Targeted Prodrug Therapy of Liver Cancers

肝癌的靶向前药治疗

• 批准号: 6794814
• 负责人: MACUS T KUO
• 金额: $ 26.88万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6794814
• 关键词: aminohydrolases; antineoplastics; chimeric proteins; circumsporozoite protein; colorectal neoplasms; confocal scanning microscopy; cytology; drug design /synthesis /production; flucytosine; fluorouracil; hepatocellular carcinoma; injection /infusion; intraperitoneal injections; laboratory mouse; liver neoplasms; metastasis; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; pharmacokinetics; prodrugs; protein transport; recombinant proteins

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) and advanced colorectal cancer (CRC) are among the most deadly diseases of mankind. CRC is the second leading cause of cancer-related death in the United States, mostly due to metastases. Hepatic metastases are the main threat for successful treatment of CRC. 5-fluorouracil (5-FU). remains the mainstay of combination chemotherapy for nonresectable liver metastases. Recent studies have demonstrated that regional 5-FU-based chemotherapy by directly hepatic fusion showed improved response rates and survival for advanced CRC patients as compared with those undergone systemic infusion treatment. However, this delivery system is technically complicated and highly invasive. The present application describes the development of a novel delivery system for the treatment of hepatic metastases of CRC. The approach involves the use of a recombinant fusion protein consisting of malarial circumsporozoite (CS) protein, a hepatocyte-specific targeting ligand, linked to bacterial cytosine deaminase (CD), a "suicide gene" product which catalyzes the synthesis of 5-fluorouracil (5-FU) from its prodrug 5-fluorocytosine (5-FC). We have demonstrated in cultured cells that the CD-CS fusion protein can be internalized by a cell type-specific manner. More importantly, the internalized recombinant protein is stable for at least four weeks and exerts bystander cell killing effects upon the administration of prodrug 5-FC. The prolonged stability is probably attributed to the mechanism that the internalized fusion recombinant protein is entrapped in particular compartment(s) that are free from cytoplasmic degradation machinery. To further develop this system, we propose the following three specific aims: (A) to elucidate the mechanism(s) underlying the prolonged stability of CD-CS in cultured cells; (B) to investigate the targeting specificity, protein stability, and enzymatic activity of CD-CS in normal mice; and (C) to investigate the efficacy of CDCS/5-FC strategy in the treatment of liver metastases of colorectal cancers in animal model. We envision that the novel hepatic prodrug targeted therapy strategy proposed here, if successfully, is technically simple and non-invasive, and cost effective, therefore, should greatly improve the treatment efficacy of these life threatening diseases.

描述(申请人提供)：肝细胞癌(HCC)和 晚期结直肠癌是人类最致命的疾病之一。 在美国，结直肠癌是癌症相关死亡的第二大原因， 主要是由于转移引起的。肝转移是成功的主要威胁 结直肠癌的治疗。5-氟尿嘧啶(5-Fu)。仍然是联合的中流砥柱 化疗治疗不能切除的肝转移瘤。最近的研究表明 以5-FU为基础的区域直接肝融合化疗 显示晚期结直肠癌患者的应答率和存活率有所提高 与接受全身输液治疗的患者比较。不过，这个 投放系统技术复杂，侵入性强。现在 申请描述了一种新型递送系统的开发 结直肠癌肝转移的治疗。该方法涉及到使用 疟疾环子孢子(CS)重组融合蛋白 蛋白质，一种肝细胞特异性的靶向配体，与细菌胞嘧啶相连 脱氨酶(CD)，一种“自杀基因”产物，催化合成 从其前体药物5-氟胞嘧啶(5-FC)中分离出5-氟尿嘧啶(5-FU)。我们有 在培养细胞中证明CD-CS融合蛋白可以 以特定于细胞类型的方式内化。更重要的是，内部化的 重组蛋白至少稳定四周并发挥旁观者细胞作用 前药5-FC的杀伤作用。经久不衰 稳定性可能归因于内化融合的机制 重组蛋白被包裹在特定的隔室(S)中，这些隔室是自由的 来自细胞质降解机械。为了进一步发展这一系统，我们 提出以下三个具体目标：(A)阐明机制(S) CD-CS在培养细胞中的长期稳定性； 研究靶向特异性、蛋白质稳定性和酶促反应 正常小鼠CD-CS活性；(C)观察丹参对小鼠免疫功能的影响。 CDCS/5-FC方案治疗结直肠癌肝转移 在动物模型中。我们设想新的肝脏前药靶向治疗 这里提出的战略，如果成功，在技术上是简单的，而且 因此，非侵入性和成本效益应该会大大提高 这些危及生命的疾病的治疗效果。