W P Phillips1, S L Gerson. 1. Division of Hematology-Oncology and the Case Western Reserve University/University Hospitals of Cleveland Ireland Cancer Center, BRB-3, 10900 Euclid Avenue, Cleveland OH 44106-4937, USA.
Abstract
PURPOSE: O(6)-benzylguanine (BG) is a pseudosubstrate inactivator of the DNA repair protein O(6)- alkylguanine-DNA alkyltransferase (AGT) that has entered clinical trials as a potentiator of the antitumor effect of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). This study was designed to evaluate potential mechanisms of BG + BCNU resistance in breast cancer cells. METHODS: We treated MCF-7 breast cancer cells three times with cytotoxic concentrations of BG + BCNU to isolate a population of MCF-7 cells possessing BG + BCNU resistance (BBR). We measured drug resistance, AGT activity, cross-resistance to other agents and sensitivity of AGT to BG inactivation. RESULTS: When compared with the parent line, MCF-7BBR cells were no longer sensitized to BCNU by BG, resulting in three-fold resistance to BG + BCNU and fourfold resistance to BG + 1-(2-chloroethyl)-1-nitrosourea (CNU). In contrast, MCF-7 and MCF-7BBR cells had similar sensitivity to BCNU, CNU, temozolomide (each in the absence of BG), cisplatin, and UV light. Acquired resistance to BG + chloroethylnitrosoureas (CENU) in MCF-7BBR cells was not accompanied by an increase in AGT or altered kinetics of BG inactivation of AGT. While glutathione-S transferase activity was increased modestly, its contribution to resistance in this setting remains unclear. CONCLUSIONS: This is the first report of acquired BG + CENU resistance in human tumor cells and the results indicate that selective pressure with BG + CENUs may result in nonresponsiveness to BG by one or more complex mechanisms. These results predict the development of acquired resistance to BG + BCNU in clinical trials.
PURPOSE: O(6)-benzylguanine (BG) is a pseudosubstrate inactivator of the DNA repair protein O(6)- alkylguanine-DNA alkyltransferase (AGT) that has entered clinical trials as a potentiator of the antitumor effect of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). This study was designed to evaluate potential mechanisms of BG + BCNU resistance in breast cancer cells. METHODS: We treated MCF-7 breast cancer cells three times with cytotoxic concentrations of BG + BCNU to isolate a population of MCF-7 cells possessing BG + BCNU resistance (BBR). We measured drug resistance, AGT activity, cross-resistance to other agents and sensitivity of AGT to BG inactivation. RESULTS: When compared with the parent line, MCF-7BBR cells were no longer sensitized to BCNU by BG, resulting in three-fold resistance to BG + BCNU and fourfold resistance to BG + 1-(2-chloroethyl)-1-nitrosourea (CNU). In contrast, MCF-7 and MCF-7BBR cells had similar sensitivity to BCNU, CNU, temozolomide (each in the absence of BG), cisplatin, and UV light. Acquired resistance to BG + chloroethylnitrosoureas (CENU) in MCF-7BBR cells was not accompanied by an increase in AGT or altered kinetics of BG inactivation of AGT. While glutathione-S transferase activity was increased modestly, its contribution to resistance in this setting remains unclear. CONCLUSIONS: This is the first report of acquired BG + CENU resistance in humantumor cells and the results indicate that selective pressure with BG + CENUs may result in nonresponsiveness to BG by one or more complex mechanisms. These results predict the development of acquired resistance to BG + BCNU in clinical trials.
Authors: Yoshinori Kato; Baasil Okollie; Venu Raman; Farhad Vesuna; Ming Zhao; Sharyn D Baker; Zaver M Bhujwalla; Dmitri Artemov Journal: Cancer Biol Ther Date: 2007-03-05 Impact factor: 4.742
Authors: M J Clemons; M C Bibby; H El Teraifi; G Forster; J Kelly; S Banerjee; B Cadman; W D J Ryder; A Howell; G P Margison Journal: Br J Cancer Date: 2002-06-05 Impact factor: 7.640