Cytosine deaminase/5-fluorocytosine gene therapy can induce efficient anti-tumor effects and protective immunity in immunocompetent mice but not in athymic nude mice.
Murine hepatocellular carcinoma cells were retrovirally transduced with the bacterial cytosine deaminase (CD) gene. CD-transduced cells exhibited more than 120-fold higher sensitivity to 5-fluorocytosine (5-FC) compared with parental cells. When syngeneic immunocompetent mice were inoculated s.c. with parental hepatocellular carcinoma cells containing as little as 5% CD-transduced cells, significant inhibition of tumor formation was induced by 5-FC treatment. Furthermore, established solid tumors in immunocompetent mice containing only 5% CD-transduced cells were infiltrated markedly with CD4- and CD8+ T lymphocytes and macrophages by 5-FC treatment, such that significant reduction or even complete regression of tumors was observed. These tumor-free mice resisted subsequent rechallenge with wild-type tumor. Conversely, when athymic nude mice were inoculated with a cell mixture containing CD-transduced cells and parental cells at a ratio of 40:60, all developed tumors despite 5-FC treatment. Our results indicate that gene therapy using the CD/5-FC system can induce efficient anti-tumor effects and protective immunity in immunocompetent mice but not in athymic immunodeficient mice, suggesting that the host's immunocompetence may be a critical factor for achieving successful gene therapy against cancer.
Kuriyama
S
S
Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan.
Kikukawa
M
M
Masui
K
K
Okuda
H
H
Nakatani
T
T
Sakamoto
T
T
Yoshiji
H
H
Fukui
H
H
Ikenaka
K
K
Mullen
C A
CA
Tsujii
T
T
D000818:Animals; D043525:Cytosine Deaminase; D005437:Flucytosine / Q000627:therapeutic use*; D005472:Fluorouracil / Q000627:therapeutic use; D015316:Genetic Therapy; D005822:Genetic Vectors; D008114:Liver Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009700:Nucleoside Deaminases / Q000235:genetics* / Q000378:metabolism; D012190:Retroviridae; D013997:Time Factors
D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil