MOLECULAR ORIGIN OF CANCER--CATECHOL/SEMIQUINOE/QUINONE

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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.