TUMOR-PROMOTING EFFECTS OF OKADAIC ACID AND PALYTOXIN

大田酸和海藻毒素的促肿瘤作用

• 批准号: 3201029
• 负责人: Jean-Pierre H Perchellet
• 金额: $ 12.52万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3201029
• 关键词: DNA replication; antioxidants; enzyme induction /repression; hydrogen peroxide; laboratory mouse; okadaic acid; ornithine decarboxylase; phorbols; protein kinase C; skin neoplasms; skin pharmacology; tumor promoters

The biochemistry of tumor promotion by okadaic acid (OKA) and palytoxin (PAL) will be studied in mouse epidermis in vivo. Complete and stage 2 skin tumor promoters increase the hydroperoxide (HPx)-producing activity of the epidermis. Ornithine decarboxylase (ODC) induction and cell proliferation are early and late events of stage 2, respectively. HPx production and ODC induction are essential for stage 2 but not correlated. Beside ODC induction in early stage 2, the production of HPx caused by 12- O-tetradecanoylphorbol-13-acetate (TPA) during the early inhibition (EI) of epidermal DNA synthesis may be crucial to trigger a greater compensatory stimulation of DNA synthesis required to achieve hyperplasia in late stage 2. OKA induces ODC activity but PAL does not. Since the non-TPA type tumor promoters OKA and PAL neither bind to the phorbol ester receptor nor activate protein kinase C (PKC), the hypothesis to be tested is that common induction of HPx production by OKA, PAL and TPA may be the key event involved in tumor promotion. The objective is to determine if there is a correlation between HPx production and the 2nd peak of DNA synthesis (P2) after OKA, PAL and TPA treatment. The following aims will be examined over the next 4 years: 1) characterize and compare the HPx responses to OKA, PAL and TPA treatments and determine if these HPx responses have different requirements for, and/or are differently modulated by, macromolecule synthesis, Ca2+ mobilization, protease, PKC and phospholipase activities, and arachidonic acid metabolism; 2) study the relationships between the increased production of HPx and the sequential EI and compensatory stimulation of epidermal DNA synthesis, especially P2, caused by OKA, PAL and TPA; 3) determine if OKA and PAL induce tumor promotion synergistically with TPA or mimic the promoting activities of TPA and mezerein during stages 1 and 2, respectively; and 4) determine if the tumor-promoting activity of PAL can be improved by pretreatment with an ODC inducer and if the promotion of skin tumors by OKA and PAL can be inhibited by the antioxidant diethyldithiocarbamate. This project should demonstrate that if all tumor promoters share the ability to increase HPx production, the drugs inhibiting this HPx response, therefore, may have the best potential for inhibiting tumor promotion, a finding which could lead to the development of new means of cancer prevention.

冈田酸（OKA）和海马毒素促进肿瘤的生物化学 (PAL) 将在小鼠表皮中进行体内研究。 完成并进入第 2 阶段 皮肤肿瘤促进剂增加氢过氧化物（HPx）的产生活性 表皮。 鸟氨酸脱羧酶（ODC）诱导和细胞 增殖分别是第二阶段的早期和晚期事件。 羟丙基x 生产和 ODC 诱导对于第 2 阶段至关重要，但不相关。 除了第 2 阶段早期的 ODC 诱导外，HPx 的产生还由 12- O-十四烷酰佛波醇-13-乙酸酯 (TPA) 在早期抑制 (EI) 过程中 表皮 DNA 合成对于触发更大的代偿可能至关重要 刺激 DNA 合成以实现晚期增生 2. OKA 诱导 ODC 活性，但 PAL 不诱导。 自非TPA型 肿瘤促进剂 OKA 和 PAL 既不结合佛波酯受体也不结合 激活蛋白激酶 C (PKC)，要检验的假设是常见的 OKA、PAL 和 TPA 诱导 HPx 生产可能是关键事件 参与肿瘤促进。 目的是确定是否存在 HPx 产量与 DNA 合成第二峰之间的相关性 (P2) 经过 OKA、PAL 和 TPA 处理后。 未来 4 年将研究以下目标： 1) 描述 比较 HPx 对 OKA、PAL 和 TPA 处理的反应，并确定 如果这些 HPx 响应有不同的要求，和/或 通过大分子合成、Ca2+ 动员进行不同调节， 蛋白酶、PKC 和磷脂酶活性以及花生四烯酸 代谢; 2）研究产量增加之间的关系 HPx 和表皮 DNA 的序贯 EI 和代偿性刺激 由OKA、PAL和TPA引起的合成，特别是P2； 3）判断是否OK PAL 与 TPA 协同诱导肿瘤促进或模仿 在第 1 和第 2 阶段促进 TPA 和 mezerein 的活动， 分别; 4) 确定 PAL 的促肿瘤活性是否可以 通过使用 ODC 诱导剂进行预处理可以得到改善，并且如果促进 抗氧化剂可以抑制 OKA 和 PAL 引起的皮肤肿瘤 二乙基二硫代氨基甲酸酯。 该项目应该证明，如果所有肿瘤 促进者分享增加 HPx 产量的能力，药物 因此，抑制 HPx 反应可能具有最大的潜力 抑制肿瘤生长，这一发现可能导致开发 预防癌症的新手段。