Document Detail

Inhibition of thymidylate synthase activity by antisense oligodeoxynucleotide and possible role in thymineless treatment.
MedLine Citation:
PMID:  11502877     Owner:  NLM     Status:  MEDLINE    
Thymidylate synthase (TS) is an important target for chemotherapeutic treatment of cancer. However, efficacy of TS-targeted anticancer drugs is limited by the development of drug resistance as a result of TS gene amplification. In this work, a phosphorothioated antisense oligonucleotide (ODN), designated ATS-2, was used to suppress cellular synthesis of TS. ATS-2 at 0.2 microM concentration was mixed with lipofectin in a charge ratio of 1:1 and was used to treat the human embryonic kidney (HEK) cell line. A reduction of TS mRNA and protein was achieved. Furthermore, a dose-dependent reduction of cumulative viable cells of up to 98% was observed. Flow cytometer analysis of cell cycle progression indicates that ATS-2-treated cells were arrested and went into apoptosis at the S phase, possibly because of thymidine shortage, suggesting that ATS-2 is specifically effective for dividing cells. When used in combination with the anticancer drug FdUrd, ATS-2 exerted a additive inhibitory effect on cellular proliferation. To elucidate the possible role of cellular thymidine kinase (TdR kinase) in ATS-2 treatment, a second cell line, HeLa, was used. Both HEK and HeLa have similar rates of cell division and ODN uptake. In contrast to HEK, which was shown to have very low levels of TdR kinase activity in [(3)H]thymidine incorporation experiments, [(3)H]thymidine incorporation in HeLa was 15-fold greater than that of HEK. We found that HeLa cells were sensitive to FdUrd but were rather resistant to ATS-2. On the contrary, HEK cells were sensitive to ATS-2 but insensitive to FdUrd. Effects of ATS-2 and FdUrd are, therefore, complementary in thymineless treatment too.
S B Lin; P O Ts'o; S K Sun; K B Choo; F Y Yang; Y P Lim; H L Tsai; L C Au
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Molecular pharmacology     Volume:  60     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2001 Sep 
Date Detail:
Created Date:  2001-08-14     Completed Date:  2001-09-06     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  474-9     Citation Subset:  IM    
School of Medical Technology, National Taiwan University, Taipei, Taiwan, Republic of China.
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MeSH Terms
Antimetabolites, Antineoplastic / pharmacology
Biological Transport / drug effects
Cell Division / drug effects
Cell Survival / drug effects
Cells, Cultured
Drug Carriers
Drug Interactions
Floxuridine / pharmacology
Hela Cells
Oligodeoxyribonucleotides, Antisense / pharmacology*
RNA, Messenger / drug effects,  metabolism
S Phase / drug effects*
Thymidylate Synthase / antagonists & inhibitors*,  genetics
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/Drug Carriers; 0/Oligodeoxyribonucleotides, Antisense; 0/Phosphatidylethanolamines; 0/RNA, Messenger; 50-91-9/Floxuridine; 76391-83-8/1,2-dielaidoylphosphatidylethanolamine; EC Synthase

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