Application of p27 gene therapy for human malignant glioma potentiated by using mutant p27.
OBJECTIVE
Malignant glioma could be an ideal candidate for local gene therapy because its invasion is local and it has little metastatic potential. A low expression level and high degradation activity of p27 are known to constitute an independent poor prognostic factor in patients with malignant glioma. In this study, the authors investigated the roles of wild-type p27 and mutant p27 on the treatment of malignant glioma.


METHODS
The authors used two adenoviruses: one expressed wild-type p27 (ad-p27wt) and the other, containing a mutation at the major metabolic site, expressed mutant p27 (ad-p27mt). The antitumor effects of the two adenoviruses were compared with respect to cell growth arrest, cell cycle alteration, apoptosis induction, and in vitro tumorigenicity in three glioblastoma mutiforme (GBM) cell lines and in a primary GBM cell line. Transduction with ad-p27wt or ad-p27mt induced the production of p27 and the dephosphorylation of pRB. The protein level of mutant p27 was significantly higher than that of wild-type p27. The ad-p27wt induced cell cycle arrest at the G1-S transition point, whereas the ad-p27mt induced arrest at the G2-M point. Both ad-p27wt and ad-p27mt induced a growth-inhibiting effect, apoptosis, and suppression of in vitro tumorigenicity; however, ad-p27mt displayed a stronger antitumor effect than ad-p27wt in brain tumor cell lines.


CONCLUSIONS
Gene therapy involving p27, especially mutant p27, has the potential to become a novel and powerful therapy for malignant glioma.
Park
Kyung-Ho
KH
Department of Internal Medicine, Lung Institute of Medical Research Center, Seoul National University College of Medicine and Clinical Research Institute, Seoul National University Hospital, Seoul, Korea.
Lee
Jaeho
J
Yoo
Chul-Gyu
CG
Kim
Young Whan
YW
Han
Sung Koo
SK
Shim
Young-Soo
YS
Kim
Seung-Ki
SK
Wang
Kyu-Chang
KC
Cho
Byung-Kyu
BK
Lee
Choon-Taek
CT
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor / Q000502:physiology; D015316:Genetic Therapy; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D016297:Mutagenesis, Site-Directed; D013912:Threonine / Q000235:genetics; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured / Q000378:metabolism* / Q000473:pathology; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D018797:Cell Cycle Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013912:Threonine