Chemoprotectants for Head-Neck Therapeutics

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、放射治疗或化疗/放射联合治疗的主要剂量限制和复杂副作用。它被认为是头颈部癌症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。喉癌治疗后吞咽功能障碍尤其会使人虚弱。化学保护剂的开发是这一第一阶段提案的中心目标。在初步研究中，反应生物学公司已经完成了三个独立的高通量筛选(HTS)活动，以寻找细胞生存的小分子调节剂。提出了三个具体目标：(1)验证细胞培养中的HITS；(2)促进最有前途的化学研究的HIT-to-Lead化学计划；以及(3)测试细胞系中的化合物的辐射毒性。这些化合物将通过局部或直接注射使用，不需要传统的口腔活动，因此可能在一定程度上偏离经典的利平斯基和ADMET限制。由于化疗和放射治疗方法由于靶外毒性而受到剂量限制，在癌症治疗过程中使用细胞存活促进剂可能会给患者带来几个好处。 公共卫生相关性：头颈部治疗的化学保护剂口腔粘膜炎是化疗、放射治疗或化疗/放射联合治疗的主要剂量限制和复杂副作用。它被认为是头颈部癌症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。喉癌治疗后吞咽功能障碍尤其会使人虚弱。尽管细胞凋亡被认为是口腔粘膜炎的中心主题，但到目前为止，针对caspase抑制剂的研究还很少。反应生物学公司已经开发了一些新的、有效的和选择性的caspase抑制剂，并希望在辐射诱导的细胞凋亡检测中评估它们的细胞死亡保护活性。在下一阶段的研究中，这些有效的化学保护剂将在小鼠模型中进一步优化和评估。

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.