ANTIMETASTATIC EFFECT OF THROMBOSPONDIN DERIVED PEPTIDES

血小板反应蛋白衍生肽的抗转移作用

• 批准号: 6298828
• 负责人: GEORGE Paul TUSZYNSKI
• 金额: $ 9.96万
• 依托单位: INKINE PHARMACEUTICAL COMPANY, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-12 至 2003-06-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6298828
• 关键词: antineoplastics; drug design /synthesis /production; drug screening /evaluation; heparin; metastasis; molecular cloning; neoplastic cell; peptide chemical synthesis; peptides; protein binding; thrombospondins

DESCRIPTION: The long term objective is to demonstrate the efficacy, safety, and cost-effectiveness of thrombospondin-I (TSP-I) peptides containing the CSVTCG sequence or mimetics, either alone or in combination with other agents, to treat cancer metastasis. The specific aim of this STTR proposal is to test the hypothesis that heparin binding sequences flanking the sequence CSVTCG, present in the type 1 repeats of TSP-I, potentiates the antimetastatic activity of CSVTCG. Recent data in the literature showing that these heparin-binding sequences inhibit breast cancer progression and our data showing that CSVTCG peptides inhibit tumor cell metastasis provide a strong rationale for these studies. We propose to synthesize 10 peptides and test their activity in in vitro assays that should be predictive of their antimetastatic activity. These assays are inhibition of TSP-I tumor cell binding, affinity of peptide binding to cloned TSP-I receptor and TSP-I mediated tumor cell invasion. Peptides displaying the greatest activity in these assays will then be evaluated in two experimental animal models of tumor cell metastasis- a mouse melanoma spontaneous metastasis model and a human xenograft orthotopic breast carcinoma model. These studies will identify peptides that will be further evaluated for toxicity and pharmacokinetics in a Phase II proposal. Phase II studies will provide information for optimal dose and treatment schedules required for testing of these compounds in man. PROPOSED COMMERCIAL APPLICATION: Improving cancer survival and quality of life is a major goal of cancer research. The therapies developed in this proposal will be used to treat metastatic disease for all forms of cancer. We will initially target lung cancer since the mortality rates for this cancer are the highest. An agent that reduces mortality and improves quality of life would have a significant clinical and economic impact by reducing the length of hospital stay and the associated costs and risks.

描述：长期目标是证明其有效性、安全性、 凝血酶敏感蛋白-I(TSP-I)多肽的成本效益 单独或与其他试剂结合的CSVTCG序列或模拟物， 用来治疗癌症转移。 这一STTR提案的具体目的是检验肝素 存在于类型1重复中的序列CSVTCG两侧的结合序列 TSP-I可增强CSVTCG的抗肿瘤活性。最近公布的数据 文献显示，这些肝素结合序列可抑制乳腺癌 CSVTCG多肽对肿瘤细胞抑制作用的研究进展 转移为这些研究提供了强有力的理论基础。我们建议 合成10个多肽，并在体外测试它们的活性， 预测它们的抗转移活性。这些检测方法都是抑制 TSP-I肿瘤细胞结合、与克隆的TSP-I受体结合肽的亲和力 TSP-I介导肿瘤细胞侵袭。展示最伟大的多肽 然后在两个实验动物身上对这些检测的活性进行评估。 肿瘤细胞转移模型--小鼠黑色素瘤自发转移模型 和人异种移植原位乳腺癌模型。 这些研究将确定将被进一步评估的多肽 第二阶段提案中的毒性和药代动力学。第二阶段研究将会 提供最佳剂量和所需治疗计划的信息 在人体上测试这些化合物。 建议的商业应用： 提高癌症存活率和生活质量是癌症研究的主要目标。这个 这项提案中开发的疗法将用于治疗各种形式的转移性疾病。 癌症的威胁。我们最初的目标是肺癌，因为这种癌症的死亡率是 最高的。一种降低死亡率和提高生活质量的药物将会有 通过减少住院时间和 相关成本和风险。