Novel Drug Development for Prostatic Cancer

前列腺癌新药开发

• 批准号: 6665513
• 负责人: SAEED Rehman KHAN
• 金额: $ 15.85万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6665513
• 关键词: antineoplastics; doxorubicin; drug design /synthesis /production; drug vehicle; laboratory mouse; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonhuman therapy evaluation; paclitaxel; prodrugs; prostate neoplasms; prostate specific antigen; thapsigargin

DESCRIPTION (provided by applicant): Approximately forty thousand American men die annually from metastatic prostate cancer. Standard chemotherapeutic agents have been ineffective at significantly prolonging the survival of men with metastatic prostate cancer and these agents are typically associated with often severe, dose-limiting side effects. New agents are therefore urgently needed. While a large number of cytotoxic agents have been demonstrated to be effective in vitro, these agents are typically general cytotoxins that cannot be administered to patients without severe systemic toxicities. Therefore, what is required is a method to target the delivery of novel, effective cytotoxic agents specifically to sites of metastatic prostate cancer. Such an approach would result in increased concentration of drug within the tumor while avoiding significant systemic toxicity. One such novel class of agents that has been demonstrated in recent studies to induce apoptosis in a variety of cell types, including prostate cancers, are doxirubicin and thapsigargin analogues. Other classes of anticancer agents such as taxol or taxotere and rhodamine 123 have shown promising therapeutic efficacy for the management of human cancer. These anticancer agents, therefore, represent a potentially novel approach toward the treatment of metastatic prostate cancer. The cytotoxicity of these agents, however, is not prostate cancer specific. In this proposal, a prostate cancer specific targeting strategy is outlined that will overcome this limitation. To achieve targeted cytotoxicity, these compounds will be converted to biologically inactive prodrugs by coupling to a peptide carrier or peptide linked with spacer group such that they can be efficiently converted back to active killing agents only upon proteolysis by the serine protease activity of a unique prostate-specific protein, Prostate-Specific Antigen (PSA). Since PSA is expressed in high levels only by normal and malignant prostate cells and not in any significant amounts by other normal cell types, this approach should allow specific targeting of the killing ability of these agents to prostate cancer cells Therefore, a series of amine containing thapsigargin analogue, taxol or taxotere, and rhodamine 123 will be synthesized and characterized. These cytotoxic agents will be chemically linked via a peptide bond to a previously identified PSA-specific peptide to produce inactive prodrugs. Prodrugs will be tested for their potency and selectivity as PSA activated killing agents against PSA-producing, androgen independent human prostate cancer cells. The lead prodrug will then be tested in vivo for activity in mice bearing PSA-producing human prostate cancers. These studies will serve to identify the best candidate prodrug that will be subsequently tested in clinical trials as treatment for metastatic prostate cancer.

描述（由申请人提供）：每年大约有四万美国男性死于前列腺癌。标准的化学治疗剂在显着延长了转移性前列腺癌男性的存活方面无效，这些药物通常与通常严重的剂量限制副作用有关。因此，迫切需要新的代理。虽然已经证明大量的细胞毒性剂是 这些药物在体外有效，通常是一般的细胞毒素，无法给予没有严重全身毒性的患者。因此，所需的方法是针对新型有效的细胞毒性剂，专门针对转移性前列腺癌部位的方法。这种方法将导致肿瘤内药物浓度的增加，同时避免严重的全身毒性。在最近的研究中已经证明了一种新型的一类药物，以诱导多种细胞类型的细胞凋亡，包括前列腺癌，是阿昔Ubibicin和thapsigargin类似物。其他类别的抗癌剂，例如紫杉醇，紫杉甲烷和若丹明123，对人类癌症的治疗表现出了有希望的治疗功效。因此，这些抗癌剂代表了潜在的 用于治疗转移性前列腺癌的新方法。但是，这些药物的细胞毒性不是前列腺癌的特异性。在此提案中，概述了将要克服此限制的前列腺癌特异性靶向策略。为了达到靶向细胞毒性，这些化合物将通过耦合到A转换为生物学无活性前药 与垫片组相关的肽载体或肽，使它们只能通过独特的前列腺特异性蛋白的丝氨酸蛋白酶活性（PROSTATE特异性抗原（PSA））的丝氨酸蛋白酶活性来有效地转换为活性杀死剂。由于PSA仅通过正常和恶性前列腺细胞以高水平表达 正常的细胞类型，这种方法应允许这些药物的杀戮能力的特定靶向前列腺癌细胞的杀戮能力，因此，将合成和表征一系列含有Thapsigargin类似物，紫杉醇或紫杉醇的胺，以及若丹明123。这些细胞毒性剂将通过肽键将其化学连接到先前鉴定的PSA特异性 肽产生非活性前药。由于PSA激活杀伤剂针对PSA产生，雄激素独立的人类前列腺癌细胞，因此前药将其效力和选择性测试。然后，将在体内对铅前药进行测试，以在产生PSA的人类前列腺癌的小鼠中进行活性。这些研究将有助于确定随后在临床试验中测试的最佳候选前药作为转移的治疗 前列腺癌。