Prolonged survival of rats with intracranial C6 gliomas by treatment with TGF-beta antisense gene.
Using an intracranial rat C6 glioma model, we tested the hypothesis that gene modification of glioma cells to block the expression of the immunosuppressive cytokine TGF-beta (transforming growth factor beta) may enhance anti-tumor immune responses and thereby prolong survival of tumor-bearing animals. The cDNA for simian TGF-beta 2 was ligated in antisense orientation into the episomal plasmid mammalian expression vector pCEP-4. This TGF-beta-antisense vector was transfected into C6 glioma cells by standard electroporation techniques. PCR was used to determine that the rat C6 clones were successfully transfected with the antisense-TGF beta construct. Twenty-nine adult female Wistar rats harboring 7-day-old intracranial C6 tumors were then subcutaneously injected with either saline (n = 9), unmodified C6 glioma cells (n = 10), or TGF-beta-antisense-modified C6 cells (n = 10). Animals were followed for survival, and Fisher's exact method was used to interpret the significance of difference between experimental groups. The survival of tumor-bearing rats injected with TGF-beta-antisense-modified C6 cells was significantly prolonged, relative to the survival of rats receiving injections of saline or unmodified C6 cells alone. Six of the ten (60%) TGF-beta-antisense treated animals survived for 12 weeks, whereas none of the nine (0%) animals treated with saline and none of ten (0%) of those treated with C6 cells alone survived past 5 weeks. These results indicate that the genetic inhibition of immunosuppressive cytokines (such as TGF-beta) may reverse the phenotypic immunosuppression caused by such factors, and thereby prolong the survival of C6 tumor-bearing animals. Future investigations using cytokine gene modifications in other brain tumor models are warranted.
Liau
L M
LM
Division of Neurosurgery, UCLA School of Medicine 90095, USA.
Fakhrai
H
H
Black
K L
KL
D000818:Animals; D016375:Antisense Elements (Genetics); D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy; D005910:Glioma / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D009336:Necrosis; D010641:Phenotype; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000276:immunology; D016896:Treatment Outcome
D016375:Antisense Elements (Genetics); D016212:Transforming Growth Factor beta