Chemoprotectants for Head-Neck Therapeutics

用于头颈治疗的化学保护剂

• 批准号: 8123886
• 负责人: HAICHING MA
• 金额: $ 75.14万
• 依托单位: REACTION BIOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8123886
• 关键词: Address; Adopted; Adverse effects; Affect; Animal Model; Animal Testing; Apoptosis; Apoptosis Regulator; Apoptotic; Biological Assay; Biological Availability; Biology; Caspase; Caspase Inhibitor; Cell Cycle Regulation; Cell Death; Cell Line; Cells; Cessation of life; Characteristics; Chemicals; Chemoprotective Agent; Clinical Trials; Collaborations; Complication; Cytoprotection; Cytoprotective Agent; DNA Damage; Deglutition; Development; Dose; Dose-Limiting; Drug Delivery Systems; Effectiveness; Environment; Exhibits; Fibroblasts; Functional disorder; Future; Gene Expression; Genes; Genome; Goals; Grant; Head and Neck Cancer; Head and neck structure; Human; In Vitro; Inhibitory Concentration 50; Lead; Life; Malignant Neoplasms; Malignant neoplasm of larynx; Metabolism; Methods; Modeling; Mucous body substance; Mutation; Normal Cell; Oncogenes; One-Step dentin bonding system; Oral; Oral mucous membrane structure; Pain; Patients; Penetration; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Prevention; Property; Radiation; Radiation therapy; Radio; Reaction; Reaction Time; Research; Signal Transduction; Site; Staging; Structure-Activity Relationship; Testing; Therapeutic; Time; Tissues; Toxic effect; Work; absorption; analog; base; cancer cell; cancer therapy; caspase-3; chemotherapy; drug discovery; improved; in vitro Model; in vivo; inhibitor/antagonist; keratinocyte; novel; oral mucositis; phase 1 study; programs; radiation effect; response; scaffold; small molecule

DESCRIPTION (provided by applicant): Chemoprotectants for Head-Neck Therapeutics Oral mucositis occurs as a major dose-limiting and complicating side effect of chemotherapy, radiotherapy, or combined chemo/radiotherapy. It is considered the most significant complication of head and neck cancer therapy. Oral mucositis is accompanied by tremendous pain and can cause life threatening complications. Dysfunction in swallowing following laryngeal cancer therapy can be particularly debilitating. The development of chemoprotectants is the central goal of this proposal. In preliminary studies, Reaction Biology Corporation has discovered selective, reversible, small molecule caspase inhibitors, which have multiple advantages compared to the compounds in the clinical trials. For example, caspase inhibitors from many pharmaceutical companies' drug discovery programs have one of more of the following characteristics: irreversible, peptide-mimic, Pan-caspase inhibitor. In Phase I studies, these compounds are very active in cell based assays, demonstrated significant cell death prevention activities in chemical and radiation induced cell death in normal cell lines. In this Phase II application, we will continue to improve these inhibitors in potency and efficacy in cell based assays and DMPK profiles, to look for the final lead(s) in animal model tests. In this new proposal, the key aims are: 1) Structure-Activity Relationship (SAR) studies to improve caspase inhibitors' potency; 2) Define caspase inhibitors' treatment conditions in vitro in conjugation with chemotherapy and radiation treatments; 3) Test caspase inhibitors' tissue penetration and efficacy in protecting oral mucous cells from radiation therapy in 3D oral mucosa model. PUBLIC HEALTH RELEVANCE: Chemoprotectants for Head-Neck Therapeutics Oral mucositis occurs as a major dose-limiting and complicating side effect of chemotherapy, radiotherapy, or combined chemo/radiotherapy. It is considered the most significant complication of head and neck cancer therapy. Oral mucositis is accompanied by tremendous pain and can cause life threatening complications. Dysfunction in swallowing following laryngeal cancer therapy can be particularly debilitating. Even though apoptosis is considered the central theme in oral mucositis, little work with caspase inhibitors has been conducted to date. Reaction Biology Corp. has discovered a few novel, potent and selective caspase inhibitors and would like to evaluate their cell death protection activities in chemotherapy and radiation induced apoptosis assays. Additional SAR studies will improve the potency of these compounds, and studies in 3D oral mucosa models will further reveal tissue penetration and cell protective properties of caspase inhibitors without testing in vivo animal model, which will help to eliminate toxic and ineffective compounds in early stage, and reducing the number of studies in animal models in the future.

口腔黏膜炎是化疗、放疗或化疗/放疗联合治疗的主要剂量限制和并发症副作用。它被认为是头颈癌治疗中最重要的并发症。口腔黏膜炎伴随着巨大的疼痛，并可能导致危及生命的并发症。喉癌治疗后的吞咽功能障碍会使人特别虚弱。化学保护剂的开发是本提案的中心目标。在初步研究中，Reaction Biology公司发现了选择性的、可逆的、小分子的半胱天冬酶抑制剂，与临床试验中的化合物相比，它具有多种优势。例如，许多制药公司的药物发现项目中的半胱天冬酶抑制剂具有以下多个特征之一：不可逆，多肽模拟，泛半胱天冬酶抑制剂。在I期研究中，这些化合物在基于细胞的分析中非常活跃，在化学和辐射诱导的正常细胞系细胞死亡中显示出显著的细胞死亡预防活性。在这个II期申请中，我们将继续提高这些抑制剂在基于细胞的测定和DMPK谱中的效力和功效，以寻找动物模型试验中的最终先导。本研究的主要目标是：1)研究结构-活性关系（SAR）以提高半胱天冬酶抑制剂的效力；2)明确caspase抑制剂联合化疗和放疗的体外治疗条件；3)在口腔黏膜三维模型中检测caspase抑制剂的组织渗透及对口腔黏膜细胞的保护作用。