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Eradication
of rat malignant gliomas by retroviral-mediated, in vivo delivery of the
interleukin 4 gene
Benedetti S, Bruzzone MG, Pollo B, DiMeco F, Magrassi L, Pirola B,
Cirenei N, Colombo MP, Finocchiaro G
Laboratory of Neuro-Oncology and Gene Therapy, Istituto Nazionale
Neurologico Besta, Milano, Italy.
Overexpression of interleukin
4 (IL-4) can impair the tumorigenicity of glioma cells, but direct evidence of
its antitumor efficacy after in vivo gene transfer into malignant gliomas has
not been provided.
To test this, we first injected into the brain of Sprague Dawley rats a 1:1
mixture of C6 rat glioblastoma cells and psi2.L4SN20 or E86.L4SN50 retroviral
producer cells (RPCs), secreting 20 and 50 ng of IL-4/5 x 10(5) cells/48 h,
respectively.
Twenty-seven and 56% of rats receiving injections with these low- or
medium-level IL-4 RPCs, respectively, survived tumor injection, whereas control
rats died in about 1 month. E86.L4SN50 RPCs coinjected with 9L gliosarcoma cells
into syngeneic Fischer 344 rats yielded similar results.
A novel IL-4 RPC clone expressing higher levels of IL-4, E86.L4SN200, coinjected
with 9L cells increased to 75% the fraction of long-term survivors and induced
tumor regression in 50% of rats when injected into established 9L
gliosarcomas.
Cured rats developed an immunological memory because they rejected a challenge
of wild-type 9L cells into the contralateral hemisphere.
Magnetic resonance imaging was used to monitor 9L and C6 gliomas and gave direct
evidence for tumor rejection in treated rats.
Immunohistology showed inflammatory infiltrates in IL-4-treated tumors in which
CD8+ T lymphocytes were more abundant, although CD4+ T lymphocytes, B
lymphocytes, and macrophages were also present.
Overall, these findings suggest that IL-4 gene transfer is a new, promising
approach for treating malignant gliomas.
PMID: 9973213 [PubMed - indexed for MEDLINE]
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