INHIBITION OF ORNITHINE DECARBOXYLASE BY ORAL COMPOUNDS

这项提议的总体目标是通过理性的 方法，一个理想的剂量和给药时间表，可以是 在一项前瞻性化学预防试验中口服给药，患者在 罹患恶性疾病的风险很高。形成这一现象的观察 这一建议的基础是小鼠表皮鸟氨酸的诱导 佛波酯促癌剂的脱羧酶(ODC)， 12-O-十四酰佛波醇-13-乙酸酯(TPA)与促进作用有关 小鼠皮肤肿瘤的形成。有证据表明，诱导 ODC活性是肿瘤促进剂的重要性质。热门话题或 防止ODC诱导的系统性药物(例如，维甲酸和维甲酸 前列腺素合成抑制剂)或抑制ODC的作用 (二氟甲基鸟氨酸，DFMO)可防止小鼠皮肤肿瘤的发生。 在小鼠中，当口服时，这些抗启动子抑制TPA引起的 3 mm穿孔小鼠皮肤组织中ODC的体外活性。这些 现在，观察已经扩展到人类皮肤。初步结果 提示TPA可在体外培养的人皮肤穿孔器中诱导ODC 组织活检及维甲酸体外抑制TPA诱导的ODC 在人的皮肤里。进一步的计划是：1)定义被试内部和 表皮ODC活性和诱导性的受试者间差异 TPA；2)在人体上证明口服给药的能力 无毒物质(如阿司匹林、维甲酸或DFMO)以防止 TPA引起的ODC活性增加；3)确定理想剂量和剂量 这种物质的时间表；以及4)提出一种前瞻性随机 化学预防药物在一组高危患者中的试验 罹患癌症。禁食志愿者将被用来确定 TPA在体外诱导3 mm皮肤穿孔活检标本的ODC活性。至 确定适当的人类化学预防药物、剂量和剂量 时间表，穿孔活检将获得体外诱导ODC的方法 口服药物前后的TPA。这是一种体外实验 人体化验系统将帮助确定必要的剂量和剂量 未来人类使用的某些化学预防药物的时间表 化学预防试验。

The overall objective of this proposal is to develop, through a rational approach, an ideal dose and administration schedule of a drug which can be administered orally in a prospective chemo-preventive trial in patients at high risk of developing malignant disease. The observation that forms the basis of this proposal is that the induction of mouse epidermal ornithine decarboxylase (ODC) by a phorbol ester tumor promoting agent, 12-O-tetradecanoylphorbol-13-acetate (TPA) is correlated to the promotion of skin tumor formation in mice. Evidence indicates that the induction of ODC activity is an essential property of tumor promoters. Topical or systemic agents that prevent the induction of ODC (eg. retinoids and prostaglandin synthesis inhibitors) or inhibit the action of ODC (difluoromethylornithine, DFMO) can prevent skin tumor promotion in mice. In mice, when administered orally, these antipromoters inhibit TPA caused ODC activity in vitro in 3 mm punch biopsies of mouse skin. These observations have now been extended to human skin. Preliminary results indicate that ODC can be induced by TPA in incubated human skin punch biopsies and that in vitro retinoic acid inhibits TPA caused ODC induction in human skin. Further plans are: 1) to define intra-subject and inter-subject variability of epidermal ODC activity and inducibility by TPA; 2) to demonstrate in humans the ability of orally administered nontoxic substances (eg., aspirin, retinoids, or DFMO) to preclude TPA-caused increased ODC activity; 3) to determine an ideal dose and dose schedule for such a substance; and 4) to propose a prospective randomized chemoprevention drug trial in a group of patients with high risk of developing cancer. Fasting volunteers will be used to determine TPA-induced ODC activity in vitro in 3 mm skin punch biopsy specimens. To determine appropriate human chemopreventive agents, doses, and dose schedules, punch biopsies will be obtained for in vitro induction of ODC by TPA both before and after oral medications are administered. This in vitro human assay system will help determine the requisite doses and dose schedules of certain chemopreventive agents for use in future human chemoprevention trials.