Novel Doxorubicin Analogs:Cardiac and Cytotoxic Effects

蒽环类药物如阿霉素和柔红霉素是有价值的抗癌药物，但它们的临床效用受到累积剂量依赖性心脏毒性的影响。蒽环类药物心脏毒性与自由基损伤有关，其机制涉及破坏铁调节和形成超氧阴离子。尽管二十年来人们已经知道蒽环类药物的醌部分氧化还原循环并形成超氧阴离子，但直到最近才有报道称C-13羟基蒽环类药物代谢产物通过不可逆地抑制铁调节蛋白（IRP-1）和胞质乌头酸酶来干扰铁调节。本提案旨在通过确定不形成C-13羟基代谢物（GPX- 100和GPX-150）或通过醌机制（GPX-150）氧化还原循环的阿霉素类似物的心脏作用来利用这一信息。超声心动图、组织病理学评分、乳头肌功能、[3H] ryanodine与肌浆网结合以及血浆肌钙蛋白I水平将被用于评估长期使用阿霉素、GPX-100和GPX-150的家兔的心脏毒性。每种蒽环类药物的抗肿瘤活性将通过评估小鼠白血病P388模型的中位生存期来评估。本研究将测试蒽环类药物的C-13羟基代谢物和醌氧化还原假说，并为确定这两种新型阿霉素类似物的商业化潜力提供重要见解。拟议的商业应用：一种新的阿霉素类似物，没有心脏毒性，但具有与阿霉素相似的抗肿瘤活性和疗效，有望广泛用于治疗白血病、淋巴瘤、乳腺癌和实体瘤。这种类似物有望最终取代化疗方案中的阿霉素。

Anthracyclines such as doxorubicin and daunorubicin are valuable anti- cancer drugs but their clinical utility is compromised by cumulative dose-dependent by a cumulative dose dependent cardiotoxicity. Anthracycline cardiotoxicity has been linked to free radical damage via mechanisms that involve disruption of iron regulation and formation of superoxide anion. Although the quinone moiety of anthracyclines has been known for two decades to redox cycle and form superoxide anion, only recently has the C-13 hydroxyl anthracycline metabolites been reported to interfere with iron regulation by irreversibly inhibiting iron regulatory protein (IRP-1) and cytosolic aconitase. This proposal is designed to utilize this information by determining he cardiac effects of doxorubicin analogs that do not form C-13 hydroxymetabolites (GPX- 100 and GPX-150) or redox cycle via quinone mechanisms (GPX-150). Echocardiography, histopathology scoring, papillary muscle function, [3H] ryanodine binding to sarcoplasmic reticulum, and plasma troponin I levels will e used to evaluate cardiac toxicity in rabbits chronically treated doxorubicin, GPX-100 and GPX-150. Anti-neoplastic activity of each anthracycline will be assessed by evaluating median survival in an in vivo P388 model of murine leukemia. This study will test the C-13 hydroxy metabolites and quinone redox hypothesis of anthracycline cardiotoxicity and provide important insights into determining the potential for commercialization of these two novel doxorubicin analogs. PROPOSED COMMERCIAL APPLICATIONS: A novel doxorubicin analog devoid of cardiotoxicity but with an anti- tumor spectrum of activity and efficacy similar to doxorubicin, would be expected to be used extensively in treatment of leukemias, lymphomas, breast cancer, and solid tumors. Such an analog could e expected to eventually replace doxorubicin in chemotherapeutic regimens.