Treatment of Cervical Cancer with Artemisinin

描述(由申请人提供) 在世界范围内，每年有超过25万名妇女死于宫颈癌，在美国，近6万名妇女被诊断出患有这种恶性肿瘤的早期阶段。目前尚无有效的药物治疗宫颈异型增生或早期宫颈癌，而这些病变的临床治疗依赖于消融外科技术。开发一种无毒、有效的药物疗法将极大地简化这种疾病的治疗。在这项提案中，我们将探索使用青蒿素选择性杀伤宫颈癌细胞。青蒿素来源于中草药青蒿素，用于治疗疟疾已有2000多年的历史，最近的研究表明，青蒿素的抗疟疾活性依赖于体内过氧键，该过氧键被亚铁还原，导致活性氧的产生。有趣的是，一些癌细胞被青蒿素(以及DHA等衍生物)杀死，这显然是基于它们铁含量的增加。这项赠款中的初步研究表明，发生肿瘤的宫颈细胞比正常宫颈细胞表达更高水平的转铁蛋白受体，并通过诱导细胞凋亡优先被青蒿素杀死。这种细胞死亡是铁依赖的，我们的直接目标是定义被激活的准确的凋亡途径。我们还将确定这种化合物是否可以用来在小鼠模型中使用局部和全身给药来杀死宫颈癌细胞。此外，我们还将探索青蒿素和放射治疗之间的潜在协同性，这是用于宫颈癌的另一种治疗方式。如果我们的细胞凋亡研究表明线粒体途径参与了青蒿素诱导的细胞死亡，我们还将确定是否可以使用抗bcl2治疗来选择性地增强青蒿素的活性。这一试点提案的最终目的是加深我们对青蒿素活性的了解，将其应用从体外扩展到体内研究，并为启动人体试验产生支持性数据。由于青蒿素已经在临床上被批准用于抗疟疾，应该大大加快向人类阶段试验的过渡

DESCRIPTION (provided by applicant) Worldwide, cervical cancer kills more than 250,000 women each year and in the United States nearly 60,000 women are diagnosed with early stages of this malignancy. There are no effective pharmacologic treatments available for either cervical dysplasia or early cervical cancer and the clinical management of these lesions relies upon ablative surgical techniques. The development of a non-toxic, effective drug therapy would greatly simplify the treatment of this disease. In this proposal, we will explore the use of artemisinin for selectively killing cervical cancer cells. Artemisinin, derived from the Chinese herb, Artemisia annua, has been used for more than 2,000 years as a therapy for malaria and recent studies indicate that its anti-malarial activity depends upon an endoperoxide bond that is reduced by ferrous iron, resulting in the generation of reactive oxygen species. Interestingly, some cancer cell lines have been shown to be killed by artemisinin (and derivatives such as DHA), apparently based upon their increased iron content. The preliminary studies in this grant demonstrate that tumorigenic cervical cells express higher levels of transferrin receptor than normal cervical cells and are preferentially killed by artemisinin via the induction of apoptosis. This cell death is iron-dependent and our immediate goals are to define the precise apoptotic pathways which are activated. We will also determine whether this compound can be used to kill cervical cancer cells in a mouse model, using both topical and systemic administration. In addition, we will explore potential cooperativity between artemisinin and radiation, which is another treatment modality used for cervical cancer. If our apoptosis studies indicate that mitochondrial pathways are involved in artemisinin-induced cell death, we will also determine whether anti bcl-2 therapy can be used to selectively augment artemisinin activity. The ultimate goal of this pilot proposal is deepen our understanding of artemisinin's activities, to extend its use from in vitro to in vivo studies, and to generate supportive data for initiating human trials. Since artemisinin is already approved clinically for use as an antimalarial, the transition to human Phase trials should be greatly accelerated