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.

冈田酸促进肿瘤（OKA）和palytoxin的生物化学 （PAL）将在体内的小鼠表皮中进行研究。 完整和第2阶段 皮肤肿瘤启动子增加氢过氧化物（HPX）的产生活性 表皮。 鸟氨酸脱羧酶（ODC）诱导和细胞 扩散分别是第2阶段的早期和晚期事件。 HPX 生产和ODC诱导对于第2阶段至关重要，但不相关。 除了早期第2阶段的ODC诱导外，HPX的产生由12-- 在早期抑制（EI）期间，O-四烷酰基-13-乙酸酯（TPA） 表皮DNA合成对于触发更大的代偿性可能至关重要 在晚期实现增生所需的DNA合成刺激 2。OKA诱导ODC活动，但PAL没有。 由于非TPA类型 肿瘤启动子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。 目的是确定是否有 HPX产生与DNA合成的第二峰之间的相关性（P2） OKA，PAL和TPA治疗后。 接下来的4年将检查以下目标：1）表征 并比较HPX对OKA，PAL和TPA治疗的反应并确定 如果这些HPX响应对和/或是不同的要求 大分子合成，Ca2+动员，不同的调节 蛋白酶，PKC和磷脂酶活性以及花生四烯酸 代谢; 2）研究增加的生产之间的关系 HPX和顺序的EI和表皮DNA的补偿性刺激 由OKA，PAL和TPA引起的合成，特别是P2； 3）确定OKA是否 和PAL与TPA或模仿诱导肿瘤促进 在第1阶段和第2阶段促进TPA和Mezerein的活动， 分别; 4）确定PAL的肿瘤促进活性是否可以 通过使用ODC诱导剂进行预处理，可以改善 OKA和PAL的皮肤肿瘤可以被抗氧化剂抑制 二硫代氨基甲酸酯。 这个项目应该证明，如果所有肿瘤 发起人具有增加HPX生产的能力，药物 因此，抑制这种HPX响应可能具有最大的潜力 抑制肿瘤促进，这一发现可能导致发展 预防癌症的新手段。