IMPROVING CRYOSURGERY THROUGH UNDERSTANDING APOPTOSIS

描述：(改编自申请人的摘要)：本第一阶段提案具有 开发改进的前列腺癌和前列腺癌冷冻治疗的总体目标 其他癌症通过联合一种药物(S)触发或促进基因激活 在传统的冷冻外科技术中，细胞死亡或凋亡。初步 提供的数据支持这样的假设，即细胞死亡发生在 细胞受到温和的冰冻侮辱(即-OC)是一个后果 对细胞凋亡的影响。坊间的冷冻外科数据表明， 在冷冻手术过程中产生的组织冰球的中间部分死亡 立即由于坏死；而冰球周围的细胞 在冷冻消融后几天，温度接近0摄氏度就会死亡，而 这个外围的其他细胞完全可以在冰冻的侮辱中存活下来。离体 提供的数据显示，在零下70摄氏度冷冻的细胞会因坏死而死亡；而在零下70摄氏度冷冻的细胞会因坏死而死亡。 在零下15摄氏度死亡的细胞中，至少有25%是通过凋亡而死亡的。这些 观察结果导致初步研究表明， 5-氟尿嘧啶(5-FU)的无毒水平，这是一种众所周知的诱导细胞凋亡的方法 抗癌药物，大大提高了冷冻诱导的细胞杀伤效果。 基于这些发现，建议确定(1)5-FU 对冷冻诱导的细胞死亡的预处理增强与其他 癌细胞类型；(2)其他抗癌剂的加入也可增强 5-FU对冷冻诱导的细胞死亡的影响；(3)其他化疗药物 化合物显示5-FU-1作用；(4)冷冻诱导的细胞凋亡与 线粒体细胞色素c释放增加和/或上调 抑癌基因P53和(5)一种新的双标记法可以 发展到这样一种情况，即凋亡和坏死细胞的相对数量可以是 在体外冷冻方案之后进行了量化。成功完成 这些研究应该为小说第二阶段的发展提供基础 双功能冷冻探头设备，也将提供化疗药物 从而提高患者在冷冻手术后的存活率 治疗。 建议的商业应用：不可用

DESCRIPTION: (Adapted from the Applicant's Abstract): This Phase I proposal has the overall goal of developing improved cryosurgical treatment for prostate and other cancers by combining a drug (s) which triggers or promote gene activated cell death, or apoptosis, with traditional cryosurgical technique. Preliminary data are presented to support the hypothesis that cell death that occurs when cells are subjected to mild freezing insults (i.e. - minus oC) is a consequence of apoptosis. Anecdotal cryosurgical data have indicated that cancer cells in the middle of a tissue iceball created during cryosurgical procedures die immediately due to necrosis; whereas cells at the iceball periphery where temperatures approach 0oC die several days subsequent to cryoablation, while other cells in this periphery survive the freezing insult altogether. In vitro data provided show that cells frozen at minus 70oC die by necrosis; whereas at least 25% of the cells that die at minus 15 oC succumb via apoptosis. These observations lead to preliminary studies that showed that the addition of non-toxic levels of 5-fluorouracil (5-FU), a well-known apoptotic-inducing anticancer drug, greatly enhances the efficacy of cryo-induced cell killing. Based on these findings, it is proposed to determine if (1) the 5-FU pre-treatment enhancement of freezing-induced cell death is common to other cancer cell types; (2) the addition of other anticancer agents also enhances 5-FU's effect on freezing-induced cell death; (3) other chemotherapeutic compounds exhibit 5-FU-1 effects; (4) freezing-induced apoptosis is related to an increase in cytochrome c release from the mitochondria and/or upregulation of the tumor suppresser gene, p53 and (5) a novel double-label assay can be developed such that the relative number of apoptotic and necrotic cells can be quantified subsequent to an in vitro freezing protocol. Successful completion of these studies should provide basis for the development in Phase II of novel dual function cryoprobe devices that will also deliver chemotherapeutic agents to the tumor and thereby increase patient survival subsequent to cryosurgical treatments. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE