Document Detail


Biochemical pharmacology and DNA methylation studies of arabinosyl 5-azacytidine and 5,6-dihydro-5-azacytidine in two human leukemia cell lines PER-145 and PER-163.
MedLine Citation:
PMID:  7540895     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
1-beta-D-arabinofuranosyl-5-azacytosine (ara-AC) and 5,6-dihydro-5-azacytidine (DHAC) are two new antitumor agents under clinical investigations, which exhibit the chemical similarities found in the tumoricidal drug cytosine arabinoside (ara-C) and the nitrogen substitution in the 5 position of the pyrimidine ring found in 5-azacytidine (5-aza-C). The cellular anabolism of ara-AC and DHAC and their effect on DNA methylation have been examined in two new human leukemia cell lines, which are sensitive (PER-145) and resistant (PER-163) to ara-C. The triphos-phate anabolite of ara-AC, ara-ACTP, was the major cellular anabolite in the cellular extracts of the PER-145 cells, reaching a cellular saturation concentration of 64.1 +/- 3.2 microM using 25 microM of the drug. Only trace levels of ara-ACTP were detected in the PER-163 cell line, which lacks deoxycytidine kinase, after exposure to a similar concentration. Notably, after 1 mM, the ara-ACTP concentration averaged 12 +/- 3 microM. DHAC was anabolized by both cell lines to a similar degree but required much higher nucleoside concentrations (100 microM or higher) to achieve similar cellular concentrations of its triphosphate, DHACTP. Although the deoxy-derivative, DHAdCTP, was detected in both cell lines, it was detected at 1-2 log10 lower concentrations than DHACTP. DNA methylation studies showed that DHAC had a profound effect in inducing DNA hypomethylation in both cell lines, with nadir values of 27.3 and 29.2% of control.(ABSTRACT TRUNCATED AT 250 WORDS)
Authors:
U R Kees; V I Avramis
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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:  Anti-cancer drugs     Volume:  6     ISSN:  0959-4973     ISO Abbreviation:  Anticancer Drugs     Publication Date:  1995 Apr 
Date Detail:
Created Date:  1995-08-03     Completed Date:  1995-08-03     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9100823     Medline TA:  Anticancer Drugs     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  303-10     Citation Subset:  IM    
Affiliation:
Institute for Child Health Research, c/o Princess Margaret Hospital, West Perth, Australia.
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MeSH Terms
Descriptor/Qualifier:
Antimetabolites, Antineoplastic / pharmacology*
Antineoplastic Agents / pharmacology*
Azacitidine / analogs & derivatives*,  metabolism,  pharmacology*
DNA / metabolism*
Humans
Leukemia / drug therapy*,  pathology
Methylation
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
CA 38905/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/Antineoplastic Agents; 320-67-2/Azacitidine; 62488-57-7/5,6-dihydro-5-azacytidine; 65886-71-7/fazarabine; 9007-49-2/DNA

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