MOLECULAR ORIGIN OF CANCER--CATECHOL/SEMIQUINOE/QUINONE

我们对最强致癌芳香族化合物的研究结果 碳氢化合物二苯并[α，1]芘提供了关键信息 关于肿瘤发生机制的研究。我们已经发现，有 净化加合物和致癌突变之间的相关性， 表明这些加合物是肿瘤的主要罪魁祸首 启动过程，并代表了识别的一个共同点 一种化学物质引发癌症的可能性。氧化的作用 致癌的4-儿茶酚雌激素(CE)可产生排便加合物 与DNA反应后，而非致癌的2-CE仅产生 稳定的加合物。这些结果构成了研究启蒙的基础。 通过儿茶酚类产物的氧化激活途径而引发癌症 半喹酮类化合物在乳腺癌的CE中产生苯醌类化合物，在 帕金森氏症中的白血病和多巴胺。我们建议(1) 反应合成4-羟基雌二醇-1-C8Ade加合物 半喹酮(E_2-S_2)阴离子自由基与DA或Ade的反应及测定 它是否与其他已经确定的排泄一起形成 Ce加合物，通过4-OHE2的酶氧化；(2)测定乳腺 (A)2-OHE1或2和4-OHE1或2对雌性ACI大鼠的致癌作用 通过背下植入硅胶管和(B)2-OHE2，4-OHE2和 其对苯二酚(含或不含等摩尔E_2)的重复应用 至6个乳头；(3)测定CE-DNA加合物的纯化水平 和CE-N-乙酰半胱氨酸[N(Ac)Cys]加合物在女性ACI患者尿液中的分布 用CE或CE对苯二酚处理的大鼠；(4)测定它们的水平 患有和不患有乳腺癌的妇女尿液样本中的加合物； (5)由邻苯二酚的苯二酚反应合成加合物， 对苯二酚和多巴胺与DG、da、Ade、GSH、Cys和N(Ac)Cys；以及 (6)鉴定和定量大黄素形成的稳定的加合物 邻苯二酚、1，4-苯二酚和多巴胺对苯二酚的反应 DNA或GSH以及酶激活的邻苯二酚、对苯二酚的反应 还有多巴胺和DNA或GSH。通过实现这些目标，我们将获得 有证据表明，儿茶酚(胺和 雌激素)形成脱氧核糖核酸加合物是其共同点 引发癌症和其他疾病。此外，我们将确定 用于乳房诊断和预防研究的生物标志物 癌症和其他疾病。

The results of our studies of the most potent carcinogenic aromatic hydrocarbon dibenzo[alpha,1]pyrene have provided critical information on the mechanism of tumor initiation. We have discovered that there is a correlation between depurinating adducts and oncogenic mutations, suggesting that these adducts are the primary culprit in the tumor initiation process and represent a common denominator for recognizing the potential of a chemical to initiate cancer. Oxidation of the carcinogenic 4-catechol estrogens (CE) produces depurinating adducts after reaction with DNA, whereas the noncarcinogenic 2-CE yield only stable adducts. These results form the basis to investigate initiation of cancer by the pathway of oxidative activation of catechols yields semiquinones yields quinones for CE in breast cancer, benzene in leukemia and dopamine in Parkinson's disease. We propose to (1) synthesize the 4-hydroxyestradiol (4-OHE2)-1-C8Ade adduct by reaction of semiquinone (E2-SQ) anion radical with dA or Ade and determine whether it is formed, along with other already determined depurinating CE adducts, by enzymic oxidation of 4-OHE2; (2) determine the mammary carcinogenicity in female ACI rats of (a) 2-OHE1 or 2 and 4-OHE1 or 2 by subdorsal implantation in silastic tubing and (b) 2-OHE2, 4-OHE2 and their quinones (with or without equimolar E2) by repeated application to six teats; (3) determine the levels of depurinating CE-DNA adducts and CE-N-acetylcysteine [N(Ac)Cys] adducts in the urine of female ACI rats treated with CE or CE quinones; (4) determine the levels of these adducts in urine specimens from women with and without breast cancer; (5) synthesize adducts by reaction of the quinones of catechol, hydroquinone and dopamine with dG, dA, Ade, GSH, Cys and N(Ac)Cys; and (6) identify and quantify the depurinating and stable adducts formed by reaction of catechol quinone, 1,4-benzoquinone and dopamine quinone with DNA or GSH and by reaction of enzyme-activated catechol, hydroquinone and dopamine with DNA or GSH. By accomplishing these aims, we will gain evidence that this pathway of oxidation of catechols (amines and estrogens) to form depurinating DNA adducts is the common denominator for triggering cancer and other diseases. In addition, we will identify biomarkers for use in diagnosis and in studies of prevention of breast cancer and other diseases.