Prevention of genomic instability by a scavenger of bifunctional electrophiles

 描述（由申请人提供）：从癌前病变进展为临床显著癌症涉及获得体细胞基因组异常，其共同驱动具有高度恶性表型的癌症的发展。已知来自环氧合酶-2（考克斯-2）、脂氧合酶和脂质过氧化的反应性二羰基形成DNA和组蛋白的共价加合物。提出了解决DNA和组蛋白的这些修饰有助于表征癌症的体细胞基因组异常的假设。两种考克斯同工型的直接产物是环状内过氧化物，前列腺素H2（PGH 2），是产生前列腺素和血栓烷A2的脱氢酶的底物。PGH 2还经历非催化重排以形成左旋甘草定，高度反应性的γ-酮醛。在癌细胞系中，我们已经证明了考克斯-2衍生的左旋葡萄糖醛酸形成DNA和组蛋白的共价加合物。我们的小组已经研究了一系列的levuglandin的清除剂与这些1，4-二羰基反应的速度比赖氨酸快3个数量级，从而抑制形成的levuglandin加合物的细胞胺的DNA碱基和组蛋白。我们已经鉴定了一种5-乙基水杨胺，其在防止赖氨酸的左旋糖定加合物中是有效的，不抑制考克斯-2并且在细胞核中起作用。重要的是，我们发现5-乙基水杨胺是活性二羰基化合物的一般清除剂，包括丙二醛和4-氧代-壬烯醛，这两者也形成DNA的共价加合物。为了评估这些反应性二羰基化合物是内源性致癌物的假设，我们将确定5-乙基水杨胺对发生在肺表达Kras突变的小鼠中的体细胞基因组异常的发展的影响，所述突变产生肺癌，所述肺癌逐渐发展具有广泛拷贝数变异的基因组不稳定性。将使用小鼠多样性基因分型阵列测定拷贝数变异。还将评价5-乙基水杨胺对肿瘤大小和组织学的影响，以及其对肿瘤中左旋花苷和DNA和组蛋白的丙二醛加合物的水平的影响。总之，许多反应性二羰基化合物，例如左甘草定、丙二醛和4-氧代-壬烯醛，由考克斯-2、脂质过氧化和脂氧合酶产生，并可形成DNA和组蛋白的共价加合物，表明它们可能是内源性致癌物.据推测，5-乙基水杨胺，这些二羰基的清除剂，将防止发生在肺癌小鼠模型中的基因组不稳定性。

 DESCRIPTION (provided by applicant): Progression from pre-malignant lesions to clinically significant cancers involves acquisition of somatic genomic abnormalities that in concert drive the development of cancers with a highly malignant phenotype. Reactive dicarbonyls derived from cyclooxygenase-2 (COX-2), the lipoxygenases and lipid peroxidation are known to form covalent adducts of DNA and histones. It is proposed to address the hypothesis that these modifications of DNA and histones contribute to the somatic genomic abnormalities that characterize cancers. The immediate product of both COX isoforms is the cyclic endoperoxide, prostaglandin H2 (PGH2), the substrate for the synthases that produce the prostaglandins and thromboxane A2. PGH2 also undergoes non-catalytic rearrangement to form the levuglandins, highly reactive γ-ketoaldehydes. In cancer cell lines, we have demonstrated that COX-2 derived levuglandins form covalent adducts of DNA and histones. Our group has investigated a series of scavengers of levuglandins that react with these 1,4-dicarbonyls at a rate 3 orders of magnitude faster than does lysine, thereby inhibiting the formation of the levuglandin adducts of cellular amines on DNA bases and on histones. We have identified one, 5-ethylsalicylamine that is potent in preventing levuglandin adducts of lysine, does not inhibit COX-2 and acts in the cellular nucleus. Importantly, we discovered that 5-ethylsalicylamine is a general scavenger of reactive dicarbonyls, including malondialdehyde and 4-oxo-nonenal, both of which also form covalent adducts of DNA. To evaluate the hypothesis that these reactive dicarbonyls are endogenous carcinogens, we will determine the effects of 5- ethylsalicylamine on the development of the somatic genomic abnormalities that occur in a mouse with lung expression of a Kras mutation that produces lung cancers which progressively develop genomic instability with extensive copy number variations. Copy number variations will be determined with the Mouse Diversity Genotyping Array. The effect of 5-ethylsalicylamine on tumor size and histology also will be evaluated as well as its effect on the levels of levuglandin and malondialdehyde adducts of DNA and histones in the tumors. In summary, a number of reactive dicarbonyls, exemplified by the levuglandins, malondialdehyde and 4-oxo- nonenal, are produced by COX-2, lipid peroxidation and the lipoxygenases and can form covalent adducts of DNA and histone, suggesting that they could be endogenous carcinogens. It is hypothesized that 5- ethylsalicylamine, a scavenger of these dicarbonyls, will prevent the genomic instability that occurs in a mouse model of lung cancer.