Document Detail


Isolation and characterization of a deoxycytidine kinase-deficient human promyelocytic leukemic cell line highly resistant to 1-beta-D- arabinofuranosylcytosine.
MedLine Citation:
PMID:  6091869     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A deoxycytidine kinase-deficient variant of a human promyelocytic leukemic cell line (HL-60/ara-C) has been isolated and characterized. These cells are capable of proliferating in the presence of 10(-6) M 1-beta-D-arabinofuranosylcytosine (ara-C), a level achieved in the plasma of leukemic patients undergoing conventional-dose ara-C therapy. The cells share numerous biological and biochemical features with the parent line, including: morphology; rate of growth; cloning characteristics; karyotype; rates of DNA, RNA, and protein synthesis; and ability to undergo terminal differentiation in the presence of agents such as 12-O-tetradecanoylphorbol acetate and dimethyl sulfoxide. In contrast, these cells display a great reduction in the total intracellular accumulation of ara-C following a 4-hr exposure to 10(-6) M ara-C (2.4 versus 99.0 pmol ara-C/10(6) cells). Resistant cells exposed to 10(-6) M ara-C for 1 hr also exhibited a reduction in the generation [1.2 versus 31.9 pmol 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP)/10(6) cells] and the 4-hr retention (0.30 versus 3.87 pmol ara-CTP/10(6) cells) of ara-CTP, the lethal ara-C metabolite, in comparison to parent cells. Incorporation of ara-C into resistant HL-60 cell DNA was also profoundly decreased. These biochemical alterations were associated with a 1000-fold decrease in the sensitivity of clonogenic cells to continuously administered ara-C (ara-C 50% inhibitory concentration: 1.8 X 10(-6) M for HL-60/ara-C; 3.0 X 10(-9) M for HL-60). A variety of antagonists of de novo pyrimidine synthesis inhibited the growth of ara-C-sensitive and -resistant cells to a similar extent. When HL-60 cells were exposed to a lethal concentration of thymidine (5 X 10(-3) M), coadministration of 5 X 10(-6) M deoxycytidine restored 90 +/- 4% (S.D.) of colony-forming capacity. Normal human bone marrow progenitor cells were protected to a similar degree by 3 X 10(-3) M deoxycytidine. In contrast, deoxycytidine concentrations as high as 5 X 10(-3) M were unable to confer any protection to HL-60/ara-C cells under identical conditions. These studies suggest that an enzymatic perturbation rendering human leukemic cells highly resistant to ara-C may be exploited to achieve a selective in vitro chemotherapeutic effect.
Authors:
K Bhalla; R Nayak; S Grant
Related Documents :
4084239 - Amino acid content of l5178y and l5178y/l-ase cells after l-asparaginase treatment.
2454689 - Leukemic cell maturation: phenotypic variability and oncogene expression in hl60 cells:...
17460729 - Nox1 induces differentiation resistance in immortalized human keratinocytes generating ...
1356339 - Overexpression of p-glycoprotein and alterations in topoisomerase ii in p388 mouse leuk...
16356169 - Lack of ceramide generation and altered sphingolipid composition are associated with dr...
7870049 - A human t lymphoid cell variant resistant to the acyclic nucleoside phosphonate 9-(2-ph...
10455409 - Increase of bcnu sensitivity by wt-p53 gene therapy in glioblastoma lines depends on th...
8041899 - Radiation dose heterogeneity in receptor and antigen mediated boron neutron capture the...
20597429 - Phase variation in flavobacterium psychrophilum: characterization of two distinct colon...
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  44     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  1984 Nov 
Date Detail:
Created Date:  1984-11-28     Completed Date:  1984-11-28     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  5029-37     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Cell Division / drug effects
Cell Line
Cytarabine / metabolism,  toxicity*
Cytidine Deaminase / metabolism
Deoxycytidine Kinase / deficiency*,  metabolism
Drug Resistance
Humans
Kinetics
Leukemia, Myeloid, Acute / enzymology*
Mutation*
Phosphotransferases / deficiency*
Pyrimidines / pharmacology
Thymidine Kinase / metabolism
Grant Support
ID/Acronym/Agency:
CA-13696-13/CA/NCI NIH HHS; CA-36501-01/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Pyrimidines; 147-94-4/Cytarabine; EC 2.7.-/Phosphotransferases; EC 2.7.1.21/Thymidine Kinase; EC 2.7.1.74/Deoxycytidine Kinase; EC 3.5.4.5/Cytidine Deaminase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Correlation of asbestos-induced cytogenetic effects with cell transformation of Syrian hamster embry...
Next Document:  Detection of a unique antigen on radiation leukemia virus-induced leukemia B6RV2.