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United States: American Society for Pharmacology and Experimental Therapeutics
Erscheinungsjahr
1996
Link zum Volltext
Quelle
Free E-Journal (出版社公開部分のみ)
Beschreibungen/Notizen
The steady state expression of glutathione S-transferases (GSTs) at both the protein and mRNA level is reported for the 60
tumor cell lines that are used for the National Cancer Institute Drug Screening Program. Individual GST isozymes were separated,
identified, and quantified (with reverse-phase calibration curves) through a novel high performance liquid chromatographic
procedure. GSTP1 was the predominant isozyme and was found at quantifiable levels in all but two of the cell lines. This isozyme
ranged from 0.03% to 2.7% of the total cytosolic protein. For the mu family, 90% of the lines had GSTM2, 68% had GSTM3, but
only 28% were positive for the M1 phenotype. The M1 proportion is lower than would be expected from the standard M1 null phenotype
for human populations. Isozymes of the alpha family were detected only at very low levels in 35% of the lines. Significant
quantitative correlations among enzyme activity, total enzyme protein, and mRNA were shown for GSTP1. However, such relationships
were not apparent for the mu or alpha families. Levels of glutathione (GSH), and the transcript levels of other enzymes involved
in GSH homeostasis were determined. gamma-Glutamyl cysteine synthetase (gamma-GCS) was present in all cell lines, but did
not correlate with levels of intracellular GSH. Glyoxalase-I and gamma-glutamyl transpeptidase, both involved in GSH salvage,
were found in 100% and 70% of the cell lines, respectively. Using a pattern-matching computer program, COMPARE, we compared
and correlated the arrays of mRNA and protein levels with the pattern of chemosensitivity or chemoresistance of the 60 cell
lines with 175 agents constituting a standard agent database. This database is composed of compounds to which a putative mechanism
of action has been assigned. Although Pearson correlation coefficients relating the target and drug patterns were generally
modest, when the patterns for the enzyme protein and mRNA levels for GST pi were correlated to drug sensitivity patterns,
the list of 30 agents most closely matching (for which P < 0.05) was enriched with alkylating agents. gamma-GCS also showed
an enrichment of alkylating agents in the COMPARE correlations, indicating that high levels of gamma-GCS may be an important
determinant of resistance. In contrast, none of the other enzymes or GSH had patterns of expression that resulted in an obvious
correlation to the sensitivity or resistance of alkylating agents.