Novel Doxorubicin Analogs:Cardiac and Cytotoxic Effects

阿霉素和柔红霉素等蒽环类药物是很有价值的抗癌药物，但其临床应用受到累积剂量依赖和累积剂量依赖性心脏毒性的影响。蒽环类药物的心脏毒性与自由基损伤有关，其机制包括扰乱铁调节和形成超氧阴离子。虽然二十年前人们就知道蒽环类化合物中的苯醌类化合物具有氧化还原循环和形成超氧阴离子的作用，但直到最近才有报道称，C-13羟基的蒽环类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的调节。这项建议旨在通过确定阿霉素类似物的心脏效应来利用这一信息，这些阿霉素类似物不形成C-13羟基代谢物(GPX-100和GPX-150)或通过醌机制形成氧化还原循环(GPX-150)。超声心动图、组织病理学评分、乳头肌功能、[~3H]兰尼定与肌浆网的结合和血浆肌钙蛋白I水平将用于评估长期使用阿霉素、GPX-100和GPX-150治疗的兔的心脏毒性。在体内P388小鼠白血病模型中，将通过评估中位存活率来评估每种蒽环类药物的抗肿瘤活性。这项研究将检验蒽环类药物心脏毒性的C-13羟基代谢物和苯醌氧化还原假说，并为确定这两个新的阿霉素类似物的商业化潜力提供重要的见解。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有效性，有望广泛用于白血病、淋巴瘤、乳腺癌和实体瘤的治疗。这种类似物有望最终在化疗方案中取代阿霉素。

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.