INFLAMMATION AND MULTISTAGE CARCINOGENESIS

描述：尽管炎症之间存在间接联系 和鳞状细胞癌的生长，还没有研究表明 直接检查了激活的白细胞的关键作用 促炎细胞因子与皮肤多阶段癌变。这个 建议研究的假设是白细胞和细胞因子 由白细胞和表皮角质形成细胞产生，对 转基因TG.AC小鼠诱导的皮肤乳头状瘤生长 通过2年TPA或暴露于5次局部治疗激活v-Ha-ras 100nmol7，12DMBA。白细胞与促炎作用的重要性 细胞因子将导致乳头状瘤向癌的恶性转化 在Sencar小鼠中使用单次20 yg剂量的DMBA，然后 用2yg TPA治疗5个月，诱发乳头状瘤的发生率高 恶性转化。选择性抑制真皮白细胞渗入 或抑制促炎症细胞因子的合成将有效 抑制(A)对病毒敏感的DNA损伤的形成 甲酰胺-N-糖基酶(FAPY)、核酸内切酶III和IV：(B)增殖 表皮和滤泡区的角质形成细胞亚群； (C)乳头状瘤的生长和(D)乳头状瘤的转化率。 癌症。要检验这一假设，具体目标如下 建议：1)检测细胞因子合成抑制物的能力 己酮可可碱能抑制白细胞群的渗透，抑制 细胞因子基因表达、抑制DNA损伤和氧化8-oxo-DG加合物 TG.AC v-Ha-ras转基因小鼠乳头状瘤生长过程中的形成 通过100nmolDMBA或2yg TPA；2)检查静脉注射的效果。注射法 抗B2整合素抗体TG.AC v-Ha-ras转基因小鼠肿瘤的研究 促进；3)确定炎症在多大程度上对 乳头状瘤转化为癌的实验研究 己酮可可碱或抗B2整合素抗体对人卵巢癌的作用 细胞周期蛋白D1的过表达与细胞内突变发生的时间 高突变的p53抑癌基因外显子5-8 恶性转化过程中的频率。这些研究提供了独特的 有机会确定炎症、促进和 恶性转化。

DESCRIPTION: Although there are circumstantial links between inflammation and squamous cell carcinoma growth, there have been no studies that have directly examined the critical role of activated leukocytes and pro-inflammatory cytokines to skin multistage carcinogenesis. The hypothesis for the proposed studies is that leukocytes and cytokines produced by leukocytes and epidermal keratinocytes are essential to the growth of skin papillomas induced in transgenic TG.AC mice that contain an activated v-Ha-ras by 5 topical treatments with 2 yg TPA or by exposure to 100 nmol 7,12 DMBA. The importance of leukocytes and pro-inflammatory cytokines to malignant conversion of papillomas to carcinomas will be assessed in Sencar mice treated with a single 20 yg dose of DMBA followed by 5 treatments with 2 yg TPA which induces papillomas with a high rate of malignant conversion. Selective inhibition of dermal leukocyte infiltration or inhibition of synthesis of pro-inflammatory cytokines will effectively inhibit (a) the formation of DNA lesions that are sensitive to formamido-N-glycosylase (FaPY), Endonuclease III and IV: (b) proliferation of keratinocyte subpopulations within the epidermis and follicular regions; (c) growth of papillomas and (d) the rate of conversion of papillomas to carcinomas. To examine this hypothesis, the following Specific Aims are proposed: 1) Examine the ability of the cytokine synthesis inhibitor Pentoxifylline to inhibit infiltration of leukocyte populations, inhibit cytokine gene expression, inhibit DNA damage and oxidative 8-oxo-dG adduct formation in TG.AC v-Ha-ras transgenic mice during papilloma growth induced by either 100 nmol DMBA or 2 yg TPA; 2) Examine the effect of i.v. injection of TG.AC v-Ha-ras transgenic mice with anti-B2 integrin antibodies on tumor promotion; 3) Determine the extent to which inflammation contributes to conversion of papillomas to carcinomas by examining the effect of administration of either Pentoxifylline or anti-B2 integrin antibodies on cyclin D1 overexpression and the timing of development of mutations within exons 5-8 of the p53 tumor suppressor gene which is mutated at high frequency during malignant conversion. These studies provide the unique opportunity to determine the direct link between inflammation, promotion and malignant conversion.