Enhancement of platinum-induced cytotoxicity by O6-Benzylguanine

Melissa L. Fishel, Shannon M. Delaney, Lindsay D. Friesen, Ryan J. Hansen, Eleanor G. Zuhowski, Robert C. Moschel, Merrill J. Egorin, M. Eileen Dolan

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

O6-Benzylguanine (O6-BG), a potent inactivator of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT), is presently in clinical trials combined with alkylating agents that modify the O6position of DNA guanine residues, i.e., 1,3-bis(2-chloroethyl)-1- nitrosourea and temozolomide. Previous work demonstrated that O6-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 μM for 2 h before treatment and 2 h during treatment) resulted in a 2-fold decrease in the ED50 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 O6-BG plus cisplatin and remained elevated for 48 h. Consistent with greater cytotoxicity and apoptosis is the ∼2-fold higher amount of DNA damage when cells are treated with O6-BG plus cisplatin compared with cisplatin alone. Modulation of cisplatin therapy with O6-BG might improve the prognosis of patients with head and neck, ovarian, testicular, or lung cancer who are treated with this drug.

Original languageEnglish (US)
Pages (from-to)633-640
Number of pages8
JournalMolecular cancer therapeutics
Volume2
Issue number7
StatePublished - Jul 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Fishel, M. L., Delaney, S. M., Friesen, L. D., Hansen, R. J., Zuhowski, E. G., Moschel, R. C., Egorin, M. J., & Dolan, M. E. (2003). Enhancement of platinum-induced cytotoxicity by O6-Benzylguanine. Molecular cancer therapeutics, 2(7), 633-640.