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Characterization and investigation of 4-hydroxyestrogen-guanine adducts as potential biomarkers of breast cancer risk.

机译：4-羟基雌激素-鸟嘌呤加合物作为乳腺癌风险潜在生物标志物的表征和研究。

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摘要

Estrogen-guanine adducts are potential biomarkers of breast cancer risk. These DNA adducts are formed through estrogen metabolism, in particular, through formation of estrogen quinones. Estrogen quinones are attacked by nucleophiles including DNA bases to form either stable or depurinating adducts. The depurinating adducts create mutagenic abasic sites in DNA and have been detected in tissues and urines of animals and humans.;Findings reported in this work include synthesis and mass spectral characterization of estrogen-guanine adducts and their isotopically labeled analogues. The adduct standards were used to understand their physical chemical stability and were also used to develop an isotope dilution mass spectrometric method to isolate and measure these compounds in biological samples. During structural characterization of the guanine adducts, two novel adduct analogues, an 8-oxo and a formamidopyrimidine derivative were identified. These derivatives were formed as reaction products under basic conditions.;The adduct standards were employed in the development of an isolation method that utilized multiple solid phase extraction columns as well as a derivatization step. The goal of the method development was its application to human samples to gain insight on the use of estrogen-guanine adducts as biomarkers of breast cancer risk. This method permitted the detection of estrogen-guanine adducts in the picogram range from both human and rat urine. Ten human urine samples were analyzed and adduct was detected in all samples validating the application of the method. Additionally, two rats strains, the estrogen sensitive ACI and the less sensitive SD rats were used to determine if there was a strain difference in adduct level following chronic estradiol treatment. There was only a borderline statistical difference between the two strains after three weeks of treatment whereas a 5-fold higher level of adducts were measured in the ACI rat urines compared to SD after six weeks of chronic dosing. The results described are encouraging and suggest there is an association between adduct level and cancer risk. It is necessary to continue work in both human and animal studies to determine if these adducts are in fact biomarkers of breast cancer and if they can be utilized for risk assessment.
机译：雌激素鸟嘌呤加合物是乳腺癌风险的潜在生物标志物。这些DNA加合物是通过雌激素代谢，特别是通过形成雌激素醌而形成的。雌激素醌受到包括DNA碱基在内的亲核试剂的攻击，形成稳定的或去嘌呤的加合物。脱嘌呤加合物在DNA中产生诱变的无碱基位点，并已在动物和人的组织和尿液中检测到。研究结果包括雌激素-鸟嘌呤加合物及其同位素标记类似物的合成和质谱表征。使用加合物标准物了解其物理化学稳定性，还用于开发同位素稀释质谱法，以分离和测量生物样品中的这些化合物。在鸟嘌呤加合物的结构表征过程中，鉴定了两个新颖的加合物类似物：8-氧代和甲酰胺基嘧啶衍生物。这些衍生物是在碱性条件下作为反应产物形成的。加合物标准品用于开发分离方法，该方法利用了多个固相萃取柱以及一个衍生步骤。该方法开发的目标是将其应用于人体样品，以深入了解雌激素-鸟嘌呤加合物作为乳腺癌风险生物标志物的用途。这种方法可以从人和大鼠尿液中检测出皮克级的雌激素-鸟嘌呤加合物。分析了十个人的尿液样本，并在所有样本中检测到加合物，验证了该方法的应用。另外，使用两只大鼠品系，雌激素敏感的ACI和较不敏感的SD大鼠，来确定慢性雌二醇治疗后加合物水平是否存在品系差异。在三周的治疗后，两种菌株之间只有统计学上的临界差异，而在慢性给药六周后，ACI大鼠尿液中的加合物水平是SD的5倍。所描述的结果令人鼓舞，表明加合物水平与癌症风险之间存在关联。有必要继续进行人类和动物研究，以确定这些加合物是否实际上是乳腺癌的生物标志物，以及是否可用于风险评估。

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  • 作者

    Bransfield, Leslie Anne Machado.;

  • 作者单位

    The Johns Hopkins University.;

  • 授予单位 The Johns Hopkins University.;
  • 学科 Chemistry Analytical.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 135 p.
  • 总页数 135
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 化学;生物化学;
  • 关键词

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