Gene Set: BACOLOD_RESISTANCE_TO_ALKYLATING_AGENTS_DN

Standard name BACOLOD_RESISTANCE_TO_ALKYLATING_AGENTS_DN
Systematic name M12518
Brief description Genes down-regulated in D-341 MED (OBR) cells (medulloblastoma) resistant to both carmustine and O6-BG [PubChem=2578;4578].
Full description or abstract Medulloblastoma (D-341 MED) and rhabdomyosarcoma (TE-671) cell lines, which are resistant to either 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or the combination of BCNU and O6-benzylguanine (O6-BG), were generated by serial escalation of BCNU. The activities of O6-alkylguanine-DNA alkyltransferase (AGT), glutathione-S-transferase (GST), and total glutathione (GSH) of the parental, BCNU-resistant (BR), and BCNU + O6-BG-resistant (OBR) cells were measured. No significant differences in GST activity or total GSH were seen between the parental, BR, and OBR cells of both TE-671 and D-341 MED. The AGT activities of D-341 MED (BR) and TE-671 (BR) were twice those of D-341 MED and TE-671, respectively, confirming the importance of this enzyme for BCNU resistance. The D-341 MED (OBR) cells did not exhibit any AGT activity, suggesting that another mechanism must play a role in the drug resistance. Fewer DNA interstrand cross-links (ICLs) were observed in D-341 MED (OBR) than in D-341 MED after 8 h BCNU (100-400 microM) treatment. However, the amounts of DNA ICLs observed in D-341 MED and D-341 MED (OBR) were stable after 24 h. Microarray analysis showed the increased expressions of several metallothionein genes and down-regulation of several proapoptotic genes. The AGT activity of TE-671 (OBR) was 223 fmol/mg when the cells were grown in 10 microM O6-BG and decreased to about half this value when the O6-BG concentration was increased 60 microM. The AGT cDNA of TE-671 (OBR) cells was cloned and found to contain a G-to-T transversion at codon 156, resulting in conversion of glycine to cysteine (G156C). In vitro mutagenesis has shown that the G156C AGT mutant is resistant to inactivation by O6-BG. Thus, the selection of a mutant AGT with decreased sensitivity to O6-BG is a significant contributing factor to BCNU + O6-BG resistance.
Collection C2: curated gene sets
      CGP: chemical and genetic perturbations
Source publication Pubmed 12479369   Authors: Bacolod MD,Johnson SP,Ali-Osman F,Modrich P,Bullock NS,Colvin OM,Bigner DD,Friedman HS
Exact source Table 1: signal ratio =< 0.3
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Organism Homo sapiens
Contributed by John Newman (University of Washington)
Source platform HUMAN_SEQ_ACCESSION
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Version history 3.0: Renamed from O6BG_RESIST_MEDULLOBLASTOMA_DN

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