Human Glioma Cell Sensitivity to the Sequence-Specific Alkylating Agent Methyl-Lexitropsin
| Autor: | Ryan D. Goff, John R. Silber, Douglas D. Kolstoe, Barry Gold, Michael S. Bobola, A. Blank, Sridhar Varadarajan, Nolan W Smith |
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| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Time Factors Methyltransferase Antineoplastic Agents Biology DNA Mismatch Repair DNA Adducts chemistry.chemical_compound Cell Line Tumor Glioma Tumor Cells Cultured medicine Humans Neoplasm Cytotoxic T cell AP site Cytotoxicity Dose-Response Relationship Drug Brain Neoplasms Netropsin Oligonucleotides Antisense medicine.disease Oncology chemistry Drug Resistance Neoplasm Immunology Cancer research DNA mismatch repair DNA |
| Zdroj: | Clinical Cancer Research. 13:612-620 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: Defining the cytotoxicity of individual adducts in DNA is necessary for mechanistic understanding of human brain tumor resistance to therapeutic alkylating agents and for design of DNA repair-related antiresistance strategies. Our purpose is to characterize the sensitivity of human glioma cells to methyl-lexitropsin (Me-lex), a sequence-specific alkylator that produces 3-methyladenine (3-meA) as the predominant (>90%) DNA lesion. Experimental Design: We quantitated the Me-lex cytotoxicity of 10 human glioma cell lines that differ in O6-methylguanine (O6-meG)-DNA methyltransferase (MGMT) and mismatch repair activity. We used antisense suppression of alkyladenine DNA glycosylase (AAG) and Ape1 to assess the contribution of 3-meA and abasic sites to lethality and measured abasic sites. Results: (a) The LD10 for Me-lex varied widely among the cell lines. (b) MGMT-proficient lines were more resistant than MGMT-deficient lines, an unexpected finding because Me-lex produces very little O6-meG. (c) Suppression of AAG increased Me-lex killing and reduced abasic site content. (d) Suppression of Ape1 increased Me-lex killing and increased abasic site content. (e) Ablation of MGMT had no effect on Me-lex cytotoxicity. Conclusions: (a) Me-lex is cytotoxic in human glioma cells and AAG promotes resistance, indicating that 3-meA is a lethal lesion in these cells. (b) Abasic sites resulting from 3-meA repair are cytotoxic and Ape1 promotes resistance to these derivative lesions. (c) A factor(s) associated with MGMT expression, other than repair of O6-meG, contributes to Me-lex resistance. (d) Me-lex may have clinical utility in the adjuvant therapy of gliomas. (e) AAG and Ape1 inhibitors may be useful in targeting alkylating agent resistance. |
| Databáze: | OpenAIRE |
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