title: Enhancement of platinum-induced cytotoxicity by O6-benzylguanine.
abstract: O(6)-Benzylguanine (O(6)-BG), a potent inactivator of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT), is presently in clinical trials combined with alkylating agents that modify the O(6) position of DNA guanine residues, i.e., 1,3-bis(2-chloroethyl)-1-nitrosourea and temozolomide. Previous work demonstrated that O(6)-BG also enhances the cytotoxicity of cyclophosphamide, ifosfamide, and nitrogen mustards in Chinese hamster ovary cells. We have extended this study to include other clinically relevant agents that form interstrand and intrastrand cross-links including cisplatin and carboplatin. Pretreatment of a series of head and neck tumor cell lines (i.e., SQ20b, JSQ3, SCC25, SCC35, and SCC61), Chinese hamster ovary cells, and HT29 human colon tumor cells with O(6)-BG (100 micro M for 2 h before treatment and 2 h during treatment) resulted in a 2-fold decrease in the ED(50) of cisplatin and a concomitant increase in the percentage of cells undergoing apoptosis. The enhancement was independent of AGT activity. Similar enhancement was observed with carboplatin, but no enhancement was seen in AGT-deficient cell lines with radiation or temozolomide, demonstrating the dependence of the effect on bifunctional, cross-linking agents. Furthermore, levels of platinum on DNA after treatment with cisplatin increased 1.4-fold in SQ20b cells and 4.5-fold in JSQ3 cells immediately after treatment with O(6)-BG plus cisplatin and remained elevated for 48 h. Consistent with greater cytotoxicity and apoptosis is the approximately 2-fold higher amount of DNA damage when cells are treated with O(6)-BG plus cisplatin compared with cisplatin alone. Modulation of cisplatin therapy with O(6)-BG might improve the prognosis of patients with head and neck, ovarian, testicular, or lung cancer who are treated with this drug.
authors.affiliation: Department of Medicine, Committee on Cancer Biology and Cancer Research Center, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Fishel
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Delaney
authors.forename: Lindsay D
authors.initials: LD
authors.lastname: Friesen
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Hansen
authors.forename: Eleanor G
authors.initials: EG
authors.lastname: Zuhowski
authors.forename: Robert C
authors.initials: RC
authors.lastname: Moschel
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016466:CHO Cells / Q000187:drug effects; D016190:Carboplatin / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D006224:Cricetinae; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects*; D004347:Drug Interactions; D004357:Drug Synergism; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; C064976:O(6)-benzylguanine; D006147:Guanine; D016190:Carboplatin; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002945:Cisplatin