Document Detail

Attenuation of WAF1/Cip1 expression by an antisense adenovirus expression vector sensitizes glioblastoma cells to apoptosis induced by chemotherapeutic agents 1,3-bis(2-chloroethyl)-1-nitrosourea and cisplatin.
MedLine Citation:
PMID:  9918219     Owner:  NLM     Status:  MEDLINE    
Previous studies have shown that the negative cell cycle regulator WAF1/Cip1 is often overexpressed in human gliomas and that WAF1/Cip1 overexpression renders glioma cells resistant to chemotherapy agents. In this study, we investigated whether down-regulation of WAF1/Cip1 would sensitize gliomas to chemotherapy. An adenoviral vector expressing antisense WAF1/Cip1 was constructed and used to infect D54 glioma cells, which express a high level of endogenous WAF1/Cip1. After D54 cells were infected with antisense WAF1/Cip1 adenovirus, Western blotting revealed a significant decrease in the WAF1/Cip1 protein level. Down-regulation of WAF1/Cip1 alone resulted in the cells rounding up and detaching from plates. Electron microscopy revealed some nuclear fragmentation in antisense WAF1/Cip1-infected cells, indicating the initiation of apoptosis. The antisense WAF1/Cip1-infected cells were then treated with the chemotherapeutic agents 1,3-bis(2-chloroethyl)-1-nitrosourea and cisplatin. Other cells were infected with sense WAF1/Cip1 adenovirus or control virus and served as controls. Trypan blue exclusion assay revealed significant cell death in antisense WAF1/Cip1-infected cells. In situ end-labeling assay by flow cytometry revealed that many cells died of apoptosis. Our results show that the attenuation of WAF1/Cip1 expression initiated glioma cell death and sensitized glioma cells to apoptosis induced by 1,3-bis(2-chloroethyl)-1-nitrosourea and cisplatin. Thus, blocking WAF1/Cip1 production may serve as a useful chemosensitization regimen for treating glioma.
S Ruan; M F Okcu; R C Pong; M Andreeff; V Levin; J T Hsieh; W Zhang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  5     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  1999 Jan 
Date Detail:
Created Date:  1999-03-24     Completed Date:  1999-03-24     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  197-202     Citation Subset:  IM    
Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
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MeSH Terms
Adenoviridae / genetics
Antineoplastic Agents / pharmacology*
Antineoplastic Agents, Alkylating / pharmacology*
Apoptosis / drug effects,  genetics*
Carmustine / pharmacology*
Cisplatin / pharmacology*
Cyclin-Dependent Kinase Inhibitor p21
Cyclins / biosynthesis*,  genetics
DNA, Complementary / genetics
Down-Regulation / drug effects,  genetics
Genetic Vectors
Glioblastoma / drug therapy*,  metabolism,  pathology
Oligodeoxyribonucleotides, Antisense / pharmacology*
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents; 0/Antineoplastic Agents, Alkylating; 0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/DNA, Complementary; 0/Oligodeoxyribonucleotides, Antisense; 154-93-8/Carmustine; 15663-27-1/Cisplatin

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