Document Detail

Acquired resistance to 6-thioguanine in melanoma cells involves the repair enzyme O6-methylguanine-DNA methyltransferase (MGMT).
MedLine Citation:
PMID:  19946217     Owner:  NLM     Status:  MEDLINE    
O(6)-methylguanine-DNA methyltransferase (MGMT), is a DNA repair enzyme that recognizes O(6)-alkylated guanine, a base analog resulting from treatment with alkylating agents. O(6)-6-thioguanine (6-TG) is used clinically to treat malignant as well as inflammatory diseases. Although MGMT participates in resistance to alkylating agents, it has not been shown to be involved in resistance of tumors to 6-TG. In this study we used a human melanoma cell line (GA) and its selected 6-TG drug resistant variant (GA-6-TG) to investigate whether MGMT plays a role in determining the drug resistant phenotype of GA-6-TG cells. We showed that GA-6-TG resistant cells express about three fold more MGMT protein and mRNA than GA cells. Treatment with 6-TG diminishes significantly MGMT amounts in both cell lines. Increased amounts of MGMT in resistant cells, are consistent with hypermethylation of the MGMT gene coding-region. Pretreatment of cells with the MGMT inhibitor O6 benzyl guanine, resulted in sensitization of GA-6-TG cells to 6-TG. Taken together, our data suggests that MGMT is associated with 6-TG drug resistance. In analogy to patients treated with alkylating agents, patients with tumors containing increased MGMT amounts, may be more resistant to 6-TG and therefore may benefit from treatment with MGMT inhibitors.
Nir Gefen; Gordana Brkic; Dalia Galron; Esther Priel; Janet Ozer; Daniel Benharroch; Jacob Gopas
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-01-09
Journal Detail:
Title:  Cancer biology & therapy     Volume:  9     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-02-18     Completed Date:  2010-06-15     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  49-55     Citation Subset:  IM    
Dept. of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University, Beer Sheva, Israel.
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MeSH Terms
Antineoplastic Agents, Alkylating / therapeutic use
Cell Line, Tumor
DNA Methylation*
Dose-Response Relationship, Drug
Guanine / analogs & derivatives,  therapeutic use
Melanoma / genetics*
O(6)-Methylguanine-DNA Methyltransferase / metabolism*
Thioguanine / pharmacology*
Reg. No./Substance:
0/Antineoplastic Agents, Alkylating; 154-42-7/Thioguanine; 20535-83-5/O-(6)-methylguanine; 73-40-5/Guanine; EC Methyltransferase

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

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