Eradication of rat malignant gliomas by retroviral-mediated, in vivo delivery of the interleukin 4 gene

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Abstract

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 Ψ2.L4SN20 or E86.L4SN50 retroviral producer cells (RPCS), secreting 20 and 50 ng of IL-4/5 x 105 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.

Original languageEnglish
Pages (from-to)645-652
Number of pages8
JournalCancer Research
Volume59
Issue number3
Publication statusPublished - Feb 1 1999

Fingerprint

Glioma
Interleukin-4
Genes
Gliosarcoma
Neoplasms
Immunologic Memory
T-Lymphocytes
Injections
Interleukin-5
Inbred F344 Rats
Glioblastoma
Sprague Dawley Rats
Survivors
B-Lymphocytes
Clone Cells
Macrophages
Magnetic Resonance Imaging
Brain

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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title = "Eradication of rat malignant gliomas by retroviral-mediated, in vivo delivery of the interleukin 4 gene",
abstract = "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 Ψ2.L4SN20 or E86.L4SN50 retroviral producer cells (RPCS), secreting 20 and 50 ng of IL-4/5 x 105 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.",
author = "Sara Benedetti and Bruzzone, {Maria Grazia} and Bianca Pollo and Francesco DiMeco and Lorenzo Magrassi and Barbara Pirola and Nicola Cirenei and Colombo, {Mario P.} and Gaetano Finocchiaro",
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T1 - Eradication of rat malignant gliomas by retroviral-mediated, in vivo delivery of the interleukin 4 gene

AU - Benedetti, Sara

AU - Bruzzone, Maria Grazia

AU - Pollo, Bianca

AU - DiMeco, Francesco

AU - Magrassi, Lorenzo

AU - Pirola, Barbara

AU - Cirenei, Nicola

AU - Colombo, Mario P.

AU - Finocchiaro, Gaetano

PY - 1999/2/1

Y1 - 1999/2/1

N2 - 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 Ψ2.L4SN20 or E86.L4SN50 retroviral producer cells (RPCS), secreting 20 and 50 ng of IL-4/5 x 105 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.

AB - 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 Ψ2.L4SN20 or E86.L4SN50 retroviral producer cells (RPCS), secreting 20 and 50 ng of IL-4/5 x 105 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.

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