报告题目：210/6/4 A p53-based strategy for cancer therapy protection
主 讲人 ：袁志敏教授
Professor Chief of Radiation Biology
Department of Radiation Oncology,The University of Texas Health Science Center at San Antonio
报告地点：上海交通大学 文选医学大楼 417室
Abstract：Radiotherapy and chemotherapy kill cancer cells primarily via DNA damage, but also affect normal tissues by strongly activating p53, causing pathological consequences and severe side effects. We recently showed that a brief treatment of non-transformed cells with sodium arsenite at low-doses (1-10 mM for 12 h) is associated with upregulation of Hdm2 and accumulation of p53 in the cytoplasm. Through the MAPK pathway, low-levels of arsenite stimulate the P2 promoter-mediated expression of Hdm2, which then promotes p53 ubiquitination and subsequent nuclear export. As a consequence, the p53 response to genotoxic stress is compromised, as evidenced by the impaired p53 activation and apoptosis in response to UV irradiation or 5FU treatment. The ability of arsenite to impede DNA damage-induced p53 activation is further demonstrated by a significantly blunted p53-dependent tissue damages induced by 5FU treatment when mice were fed with arsenite-containing water. To exploit the distinct p53 status between normal tissues and tumors, we explored the use of low-dose arsenic-induced transient p53 suppression as a novel strategy for cancer therapy protection by using mouse tumor xenografts models. A breast carcinoma cell line MBA-MD-231 was used to generate a mouse xenograft model. Treatments were initiated three weeks after implantation when the breast carcinoma cells developed into readily visible tumor with an average volume approximately 100 mm3. Arsenic pretreatment was carried out by feeding tumor-bearing mice with water containing with or without 1.0 mg/L sodium arsenic for three days. Mice were then treated with 5FU (30mg/kg) or irradiated with 2Gy TBI daily for one week. In the vehicle or control group, the tumor volume continued increase with time. Arsenic treatment did not have any detectable effect on growth of the implant tumors, indicating that such a short arsenic treatment causes neither promotion nor inhibition of tumor progression. As expected, 5FU or radiation treatment for one week resulted in marked tumor regression. Arsenic pretreatment showed little effect on 5FU or irradiation-induced tumor suppression, indicating that low-dose arsenic pretreatment does not detectably affect the efficacy of 5FU or radiation, at least in the human breast carcinoma xenograft mouse model. We monitored body weight change to assess 5FU or radiation-induced toxicity. Mice treated with 5FU or irradiation significantly lost their body weight. Significantly, such therapy-induced body weight loss was effectively prevented by arsenic pretreatment. We also examined the small intestine and bone marrow cells, two tissues most sensitive to chemotherapy or radiation treatment. Consistent with the observations at the whole animal level, 5FU and radiation treatments were associated with severe damages to small intestine and bone marrow cells, and such damages were significantly reduced by low-dose arsenic pretreatment. Collectively, the results demonstrate that a brief treatment with low-dose arsenic is associated with a marked protection of normal tissues without compromising the ability of 5FU or irradiation to kill carcinoma cells. The animal studies have provided proof-of-principle for the use of low-dose of arsenic in chemotherapy and radiotherapy protection, serving as strong rationales to initiate clinical trials. The overarching goal of this research is to provide more effective treatment for cancer patients by minimizing adverse side effects and thereby to reduce patient mortality and improve quality of life. If successful, the proposed work may have potential to impact patient care in a fundamental way.