1. Decreased cisplatin/DNA adduct formation is associated with cisplatin resistance in human head and neck cancer cell lines.
- Author
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Yang Z, Faustino PJ, Andrews PA, Monastra R, Rasmussen AA, Ellison CD, and Cullen KJ
- Subjects
- Apoptosis drug effects, Cell Line, DNA Adducts genetics, DNA Repair drug effects, Glutathione metabolism, Head and Neck Neoplasms metabolism, Head and Neck Neoplasms pathology, Humans, Neoplasms, Squamous Cell metabolism, Neoplasms, Squamous Cell pathology, Platinum chemistry, Spectrophotometry, Atomic, Tumor Cells, Cultured, Antineoplastic Agents toxicity, Cisplatin toxicity, DNA Adducts drug effects, Drug Resistance, Neoplasm genetics, Head and Neck Neoplasms drug therapy, Neoplasms, Squamous Cell drug therapy
- Abstract
Purpose: To evaluate the correlation between cisplatin sensitivity, intracellular glutathione, and platinum/DNA adduct formation (measured by atomic absorption spectroscopy) in a series of seven head and neck cancer cell lines, and to evaluate the effect of biochemical modulation of glutathione on platinum/DNA adduct formation and repair., Methods: Cisplatin/DNA adducts were measured by atomic absorption spectroscopy. Glutathione content was measured by enzymatic assay and was modulated with buthionine sulfoximine. Apoptosis was measured by double-labeled flow cytometry., Results: Intracellular glutathione concentration was strongly correlated with cisplatin resistance (P = 0.002, R2 = 0.7). There was also a statistically significant inverse correlation between cisplatin/DNA adduct formation and the IC50 for cisplatin in these cell lines. (P = 0.0004, R2 = 0.67). In addition, resistant cells were able to repair approximately 70% of cisplatin/DNA adducts at 24 h, while sensitive cells repaired less than 28% of adducts in the same period. However, despite the positive correlation between cellular glutathione and cisplatin resistance, there was no direct correlation between intracellular glutathione concentration and platinum/DNA adduct formation. Further, depletion of intracellular glutathione by buthionine sulfoximine did not dramatically alter formation of cisplatin/DNA adducts even though it resulted in marked increase in cisplatin cytotoxicity and was associated with increased apoptosis., Conclusions: These results suggest that glutathione has multiple effects not directly related to formation of cisplatin/DNA adducts, but may also be an important determinant of the cell's ability to repair cisplatin-induced DNA damage and resist apoptosis.
- Published
- 2000
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