Experimental gene therapy for brain tumors using adenovirus-mediated transfer of cytosine deaminase gene and uracil phosphoribosyltransferase gene with 5-fluorocytosine.
Transduction of the cytosine deaminase (CD) gene into tumor cells followed by administration of 5-fluorocytosine (5-FC), called 5-FC/CD gene therapy, was created as suicide gene therapy for various cancers. The uracil phosphoribosyltransferase (UPRT) gene, which is absent from mammalian cells, directly converts 5-fluorouracil (5-FU) to 5-fluorouridine 5'-monophosphate. We evaluated whether the coexpression of CD and UPRT genes could generate a synergistic antitumor effect on experimental brain tumors. In vitro study showed that 9L cells, transduced with the UPRT gene by an adenovirus, were 16 times more sensitive to 5-FU, and CD + UPRT-transduced cells were 6,000 times more sensitive to 5-FC than parent cells, indicating that the acquisition of CD and UPRT further increased the 5-FC sensitivity of 9L cells compared with cells transduced with CD alone. In a rat brain tumor model, decreased amounts of CD and UPRT vectors were inoculated into the tumors to detect any additional effect of UPRT. CD and UPRT coexpression followed by 5-FC administration showed an antitumor effect as detected by sequential magnetic resonance imaging. This therapy significantly prolonged animal survival. These results suggest that 5-FC/CD + UPRT gene therapy can enhance the antitumor effect of 5-FC/CD gene therapy. Consequently, this approach might be a more feasible modality for the treatment of malignant brain tumors.
Adachi
Y
Y
Department of Neurological Surgery, Okayama University Medical School, Japan.
Tamiya
T
T
Ichikawa
T
T
Terada
K
K
Ono
Y
Y
Matsumoto
K
K
Furuta
T
T
Hamada
H
H
Ohmoto
T
T
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D043525:Cytosine Deaminase; D005437:Flucytosine / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000009:adverse effects; D008279:Magnetic Resonance Imaging; D009700:Nucleoside Deaminases / Q000235:genetics*; D010430:Pentosyltransferases / Q000235:genetics*; D051381:Rats; D011995:Recombination, Genetic; D014407:Tumor Cells, Cultured
D005437:Flucytosine; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase