Document Detail

Antisense candidates against protein kinase C-alpha designed based on phylogenesis and simulant structure of mRNA.
MedLine Citation:
PMID:  12617778     Owner:  NLM     Status:  MEDLINE    
AIM: To optimize the antisense drug design by the combined method of phylogenetic analysis and secondary structure prediction and to get ideal candidates.
METHODS: The phylogenetic analysis and the secondary structure simulation were performed by computer. Oligodeoxynucleotides (ODN) were designed against the full-conserved blocks with low local reaction free energy of protein kinase C (PKC)-alpha mRNA. The in vitro effects of ODN were evaluated by human A549 lung carcinoma cells and mouse B16-BL6 melanoma cells, the expression of target mRNA was detected by in situ hybridization and RT-PCR. The in vivo effects of ODN were also evaluated by models of A549 xenografts in nude mice and B16 melanoma in mice.
RESULTS: Three ODN had significantly lower IC50 values than that of ISIS3521, the positive control, on A549 cells in vitro. Five ODN inhibited the growth of B16-BL6 cells with IC50 <100 nmol/L, while IC50 of ISIS3521 was >200 nmol/L. In situ hybridization and RT-PCR showed that the best candidate AP1261 inhibited the expression of PKC-alpha at mRNA level in a dose-dependent manner. AP1261 inhibited the growth of A549 and B16 tumors in vivo at 0.005-0.5 The inhibitory rate of AP1261 on A549 tumors was greater than that of ISIS3521 at the same dose. ISIS3521 did not affect the growth of B16 tumors.
CONCLUSION: AP1261 may be of value as an antitumor agent or adjuvant and the combined method of phylogenetic analysis and secondary structure prediction is a potential helpful tool for antisense drug design.
Hai-Feng Song; Zhong-Ming Tang; Shou-Jun Yuan; Bao-Zhen Zhu; Xiu-Wen Liu
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Acta pharmacologica Sinica     Volume:  24     ISSN:  1671-4083     ISO Abbreviation:  Acta Pharmacol. Sin.     Publication Date:  2003 Mar 
Date Detail:
Created Date:  2003-03-05     Completed Date:  2004-12-14     Revised Date:  2012-06-25    
Medline Journal Info:
Nlm Unique ID:  100956087     Medline TA:  Acta Pharmacol Sin     Country:  China    
Other Details:
Languages:  eng     Pagination:  269-76     Citation Subset:  IM    
Department of Pharmacology and Toxicology, Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing 100850, China.
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MeSH Terms
Adenocarcinoma / metabolism,  pathology
Antineoplastic Agents / chemical synthesis,  pharmacology
Cell Division / drug effects
Cell Line, Tumor
Computer-Aided Design
Drug Design*
Isoenzymes / chemistry,  pharmacology
Lung Neoplasms / metabolism,  pathology
Melanoma, Experimental / pathology
Mice, Nude
Neoplasm Transplantation
Oligodeoxyribonucleotides, Antisense / chemical synthesis*,  pharmacology
Protein Kinase C / biosynthesis*,  chemistry,  genetics
Protein Kinase C-alpha
Protein Structure, Secondary
RNA, Messenger / biosynthesis,  genetics
Reg. No./Substance:
0/Antineoplastic Agents; 0/Isoenzymes; 0/Oligodeoxyribonucleotides, Antisense; 0/RNA, Messenger; EC protein, human; EC protein, mouse; EC Kinase C; EC Kinase C-alpha

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