TY - JOUR
T1 - Limited efficacy of the HSV-TK/GCV system for gene therapy of malignant gliomas and perspectives for the combined transduction of the interleukin-4 gene
AU - Benedetti, Sara
AU - Dimeco, Francesco
AU - Pollo, Bianca
AU - Cirenei, Nicola
AU - Colombo, Bruno M.
AU - Bruzzone, Maria Grazia
AU - Cattaneo, Elena
AU - Vescovi, Angelo
AU - Didonato, Stefano
AU - Colombo, Mario P.
AU - Finocchiaro, Gaetano
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 1997/7/20
Y1 - 1997/7/20
N2 - The growth of U-87 or C6 gliomas co-implanted in nude mice with retroviral producer cells (VPC) expressing the herpes simplex virus-thymidine kinase (HSV-tk) gene is only partially impaired by treatment with ganciclovir (GCV). The effect of GCV is even less evident when C6 and VPC are co-implanted into the rat brain. Furthermore, tumors from C6 cells carrying the HSV-tk gene are not eradicated by GCV, although they remain sensitive to GCV when replated in vitro. These limits of the HSV-tk/GCV system in glioma gene therapy may be due to insufficient gene transfer and/or insufficient delivery of GCV to glioma cells. Combination of HSV-tk and one or more cytokines may improve the antitumor efficacy. Among cytokines, interleukin-4 (IL-4) has already been shown to be active against gliomas. In nude mice, GCV treatment inhibited tumor growth more effectively after co-injection of C6 cells with a mixture of VPC transducing IL-4 and HSV-tk genes than after co-injection with either IL-4 or HSV-tk VPC only. In immunocompetent Sprague-Dawley rats, co-injection of IL-4 VPC and C6 cells was also effective in inhibiting the growth of C6 brain tumors, 38% of the animals surviving for at least 2 months. Furthermore, increased and prolonged antitumor efficacy was obtained by transducing both IL-4 and HSV-tk genes.
AB - The growth of U-87 or C6 gliomas co-implanted in nude mice with retroviral producer cells (VPC) expressing the herpes simplex virus-thymidine kinase (HSV-tk) gene is only partially impaired by treatment with ganciclovir (GCV). The effect of GCV is even less evident when C6 and VPC are co-implanted into the rat brain. Furthermore, tumors from C6 cells carrying the HSV-tk gene are not eradicated by GCV, although they remain sensitive to GCV when replated in vitro. These limits of the HSV-tk/GCV system in glioma gene therapy may be due to insufficient gene transfer and/or insufficient delivery of GCV to glioma cells. Combination of HSV-tk and one or more cytokines may improve the antitumor efficacy. Among cytokines, interleukin-4 (IL-4) has already been shown to be active against gliomas. In nude mice, GCV treatment inhibited tumor growth more effectively after co-injection of C6 cells with a mixture of VPC transducing IL-4 and HSV-tk genes than after co-injection with either IL-4 or HSV-tk VPC only. In immunocompetent Sprague-Dawley rats, co-injection of IL-4 VPC and C6 cells was also effective in inhibiting the growth of C6 brain tumors, 38% of the animals surviving for at least 2 months. Furthermore, increased and prolonged antitumor efficacy was obtained by transducing both IL-4 and HSV-tk genes.
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U2 - 10.1089/hum.1997.8.11-1345
DO - 10.1089/hum.1997.8.11-1345
M3 - Article
C2 - 9295129
AN - SCOPUS:16944361879
VL - 8
SP - 1345
EP - 1353
JO - Human Gene Therapy
JF - Human Gene Therapy
SN - 1043-0342
IS - 11
ER -