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Acquired resistance to O6-benzylguanine plus chloroethylnitrosoureas in human breast cancer.

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.

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

Phillips WP Jr,Gerson SL

doi

10.1007/s002800050984

keywords:

subject

Has Abstract

pub_date

1999-01-01 00:00:00

pages

319-26

issue

4

eissn

0344-5704

issn

1432-0843

pii

90440319.280

journal_volume

44

pub_type

杂志文章

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