
Department of Surgery, University of Liverpool, Liverpool, UK.
Ghaneh
P
P
Greenhalf
W
W
Campbell
F
F
Clayton
T M
TM
Everett
P
P
Huber
B E
BE
Richards
C A
CA
Ford
M J
MJ
Neoptolemos
J P
JP
D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000235:genetics; D002277:Carcinoma / Q000628:therapy*; D003110:Colonic Neoplasms / Q000628:therapy*; D043525:Cytosine Deaminase; D005437:Flucytosine / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006499:Hepatic Artery; D007269:Injections, Intra-Arterial; D007274:Injections, Intraperitoneal; D008113:Liver Neoplasms / Q000556:secondary* / Q000628:therapy*; D008297:Male; D023421:Models, Animal; D009368:Neoplasm Transplantation; D009700:Nucleoside Deaminases / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051381:Rats; D012190:Retroviridae / Q000235:genetics; D014407:Tumor Cells, Cultured
D000963:Antimetabolites; D002272:Carcinoembryonic Antigen; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase