Naked DNA injection for liver metastases treatment in rats.
The cytosine deaminase (CD) gene converts the nontoxic prodrug, 5-fluorocytosine (5-FC), into 5-fluorouracil (5-FU). We previously showed that injection of CD-bearing cancer cells followed by 5-FC treatment can act as an autologous tumor vaccine in a syngenic liver metastasis model in rats. In the present work, we analyzed the antitumor efficiency of a direct intratumoral injection of a CD-expressing plasmid. In rats bearing microscopic or macroscopic metastases in right and left liver lobes, an injection of a CD-expressing plasmid was performed in the left lobe tumor, followed by 5-FC treatment of the animals. A significant regression of the DNA-injected tumor was observed in 5-FC-treated rats, both in microscopic (P =.007) or advanced (P <.0001) tumor models. Moreover, this treatment also induced a potent distant bystander effect on untreated controlateral liver tumors and extrahepatic metastases, resulting in an increased survival compared with control animals in both tumor models (P <.05). In conclusion, these data suggest that direct intratumoral injection of a CD-expressing plasmid, associated to 5-FC administration, can constitute a powerful and innocuous alternative treatment for unresectable liver metastases from colon carcinoma.
Baqué
Patrick
P
Service de Chirurgie Abdominale et Thoracique, Hôpital l'Archet II, Nice cédex 3, France.
Pierrefite-Carle
Valérie
V
Gavelli
Adolfo
A
Brossette
Nicole
N
Benchimol
Daniel
D
Bourgeon
André
A
Staccini
Pascal
P
Saint-Paul
Marie-Christine
MC
Rossi
Bernard
B
D000818:Animals; D000963:Antimetabolites / Q000493:pharmacokinetics; D003110:Colonic Neoplasms; D043525:Cytosine Deaminase; D004195:Disease Models, Animal; D005437:Flucytosine / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006498:Hepatectomy; D007694:Killer Cells, Natural / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000401:mortality / Q000556:secondary* / Q000628:therapy*; D008297:Male; D009368:Neoplasm Transplantation; D009700:Nucleoside Deaminases / Q000235:genetics*; D010957:Plasmids / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D015996:Survival Rate; D014407:Tumor Cells, Cultured / Q000637:transplantation
D000963:Antimetabolites; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil