ANTITUMOR&SIGNAL TRANSDUCTION AGENTS FROM MARINE SPONGES

抗肿瘤

• 批准号: 3200174
• 负责人: OLIVER J MCCONNELL
• 金额: $ 15.15万
• 依托单位: HARBOR BRANCH OCEANOGRAPHIC INST, INC.
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-15 至 1995-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3200174
• 关键词: Porifera; animal extract; antineoplastics; biological signal transduction; enzyme induction /repression; lung neoplasms; protein kinase C; saltwater environment; tissue /cell culture

The broad goal of the proposed research is to explore selected shallow and deep water sponges for their synthesis of bioactive natural products with potential chemotherapeutic uses in the treatment of cancer, especially lung cancer. Protein kinase C (PKC) has been selected as the mechanistic focus in the proposed research based on 1) the concept that carcinogens can be viewed as a distortion in signal transduction, 2) the belief that effective new anticancer treatments can be obtained through research on new targets other than the traditional ones of the cell nucleus and DNA, and 3) the pivotal role recognized for PKC in processes mediating cell proliferation and differentiation. A number of naturally derived substances have recently been discovered to affect PKC and exhibit cytotoxic or antitumor properties, i.e., the bryostatins, which were derived from the marine bryozoan, Bugula neritina, and are scheduled for phase I clinical trials, staurosporine, sangivamycin and calphostin. Shallow water marine sponges have proven to be chemically rich, however, their metabolites have been poorly studied with respect to their effects on signal transduction. Recent research on deep water marine sponges has revealed that this understudied group is also a rich source of novel, bioactive compounds with potential utility as chemotherapeutic agents. During the three-year period of the proposed research, the emphasis will be placed on the discovery of marine sponge-derived natural products that: -have demonstrable activity against human lung cancer cells (A549) in vitro and in vivo, and -exhibit significant agonistic or antagonistic activity against PKC.

拟议研究的广泛目标是探索选定的浅层和 深水海绵，用于合成生物活性天然产物与 在癌症治疗中的潜在化学治疗用途，尤其是肺 癌症。 蛋白激酶C（PKC）已被选为机械焦点 在拟议的研究中，基于1）致癌物可以是 被视为信号转导中的失真，2）有效的信念 可以通过对新目标的研究获得新的抗癌治疗方法 除了传统的细胞核和DNA，以及3） PKC在介导细胞增殖的过程中识别的关键作用 和分化。 许多自然衍生的物质具有 最近发现会影响PKC并表现出细胞毒性或抗肿瘤 特性，即源自海洋的胸丁蛋白 Bryozoan，Bugula Neritina，计划进行I期临床试验， 星形孢菌素，桑吉霉素和钙霉素。 浅水海绵已被证明是化学丰富的 他们的代谢物在对其对影响的影响方面的研究很差 信号转导。 关于深水海绵的最新研究 揭示了这个经过研究的群体也是新颖的丰富来源， 具有潜在效用作为化学治疗剂的生物活性化合物。 在拟议的研究的三年期间，重点将是 放置在发现海绵衍生的天然产品的基础上： - 在体外对人肺癌细胞（A549）具有明显的活性 和体内，以及 - 探测针对PKC的重要激动或拮抗活性。