INFLAMMATION AND MULTISTAGE CARCINOGENESIS

炎症和多期致癌

• 批准号: 2733319
• 负责人: FREDIKA A ROBERTSON
• 金额: $ 28.09万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2733319
• 关键词: benzanthracenes; cancer prevention; chemical carcinogen; chemical carcinogenesis; chemoprevention; cutaneous papilloma; cytokine; gene induction /repression; genetically modified animals; inflammation; integrins; intravenous administration; laboratory mouse; leukocytes; neoplasm /cancer chemotherapy; neoplasm /cancer classification /staging; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplastic growth; neutralizing antibody; nonhuman therapy evaluation; oncogenes; pentoxifylline; phorbols

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.

描述：虽然炎症与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 直接研究了活化白细胞的关键作用， 促炎细胞因子对皮肤多阶段癌变的影响。 的 提出的研究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的是必不可少的 在转基因TG.AC小鼠中诱导的皮肤乳头状瘤的生长， 用2 μ g TPA局部处理5次或暴露于 100 nmol 7.12 DMBA。 白细胞和促炎因子的重要性 细胞因子对乳头状瘤向癌的恶性转化的作用将是 在用单次20 μ g剂量的DMBA处理的Sencar小鼠中评估， 用2 μ g TPA进行5次治疗，诱导乳头状瘤， 恶性转化 选择性抑制真皮白细胞浸润 或抑制促炎细胞因子的合成将有效地 抑制（a）对以下物质敏感的DNA损伤的形成 甲酰胺基-N-糖基化酶（FaPY），核酸内切酶III和IV：（B）增殖 表皮和毛囊区域内的角质形成细胞亚群; (c)乳头状瘤的生长和（d）乳头状瘤转化为 癌 为了检验这一假设，以下具体目标是 建议：1）检查细胞因子合成抑制剂的能力 喷替福林抑制白细胞群浸润，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转基因小鼠在乳头状瘤生长诱导过程中形成 用100 nmol DMBA或2 μ g TPA分别对小鼠进行了免疫组化检测; 2）检测静脉注射DMBA或TPA的效果 抗B2整合素抗体对TG.AC v-Ha-ras转基因小鼠肿瘤生长的影响 3）确定炎症在多大程度上有助于促进 乳头状瘤向癌的转化， 施用喷替福林或抗B2整联蛋白抗体， 细胞周期蛋白D1的过度表达和细胞内突变的发生时间 p53肿瘤抑制基因的外显子5-8，其在高水平突变， 恶性转化的频率。 这些研究提供了独特的 有机会确定炎症、促进和 恶性转化