TUMOR-PROMOTING EFFECTS OF OKADAIC ACID AND PALYTOXIN

冈田酸（OKA）和海葵毒素促肿瘤生物化学 (PAL)将在小鼠表皮中进行体内研究。 完成和阶段2 皮肤肿瘤促进剂增加了 表皮 鸟氨酸脱羧酶（ODC）诱导和细胞 增殖分别是第2阶段的早期和晚期事件。 HPX 生产和ODC诱导对于第2阶段是必不可少的，但不相关。 除了早期阶段2的ODC诱导外，12- O-十四酰基佛波醇-13-乙酸酯（TPA）在早期抑制（EI）过程中 表皮DNA合成可能是触发更大的代偿性 刺激DNA合成以实现晚期增生 2. OKA诱导ODC活性，而PAL不诱导ODC活性。 由于非TPA型 肿瘤促进剂OKA和PAL既不与佛波酯受体结合， 激活蛋白激酶C（PKC），要测试的假设是， OKA、PAL和TPA诱导HPx产生可能是关键事件 参与肿瘤的促进。 目的是确定是否存在 HPx产生与DNA合成第2个峰（P2）之间的相关性 OKA、PAL和TPA治疗后。 在今后4年中，将审查以下目标：1） 比较HPx对OKA、PAL和TPA处理的反应，并确定 如果这些HPx响应具有不同的要求，和/或 通过大分子合成，Ca 2+动员， 蛋白酶、PKC和磷脂酶活性以及花生四烯酸 （2）研究增加生产之间的关系， HPx与表皮DNA的顺序EI和代偿刺激 OKA、PAL和TPA引起的合成，尤其是P2; 3）确定OKA是否 和PAL与TPA协同诱导肿瘤促进或模拟肿瘤促进。 在第1和第2阶段促进TPA和mezerein的活动， 以及4）确定PAL的促肿瘤活性是否可以 通过用ODC诱导剂预处理来改善，如果促进 抗氧化剂对OKA和PAL诱发的皮肤肿瘤有抑制作用 二乙基二硫代氨基甲酸盐。 这个项目应该证明，如果所有的肿瘤 启动子共享增加HPx生产的能力， 因此，抑制这种HPx反应可能具有最大的潜力， 抑制肿瘤的发展，这一发现可能导致发展 癌症预防的新方法。

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.