title: Evaluation of combination gene therapy with PTEN and antisense hTERT for malignant glioma in vitro and xenografts.
abstract: Telomerase activation is a critical event in cell immortalization, and an increase in human telomerase reverse transcriptase (hTERT) expression is the key step in activating telomerase. The phosphatase and tensin homolog (PTEN) gene encodes a double-specific phosphatase that induces cell cycle arrest, inhibits cell growth, and causes apoptotic cell death. Here, we evaluated a combined PTEN and antisense hTERT gene therapy for experimental glioma in vitro and in vivo. We demonstrated that infection with antisense-hTERT and wild-type-PTEN adenoviruses significantly inhibited human U251 glioma cell proliferation in vitro and glioma growth in a xenograft mouse model. The efficacy of therapy was obviously higher in the tumor xenografts infected with both PTEN and antisense hTERT than in the gliomas infected with either agent alone at the same total viral dose. Consistent with these results, we showed that telomerase activity and hTERT protein levels were markedly reduced in the glioma cells following adenovirus infection. In contrast, the levels of PTEN protein expression were dramatically increased in these cells. Our data indicate that combination treatment with antisense hTERT and wild-type PTEN effectively suppresses the malignant growth of human glioma cells in vitro and in tumor xenografts, suggesting a promising new approach in glioma gene therapy that warrants further investigation.
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, P. R. China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: You
authors.forename: Xiaozeng
authors.initials: X
authors.lastname: Geng
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Zhen
authors.initials: Z
authors.lastname: Fu
authors.forename: Cunzu
authors.initials: C
authors.lastname: Wang
authors.forename: Shengwu
authors.initials: S
authors.lastname: Chao
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.forename: Ailing
authors.initials: A
authors.lastname: Lu
authors.forename: Kevin
authors.initials: K
authors.lastname: Gardner
authors.forename: Peiyu
authors.initials: P
authors.lastname: Pu
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Kong
authors.forename: Yun
authors.initials: Y
authors.lastname: Ge
authors.forename: Susan I V
authors.initials: SI
authors.lastname: Judge
authors.forename: Qingdi Q
authors.initials: QQ
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D016373:DNA, Antisense / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000627:therapeutic use*; D019098:Telomerase / Q000235:genetics* / Q000627:therapeutic use; D014183:Transplantation, Heterologous
chemical_list: D016373:DNA, Antisense; C509186:TERT protein, human; D019098:Telomerase; D051059:PTEN Phosphohydrolase