Glioma cells transduced with selection transgenes may not form gliomas in vivo and can also inhibit glioma formation by admixed wild glioma cell lines.
Following in vitro lipofection transfection of the rat glioma cell line A15A5 with the plasmid transgene CMV/HyTK, which confirms hygromycin resistance and ganciclovir sensitivity, a series of experiments was planned in which the "bystander" phenomenon would be evaluated using the rodent implantation glioma model. However examination of the brain of rodents in which the A15A5HyTK cells were implanted showed no evidence of glioma growth. Furthermore, rodents having intracerebral implantation of (i) wild A15A5 and A15A5HyTK cells in a 50/50 mix, (ii) wild A15A5 and A15A5HyTK cells in a 90/10 mixture and (iii) wild C6 and A15A5HyTK cells in a 50/50 mix all failed to grow macroscopic tumours by 15-17 days irrespective of whether the animals had been administered ganciclovir (GCV) in the week before sacrifice. Neuropathological and immunocytochemical analysis of the implantation sites showed no difference between the GCV and saline treated groups of animals for any implantation cell mix. These observations confirm previous results that suggest transduction of malignant rodent glioma cell lines with a variety of selection, oncogenic and marker genes significantly impairs their in vivo tumorigenic potential compared to the wild type cell lines. This study also demonstrates that even without GCV treatment the transduced cells inhibit, by an unknown mechanism(s), the tumorigenicity of other non transfected malignant cells. The implications of this study for gene therapy of human malignant glioma are discussed.
Whittle
I R
IR
Department of Clinical Neurosciences, Western General Hospital, Edinburgh, Scotland, UK.
Kimber
W L
WL
Li
M
M
Bell
H S
HS
Ironside
J W
JW
D000818:Animals; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D002470:Cell Survival / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D003587:Cytomegalovirus / Q000235:genetics; D015774:Ganciclovir / Q000494:pharmacology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005910:Glioma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D009368:Neoplasm Transplantation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013937:Thymidine Kinase / Q000235:genetics; D014161:Transduction, Genetic / Q000235:genetics*; D019076:Transgenes / Q000235:genetics*; D014407:Tumor Cells, Cultured
D017853:Phosphotransferases (Alcohol Group Acceptor); C063242:hygromycin-B kinase; D013937:Thymidine Kinase; D015774:Ganciclovir