PURPOSE: The purpose of this work is to evaluate the extent of the binding of cisplatin (cis-diamminedichloroplatinum(II)) to DNA in the presence and absence of biological thiols, glutathione, and cysteine, and to test the hypothesis whether the platinum-thiol complexes can serve as a drug reservoir for subsequent binding to DNA. METHODS: Reactions of cisplatin (50 microM to 1.0 mM) with calf thymus DNA (870 microM to 6.75 mM) in the presence and absence of glutathione and cysteine (0 to 10 mM) were carried out at pH 4.4, 7.0, and 7.3. Following the reactions, the DNA was enzymatically digested with nucleases, separated by RP HPLC, and analyzed to determine the extent of DNA binding. The method was independently verified by proton NMR measurements. RESULTS: At neutral pH, and equimolar concentrations of DNA and thiols, only a very small amount of platinum (<5%) was coordinated to DNA, and most of the platinum was coordinated to the thiols. At pH 4.4, binding to DNA was dominant over the binding to thiols. No conversion of platinum-thiol to platinum-DNA complexes was observed up to 7 days of incubation. CONCLUSION: At physiological pH, the cisplatin was exclusively coordinated to biological thiols and platinum-DNA was a minor adduct. Data presented in this paper does not support the "drug reservoir" hypothesis.
PURPOSE: The purpose of this work is to evaluate the extent of the binding of cisplatin (cis-diamminedichloroplatinum(II)) to DNA in the presence and absence of biological thiols, glutathione, and cysteine, and to test the hypothesis whether the platinum-thiol complexes can serve as a drug reservoir for subsequent binding to DNA. METHODS: Reactions of cisplatin (50 microM to 1.0 mM) with calf thymus DNA (870 microM to 6.75 mM) in the presence and absence of glutathione and cysteine (0 to 10 mM) were carried out at pH 4.4, 7.0, and 7.3. Following the reactions, the DNA was enzymatically digested with nucleases, separated by RP HPLC, and analyzed to determine the extent of DNA binding. The method was independently verified by proton NMR measurements. RESULTS: At neutral pH, and equimolar concentrations of DNA and thiols, only a very small amount of platinum (<5%) was coordinated to DNA, and most of the platinum was coordinated to the thiols. At pH 4.4, binding to DNA was dominant over the binding to thiols. No conversion of platinum-thiol to platinum-DNA complexes was observed up to 7 days of incubation. CONCLUSION: At physiological pH, the cisplatin was exclusively coordinated to biological thiols and platinum-DNA was a minor adduct. Data presented in this paper does not support the "drug reservoir" hypothesis.
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