Chemoprotectants for Head-Neck Therapeutics

用于头颈治疗的化学保护剂

• 批准号: 7669878
• 负责人: HAICHING MA
• 金额: $ 25.29万
• 依托单位: REACTION BIOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669878
• 关键词: 2-Mercaptoethanol; Adverse effects; Animal Testing; Antineoplastic Agents; Apoptosis; Biological Assay; Biology; Biotechnology; Cancer cell line; Caspase; Caspase Inhibitor; Caspase-1; Cell Count; Cell Culture Techniques; Cell Death; Cell Line; Cell Survival; Cells; Cellular Assay; Chemicals; Chemistry; Chemoprotective Agent; Cisplatin; Collaborations; Complication; Cysteine; Cytoprotection; Cytoprotective Agent; DEVDase; Deglutition; Dermal; Development; Dose-Limiting; Doxorubicin; Drug Formulations; Drug Industry; Embryo; Endothelium; Esophagus; Evaluation; Exclusion; Family; Fibroblasts; Functional disorder; Generations; Gland; Goals; Head and Neck Cancer; Head and neck structure; Human; Human Cell Line; In Situ Nick-End Labeling; Inhibitory Concentration 50; Injection of therapeutic agent; Life; Liver; Malignant Epithelial Cell; Malignant neoplasm of larynx; Mammalian Cell; Measures; Methotrexate; Microarray Analysis; Molecular; Mus; Normal Cell; Oral; Oral cavity; Oxidation-Reduction; Pain; Patients; Peptide Hydrolases; Periodontal Ligament; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phosphotransferases; Protein Isoforms; Radiation; Radiation therapy; Rattus; Reaction; Saliva; Small Business Innovation Research Grant; Specificity; Structure; Structure-Activity Relationship; System; Testing; Therapeutic; Toxic effect; Triage; Trypan Blue; Validation; Work; analog; cancer cell; cancer therapy; chemotherapy; cytotoxicity; drug development; experience; functional group; hepatoma cell; high throughput screening; in vitro testing; inhibitor/antagonist; keratinocyte; meetings; mouse model; novel; oral mucositis; programs; prototype; public health relevance; research study; scaffold

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 Phase I proposal. In preliminary studies, Reaction Biology Corporation has completed three separate high throughput screening (HTS) campaigns for small molecular regulators of cellular survival. Three specific aims are proposed: (1) validation of hits in cell culture; (2) hit-to-lead chemistry program to advance the most promising chemistries; and (3) testing of compounds in cell lines for radiotoxicity. Such compounds will be used topically or by direct injection and do not require traditional oral activity and therefore may deviate to some degree from classic Lipinsky and ADMET constraints. Since chemotherapy and radiotherapeutic approaches are dose-limited due to off-target toxicity, the use of cell survival promoting agents during cancer treatments may offer several benefits to patients. 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 developed a few novel, potent and selective caspase inhibitors and would like to evaluate their cell death protection activities in radiation induced apoptosis assays. The potent chemoprotectants will be further optimized and evaluated in mice models in next phase study.

描述（由申请人提供）：头颈部治疗的化学保护剂口腔粘膜炎是化疗、放疗或联合化疗/放疗的主要剂量限制性和复杂副作用。它被认为是头颈癌治疗中最重要的并发症。口腔粘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可能特别虚弱。化学保护剂的开发是第一阶段提案的中心目标。在初步研究中，Reaction Biology Corporation已经完成了三个独立的高通量筛选（HTS）活动，用于细胞存活的小分子调节剂。提出了三个具体目标：（1）在细胞培养中验证命中;（2）命中到铅化学程序，以推进最有前途的化学;和（3）测试细胞系中的化合物的放射毒性。此类化合物将局部使用或通过直接注射使用，并且不需要传统的口服活性，因此可能在一定程度上偏离经典的Lipinsky和ADMET限制。由于化疗和放疗方法由于脱靶毒性而受到剂量限制，因此在癌症治疗期间使用细胞存活促进剂可为患者提供若干益处。 公共卫生相关性：口腔粘膜炎是化疗、放疗或联合化疗/放疗的主要剂量限制性和并发性副作用。它被认为是头颈癌治疗中最重要的并发症。口腔粘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可能特别虚弱。尽管细胞凋亡被认为是口腔粘膜炎的中心主题，但迄今为止几乎没有进行半胱天冬酶抑制剂的研究。Reaction Biology Corp.已经开发了一些新的、有效的和选择性的半胱天冬酶抑制剂，并且希望在辐射诱导的细胞凋亡测定中评估它们的细胞死亡保护活性。在下一阶段的研究中，将在小鼠模型中进一步优化和评估有效的化学保护剂。