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.
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.
Benedetti
S
S
Istituto Nazionale Neurologico C. Besta, Department of Biochemistry and Genetics, Milano, Italy.
Dimeco
F
F
Pollo
B
B
Cirenei
N
N
Colombo
B M
BM
Bruzzone
M G
MG
Cattaneo
E
E
Vescovi
A
A
Didonato
S
S
Colombo
M P
MP
Finocchiaro
G
G
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D005910:Glioma / Q000628:therapy*; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D017207:Rats, Sprague-Dawley; D012190:Retroviridae / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics*; D014161:Transduction, Genetic; D014764:Viral Proteins / Q000235:genetics*
D000963:Antimetabolites; D014764:Viral Proteins; D015847:Interleukin-4; D013937:Thymidine Kinase; D015774:Ganciclovir