? 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 ? ?
|Disbrow, Gary L; Baege, Astrid C; Kierpiec, Katie A et al. (2005) Dihydroartemisinin is cytotoxic to papillomavirus-expressing epithelial cells in vitro and in vivo. Cancer Res 65:10854-61|