EXPERIMENTAL CHEMOTHERAPY OF PROLIFERATIVE SKIN DISEASES

牛皮癣是一种常见且可能使人虚弱的疾病，其特征是 通过增加皮肤的增殖。几种抗增殖剂， 包括甲氨蝶呤和羟基脲，对临床均有效 全身给药时对这种疾病的控制。在过去的5年里， 我们研究了邻苯二酚的抗增殖特性。 衍生品，并已表明这种影响是通过部分中介，通过 抑制核糖核酸还原酶和DNA聚合酶。 因为核糖核苷酸还原酶是控制DNA合成的中心 在哺乳动物细胞中，我们建议系统地研究它的作用。 酶和脱氧核糖核酸池大小在控制细菌生长中的作用 人的表皮及相关细胞。我们还将合成亲脂性 这种酶的已知抑制剂的类似物作为潜在的局部应用 治疗牛皮癣的药物。具体地说，我们将在 比较正常人和银屑病患者皮肤中脱氧核糖核苷酸的水平。 正常皮肤和异常皮肤，并确定核糖核苷酸的关系 还原酶和DNA聚合酶在控制DNA合成中的作用。我们还将 制备4类衍生物，其中包括脂溶类似物 羟基脲、胸腺嘧啶核苷、邻苯二酚和胍唑。一系列长链 N-取代羟基脲的烷基衍生物，烷基磷酸酯 胸腺嘧啶核苷、邻苯二酚的烷基氨基衍生物和烷基乙酰衍生物 将会制备一种新型的。生物化验将使用高度的 人鳞状细胞癌细胞体外分化培养 表皮细胞，以及裸鼠与人类表皮的异种照片。这些 化验将证实抗增殖活性被保留并 适当的生物物理分区，表明亲脂性增加，已经 已经实现了。希望这项提议的结果将使我们能够 理解重要的控制酶--核糖核苷酸的作用 还原酶在人类皮肤的生长和分化中的作用 评价其作为局部药物靶点的潜力 男性增生性皮肤病的化疗。

Psoriasis is a common and potentially debilitating disease, characterized by increased proliferation of skin. Several anti-proliferative agents, including methotrexate and hydroxyurea, are effective for the clinical control of this disease when given systemically. During the past 5 years, we have studied the anti-proliferative proper ties of o-dihydroxybenzene derivatives and have shown this effect to be mediated, in part, through inhibition of the enzymes ribonucleotide reductase and DNA polymerase. Since ribonucleotide reductase is central to the control of DNA synthesis in mammalian cells, we propose to study systemically the role of this enzyme and deoxyribonucleotide pool sizes in the control of the growth of human epidermal and related cells. We will also synthesize lipophilic analogs of known inhibitors of this enzyme as potential topical anti-psoriatic agents. Specifically, we will determine enzyme activity in normal and psoriatic skin, compare the levels of deoxyribonucleotides in normal and abnormal skin, and determine the relationship of ribonucleotide reductase and DNA polymerase in the control of DNA synthesis. We will also prepare 4 classes of derivatives, which include lipid-soluble analogs of hydroxyurea, thymidine, catechol, and guanazole. A series of long chain alkyl N-substituted derivatives of hydroxyurea, alkylphosphate esters of thymidine, alkylamino derivatives of catechol, and alkylacetyl derivatives of guanazole will be prepared. Bioassay will be conducted using highly differentiated squamous cell carcinoma cells in vitro, cultures of human epidermal cells, and nude mouse xenographs with human epidermis. These assays will confirm that the anti-proliferative activity is retained and that proper biophysical partition, indicating increased lipophilicity, has been achieved. Hopefully, the results of this proposal will permit us to understand the role of the important controlling enzyme ribonucleotide reductase in the growth and differentiation of human skin, as well as to evaluate its potential as a pharmacologic target for the topical chemotherapy of proliferative skin disease in man.