Adenovirus-mediated p53 gene transfer suppresses growth of human glioblastoma cells in vitro and in vivo.
Alterations in the p53 tumor-suppressor gene occur in 35-60% of human glioblastomas, and re-introduction of p53 can suppress neoplastic growth. To evaluate the potential for p53 gene therapy of glioblastoma, we have analyzed the response of human glioblastoma cell lines in vitro and in vivo to experimental therapy with replication-deficient recombinant adenoviruses encoding wild-type p53 (rAd-p53). Western blot analyses showed high-level expression of p53 protein after treatment with rAd-p53, and transgene expression was dependent on promoter strength. A p53-specific dose-dependent inhibition of in vitro cellular proliferation was observed in 5 of 6 cell lines, and growth inhibition corresponded to adenovirus-mediated gene transfer and expression. p53-specific cell death was quantitated by release of the lactate dehydrogenase enzyme. Fragmentation of DNA into nucleosomal oligomers and the occurrence of a hypodiploid cell population detected by flow cytometry provided evidence for apoptosis. Studies in nude mice demonstrated that ex vivo infection with rAd-p53 suppressed the tumorigenic potential of human glioblastoma cells. Furthermore, direct injection of rAd-p53 into established s.c. xenografts inhibited tumor growth. Our observations suggest that re-introduction of wild-type p53 may have potential clinical utility for gene therapy of glioblastoma.
Köck
H
H
Department of Neurological Surgery, University Hospital Eppendorf, Hamburg, Germany.
Harris
M P
MP
Anderson
S C
SC
Machemer
T
T
Hancock
W
W
Sutjipto
S
S
Wills
K N
KN
Gregory
R J
RJ
Shepard
H M
HM
Westphal
M
M
Maneval
D C
DC
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002455:Cell Division / Q000235:genetics; D018014:Gene Transfer Techniques; D016158:Genes, p53 / Q000235:genetics*; D015316:Genetic Therapy; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051381:Rats; D014407:Tumor Cells, Cultured
D007770:L-Lactate Dehydrogenase