FGF-SAP AS AN ANTI-TUMOR AGENT--DESIGN FOR HUMAN STUDIES

FGF-SAP 作为抗肿瘤剂——为人类研究而设计

• 批准号: 3493486
• 负责人: BARBARA A SOSNOWSKI
• 金额: $ 4.65万
• 依托单位: SELECTIVE GENETICS, INC.
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-15 至 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3493486
• 关键词: antineoplastics; chemical conjugate; drug design /synthesis /production; fibroblast growth factor; growth factor receptors; plant proteins; recombinant DNA

Basic fibroblast growth factor (FGF) is an autocrine growth factor for numerous tumor cells. FGF-SAP (a chemical conjugate of FGF and saporin, an enzyme that inhibits protein synthesis) inhibits melanoma and Kaposi's sarcoma cell growth in culture and is also active in tumor animal models. In its current form, the chemical conjugate of FGF-SAP is a highly heterogeneous mixture at the molecular level. Thus, it does not lend itself to the rigorous chemical characterization required for clinical evaluation of its potential application in the treatment of FGF receptor- dependent, proliferative disease. For this reason, we propose to apply recombinant DNA technology to generate a homogeneous product. The specific aims are to: l) design and synthesize forms of FGF that retain all of the growth factor's mitogenic activity, but have only one reactive site for its conjugation to SAP, 2) prepare a homogeneous preparation of derivatized SAP, giving it only one reactive site for its conjugation to FGF, and 3) produce a homogeneous chemical conjugate FGF-SAP by using these new starting materials. This proposal presents major improvements in an innovative technology for tumOr treatment: direct tumor targeting by growth factors through their receptors.

碱性成纤维细胞生长因子（FGF）是一种自分泌生长因子， 大量的肿瘤细胞。 FGF-SAP（FGF 和皂草素的化学结合物，一种 抑制蛋白质合成的酶）抑制黑色素瘤和卡波西氏病 肉瘤细胞在培养物中生长，并且在肿瘤动物模型中也很活跃。 在目前的形式中，FGF-SAP 的化学共轭物是一种高度 分子水平上的异质混合物。因此，它不借 本身符合临床所需的严格化学特性 评估其在治疗 FGF 受体方面的潜在应用- 依赖性、增殖性疾病。为此，我们建议申请 重组DNA技术产生同质产品。具体的 目标是： l) 设计和合成保留所有功能的 FGF 形式 生长因子的有丝分裂活性，但只有一个反应位点 其与 SAP 的结合，2) 制备均质制剂 SAP 衍生化，仅提供一个反应位点来缀合 FGF，和3)通过使用产生均质化学共轭物FGF-SAP 这些新的起始材料。该提案提出了以下方面的重大改进： 肿瘤治疗的创新技术：直接肿瘤靶向 生长因子通过其受体。