NOVEL THERAPIES FOR DOXORUBICIN CARDIOTOXICITY

描述（由申请人提供）：多柔比星（DOX）是一种重要的抗癌药物，具有广泛的治疗用途。尽管其非常频繁的临床使用，但DOX的效用受到剂量限制性心脏毒性的严重损害。虽然DOX心脏毒性已被发现多年，但它仍然是一个当代问题，预防它的治疗方法尚未优化。目前唯一批准的治疗（去氮烷）只有适度的临床价值，实际上可能会降低DOX作为杀肿瘤剂的临床疗效。我们建议设计，测试和优化新的机制为基础的方法来预防DOX诱导的心脏损伤和功能障碍，是有效的，安全的，相对具有成本效益。第1阶段的目标包括9种新型双重作用化合物（新化学实体）和相应的两种组分混合物的体外筛选评估和体内药理学实验，用于基于机制的心脏保护。研究包括心肌细胞评估（对阿霉素毒性的细胞保护、吸收动力学、细胞毒性）和制剂策略（溶解度、稳定性、pH值变化率）以及使用DOX心脏毒性和DOX肿瘤杀伤功效相关小鼠模型的初步研究。 拟议的商业应用： 这项研究的商业产品包括一种药物输注溶液，用于预防阿霉素治疗期间的心脏毒性。该产品将提供针对这种危及生命的病症的保护，而不会对多柔比星的杀肿瘤作用产生负面影响，并且具有成本效益。

DESCRIPTION (provided by applicant): Doxorubicin (DOX) is an important anticancer drug with a wide array of therapeutic uses. Despite its very frequent clinical use, the utility of DOX is severely compromised by dose-limiting cardiotoxicities. While DOX cardiotoxicity has been known for many years, it remains a contemporary problem and therapies to prevent it have not been optimized. The only currently approved therapy (derazoxane) has only modest clinical value and may actually reduce the clinical efficacy of DOX as a tumoricidal agent. We propose to design, test, and optimize novel mechanism-based approaches for prevention of DOX induced cardiac injury and dysfunction that are effective, safe, and relatively cost-efficient. Phase 1 aims include in vitro screening assessments and in vivo pharmacological experiments of nine novel dual acting compounds (new chemical entities) and corresponding two component mixtures for mechanism- based cardioprotection. Studies include cardiomyocyte evaluations (cytoprotection from doxorubicin toxicity, uptake kinetics, cytotoxicities) and formulation strategies (solubilities, stabilities, pH-rate profiles) and pilot studies using relevant mouse models of DOX cardiotoxicity and DOX tumoricidal efficacy. PROPOSED COMMERCIAL APPLICATIONS: The perceived commercial product of this research includes a drug infusion solution used to prevent cardiotoxicity during doxorubixin therapy. The product will provide protection against this life-threatening condition without having negative effects on doxorubicin tumoricidal actions, and will be cost effective.