MOLECULAR ORIGIN OF CANCER--CATECHOL/SEMIQUINOE/QUINONE

我们对最强致癌芳香剂的研究结果 碳氢化合物二苯并[α，1]芘提供了关键信息 肿瘤发生的机制。 我们发现 脱嘌呤加合物和致癌突变之间的相关性， 这表明这些加合物是肿瘤的罪魁祸首 启动过程，并代表一个共同的分母， 一种化学物质引发癌症的可能性 氧化 致癌的4-儿茶酚雌激素（CE）产生脱嘌呤加合物 与DNA反应后，而非致癌性的2-CE只产生 稳定的加合物。 这些结果构成了研究启动的基础 通过儿茶酚的氧化活化途径产生癌症 在乳腺癌中，半醌产生用于CE的醌， 白血病和帕金森病中的多巴胺我们建议（1） 通过反应合成4-羟基乙烯（4-OHE 2）-1-C8 Ade加合物， 半醌（E2-SQ）阴离子自由基与dA或Ade的反应， 是否形成，沿着其他已确定的脱嘌呤 CE加合物，通过4-OHE 2的酶促氧化;（2）测定乳腺 （a）2-OHE 1或2和4-OHE 1或2在雌性ACI大鼠中的致癌性 通过背下植入硅橡胶管和（B）2-OHE 2，4-OHE 2和 通过重复应用它们的醌（有或没有等摩尔的E2） 测定CE-DNA加合物的脱嘌呤水平 和CE-N-乙酰半胱氨酸[N（Ac）Cys]加合物 用CE或CE醌处理的大鼠;（4）测定这些化合物的水平 加合物的尿液标本，从妇女和非乳腺癌; (5)通过邻苯二酚的醌类反应合成加合物， 氢醌和多巴胺与dG、dA、Ade、GSH、Cys和N（Ac）Cys;和 (6)鉴定和定量由以下物质形成的脱嘌呤和稳定加合物： 邻苯二酚醌、1，4-苯醌和多巴胺醌与 DNA或GSH与酶活化的邻苯二酚、对苯二酚反应 和多巴胺与DNA或GSH结合。 通过实现这些目标，我们将获得 有证据表明，这种儿茶酚（胺和 雌激素）形成脱嘌呤DNA加合物是共同点 引发癌症和其他疾病。 此外，我们将确定 用于乳腺癌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.