NOVEL THERAPIES FOR DOXORUBICIN CARDIOTOXICITY

说明(申请人提供)：阿霉素(DOX)是一种重要的抗癌药物，具有广泛的治疗用途。尽管DOX的临床应用非常频繁，但其实用性受到剂量限制的心脏毒性的严重影响。虽然DOX的心脏毒性已经知道很多年了，但它仍然是一个当代的问题，预防它的治疗方法还没有得到优化。目前唯一被批准的治疗方法(地拉唑烷)只有适度的临床价值，实际上可能会降低DOX作为杀瘤剂的临床疗效。我们建议设计、测试和优化新的基于机制的方法来预防DOX引起的心脏损伤和功能障碍，这些方法是有效、安全和相对经济的。第一阶段的目标包括九种新的双重作用化合物(新化学实体)和相应的基于机制的心脏保护的两组分混合物的体外筛选评估和体内药理实验。研究包括心肌细胞评估(阿霉素毒性的细胞保护、摄取动力学、细胞毒性)和配方策略(溶解性、稳定性、pH速率曲线)，以及使用相关小鼠模型进行的DOX心脏毒性和DOX杀瘤效果的初步研究。 建议的商业应用： 这项研究的预期商业产品包括一种用于预防多柔比星治疗期间心脏毒性的药物输液。该产品将提供对这种危及生命的疾病的保护，而不会对阿霉素的抗肿瘤作用产生负面影响，并且将具有成本效益。

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.