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Combined depletion of O6-alkylguanine-DNA alkyltransferase and glutathione to modulate nitrosourea resistance in breast cancer.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 1994 Aug 03; Vol. 48 (3), pp. 543-8. - Publication Year :
- 1994
-
Abstract
- MCF-7 human breast cancer cells possess high levels of O6-alkylguanine-DNA alkyltransferase and moderate levels of glutathione, and are more resistant to chloroethylnitrosoureas (CNUs) than cells with low levels of either molecule. The role of each as a component of CNU resistance was assessed using O6-benzylguanine (O6-bG) or O6-methylguanine (O6-mG) to deplete the alkyltransferase and L-buthionine sulfoxamine (L-BSO) to deplete glutathione. O6-bG and O6-mG potentiated 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) cytotoxicity, resulting in a dose modification factor of 5.4 and 2.3, respectively, which reflected the more potent inhibitory effect of O6-bG. L-BSO alone had little effect on the survival of MCF-7 cells following BCNU exposure, but when combined with O6-mG, BCNU cytotoxicity was additive, yielding a dose modification factor of 3.2. O6-bG or O6-mG and L-BSO acted independently, as neither class of inhibitor affected the other's mechanism of CNU resistance. Furthermore, MCF-7 cells overexpressing GST mu were not more resistant to BCNU than the parent cell line in either the presence or absence of O6-bG or L-BSO. These results indicate that on a relative basis in MCF-7 cells, the alkyltransferase is the cell's first line of defense against CNUs. This suggests that therapeutic trials based on O6-bG-induced biochemical modulation of CNU resistance may increase the efficacy of these chemotherapeutic agents against human malignant cells and that L-BSO may have little additive effect when used with these agents.
- Subjects :
- Carmustine pharmacology
Cell Line
Cell Survival
Drug Resistance
Ethylnitrosourea pharmacology
Glutathione Transferase analysis
Guanine analogs & derivatives
Guanine pharmacology
Humans
O(6)-Methylguanine-DNA Methyltransferase
Breast Neoplasms metabolism
Ethylnitrosourea analogs & derivatives
Glutathione antagonists & inhibitors
Methyltransferases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0006-2952
- Volume :
- 48
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 8068041
- Full Text :
- https://doi.org/10.1016/0006-2952(94)90284-4