Abstract
Adriamycin-resistant (AdrR) human breast cancer cells have been selected which exhibit cross-resistance to a wide range of anti-cancer drugs. This multidrug-resistant phenotype is associated with increases in the activities of glutathione peroxidase and glutathione transferase. The 45-fold increase in glutathione transferase activity is associated with the appearance of a new anionic isozyme in AdrR cells which is immunologically related to the anionic glutathione transferase present in human placenta. The increase in transferase and the level of drug resistance is relatively stable during passage of AdrR cells in the absence of adriamycin for over 10 months. A similar anionic glutathione transferase isozyme is also found in rat hyperplastic liver nodules, a preneoplastic state resulting from exposure to carcinogens. A rat cDNA which codes for the anionic glutathione transferase in rat hyperplastic nodules hybridizes to a 1.1-kilobase pair mRNA which is overexpressed in the AdrR MCF-7 cells. The anionic transferase has been purified from the AdrR cells and found to have characteristics which distinguish it from other anionic human glutathione transferases, including high levels of intrinsic peroxidase activity. The overexpression of a similar anionic glutathione transferase in human breast cancer cells selected for multidrug resistance and in rat hyperplastic liver nodules, which develop resistance to various hepatotoxins, suggests a possible role for this drug-conjugating enzyme in the mechanism of resistance in both of these states.
Highlights
Adriamycin-resistant(AdrR)humanbreastcancer accumulation, suggests that other mechanismsbesides altercells have been selected which exhibit cross-resistance ationsindrugaccumulation mayalso be involved inthe to a wide range of anti-cancer drugs
Tic liver nodules, a preneoplastic state resulting from Organicperoxidase is an activity that can be associated exposure to carcinogens.A rat cDNA which codes for with the enzyme glutathione transferase, an enzyme that is the anionic glutathione transferase in rat hyperplastpicrimarily noted for its ability todetoxify substances through nodules hybridizes toa 1.1-kilobase pair mRNA which conjugation withglutathione.We have thereforeexamined is overexpressed in the AdrMRCF-7 cells
We show that transferase hasbeen purified from the AdrRcells and resistance in the AdrR MCF-7 cells is associated with a 45
Summary
Isoelectric points have been identified in human placenta, erythrocytes, and lung [25,33,34].Immunoprecipitation studies were performed to compare the enzyme found in the AdrR MCF-7 cells toother transferases. Antibodies prepared against the anionic glutathione transferase from AdrR cells cross-reacts withthe enzyme present in humanplacenta (Fig. 3B). There is essentially no crossreactivity of the enzyme in the AdrR MCF-7 cells with antibodies prepared against abasic isozyme purified from human liver (Fig. 3A). We have purified the anionic glutathione transferase from the AdrR MCF-7 cells using standard techniques [22] This enzyme, which was purified over 400-fold, has a molecular weight of 46,000 as determined by gel exclusion chromatography.
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