Novel Amiloride Conjugates Selectively Kill Gliomas

新型阿米洛利结合物选择性杀死神经胶质瘤

• 批准号: 7035267
• 负责人: FREDRIC A GORIN
• 金额: $ 33.78万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035267
• 关键词: amiloride; aminoacid; antineoplastics; astrocytoma; calcium; cell death; cell line; cell proliferation; chemical conjugate; chemical structure function; cytotoxicity; disease /disorder model; drug design /synthesis /production; drug screening /evaluation; glioma; histology; inhibitor /antagonist; laboratory rat; magnetic resonance imaging; neoplastic growth; neurons; peptides; pharmacokinetics; sodium; sodium hydrogen exchanger; tissue /cell culture; xenotransplantation

DESCRIPTION (provided by applicant): High grade malignant gliomas are the most frequent type of lethal adult brain tumor, and there is no current effective treatment. Amiloride is an FDA-approved diuretic that inhibits the proliferation of malignant glioma cells and, at high concentrations, selectively kills human glioma cells. Intracranial infusion of amiloride significantly decreased the rate of tumor growth of intracerebral human glioma xenografts in athymic rats, and killed glioma cells in poorly vascularized tumor regions. A primary objective of this application is to identify the cellular mechanisms by which amiloride selectively kills malignant glioma cells. Recently published data indicate that glioma cytotoxicity could arise from amiloride's dual inhibition of the sodium calcium exchanger (NCX) and of the type 1 sodium proton exchanger (NHE1). Nonspecific cellular toxicities of the more potent, lipophilic amiloride derivatives correspond with their intracellular permeation. We hypothesize that conjugating amino acids or peptides to the C (5) position and to the C(2) guanidine moiety of amiloride can generate novel hydrophilic amiloride derivatives, and limit drug activities to cell surface transporters. C (2) amiloride glycine conjugate inhibits NCX>NHE1, and is at least 50-fold more potent than amiloride in selectively killing glioma cells. C (5) amiloride glycine conjugate inhibits NHE1"NCX, and when coupled to an opioid-like pentapeptide created an inactive prodrug. This prodrug liberates bioactive C (5)-Am-Gly when incubated with enkephalinase. In a similar fashion, we envision that glioma-specific peptidases, such as metalloproteinases, could regionally activate amiloride-peptide prodrugs. The investigator proposes to further analyze the cellular mechanisms by which inhibitors of NCX and NHE1 selectively kill glioma cells. Syntheses of novel amiloride amino acid and peptide conjugates will be guided by these mechanistic studies, by their inhibitory activities on NCX and NHE1, and by screening their anti-cancer properties in a panel of human glioma cell lines and primary astrocytes. The most selective and efficacious of these novel amiloride derivatives will be infused intracranial into human glioma xenografts implanted intracerebrally into athymic rats. The pharmacokinetics, neurotoxicities, and neuropathology of these compounds also will be evaluated.

描述（由申请人提供）：高级恶性神经胶质瘤是最常见的致命成人脑肿瘤类型，目前尚无有效治疗。 Amiloride是一种经FDA批准的利尿剂，可抑制恶性神经胶质瘤细胞的增殖，并在高浓度下选择性地杀死人神经胶质瘤细胞。颅内输注明显降低了无胸腺大鼠中脑神经胶质瘤异种移植的肿瘤生长速率，并杀死了血管性较差的肿瘤区域中神经胶质瘤细胞。该应用的主要目的是识别氨基层选择性杀死恶性神经胶质瘤细胞的细胞机制。最近发表的数据表明，胶质瘤细胞毒性可能是由阿米洛德（Amiloride）双重抑制钙钙溶剂（NCX）和1型钠质子浓度口气（NHE1）引起的。更有效的亲脂胺衍生物的非特异性细胞毒性与其细胞内渗透相对应。我们假设将氨基酸或肽偶联到C（5）位置，而在氨基层的C（2）鸟根部分可以产生新型的亲水性氨基层衍生物，并将药物活性限制为细胞表面转运蛋白。 C（2）氨洛里德甘氨酸结合物抑制NCX> NHE1，并且在有选择地杀死神经胶质瘤细胞的情况下，其有效性至少比Amiloride高50倍。 C (5) amiloride glycine conjugate inhibits NHE1"NCX, and when coupled to an opioid-like pentapeptide created an inactive prodrug. This prodrug liberates bioactive C (5)-Am-Gly when incubated with enkephalinase. In a similar fashion, we envision that glioma-specific peptidases, such as metalloproteinases, could regionally激活Amiloride肽前药。胶质瘤细胞系和原发性星形胶质细胞。这些新型的amiloride衍生物的最有效和有效性将被颅内注入人神经胶质瘤异种移植物中。