In vivo efficacy and toxicity of 5-fluorocytosine/cytosine deaminase gene therapy for malignant gliomas mediated by adenovirus.
We evaluated the therapeutic efficacy and neurotoxicity of adenovirus-mediated transduction of the cytosine deaminase (CD) gene and 5-fluorocytosine (5-FC) for experimental malignant brain tumors. The 5-FC sensitivity in 9 L cells infected by an adenovirus vector expressing CD (AdexCACD) was increased 1700-fold compared with control cells. Rats bearing 9 L brain tumors were treated with an intratumoral injection of AdexCACD followed by intraperitoneal administration of 5-FC. The rats demonstrated remarkable inhibition of tumor growth by magnetic resonance imaging, and 7 of 10 rats survived for >90 days. To evaluate the potential side-effects of the 5-FC/CD gene therapy, rats were treated with an intracerebral injection of AdexCACD into the right basal ganglia and with 5-FC. The magnetic resonance imaging showed a highly enhanced area on the gadollinium-enhanced T1-weighted image at 18 days postinjection. Pathologically, this corresponded to an area of necrosis with surrounding apoptotic cells. In addition, there was demyelination and gliosis with enlargement of the lateral ventricles. These results suggest that the 5-FC/CD gene therapy may provide an anticancer effect for malignant brain tumors in humans, but also show that there are neurotoxic effects on normal brain tissue.
Ichikawa
T
T
Department of Neurological Surgery, Okayama University Medical School, Japan.
Tamiya
T
T
Adachi
Y
Y
Ono
Y
Y
Matsumoto
K
K
Furuta
T
T
Yoshida
Y
Y
Hamada
H
H
Ohmoto
T
T
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000628:therapy*; D043525:Cytosine Deaminase; D005069:Evaluation Studies as Topic; D005437:Flucytosine / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors; D005910:Glioma / Q000235:genetics / Q000628:therapy*; D008297:Male; D009700:Nucleoside Deaminases / Q000009:adverse effects / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase