Treating Cancer of the GI using Cryomolecular Biology

描述(由申请人提供)：合作的冷冻医学科学公司(CMSI) 与德克萨斯大学医学中心和约翰霍普金斯医学中心合作 建议开发冷冻外科程序来治疗 胃肠道(GI)癌。这一阶段的研究将集中在分子方面 低温外科设备原型的生物学研究和开发； 第二阶段的工作将集中在这些内窥镜的应用上 犬类模型中的冷冻外科设备。CMSI认识到有必要探索 细胞死亡的分子生物学机制 体温过低(15至4摄氏度)和冰冻(0至-196摄氏度)。CMSI正在使用 分子生物学研究开发改进的冷冻手术方案 通过了解冷冻相关的细胞死亡和存活。数据来自 在过去的几年里，冷冻外科医生已经表明，人体内的癌细胞 冷冻手术过程中产生的组织冰球的中间部分死亡 立即由于坏死而死亡；而许多死于冰球的细胞 温度接近0摄氏度的外围地区在几天后死亡 冷冻消融。而一些外周细胞在冰冻的折磨中幸存下来。 CMSI进行的体外和分子遗传学研究表明，细胞被冷冻 在-70℃下死亡；而在-70℃下死亡的细胞中至少有25% -15C通过细胞凋亡而死亡。这些观察结果导致了CMSI的体外 冷冻化疗辅助治疗研究表明，添加无毒水平 细胞凋亡启动剂5-氟尿嘧啶(5-FU)对肾、肝、前列腺癌的影响 最值得注意的是，结肠癌细胞增强了冷冻消融的效果。这 第一阶段赠款将确定是否(1)对HT-29和/或Caco-2进行亚致死冷冻 结肠癌细胞导致合成增多的细胞死亡 调节因子、bcl2、bax、APAF1、FADD、Fas和PARP；(2)亚致死性冷冻 导致caspase mRNA水平上调；(3)细胞因冷冻而死亡 损伤是细胞周期时相依赖的，(4)可以修改为两个 目前正在设计用于治疗的原型冷冻外科设备 Barrett‘s食道癌和结肠癌，使它们更有用和有效 在冷冻外科套房里。 建议的商业应用：不可用

DESCRIPTION (provided by applicant): Cryomedical Sciences Inc. (CMSI) teamed with the University of Texas Medical Center and Johns Hopkins Medical Center proposes to develop cryosurgical procedures for the treatment of gastrointestinal (GI) cancers. This Phase 1 study will focus on molecular biological studies and development of prototype cryosurgical devices; whereas the Phase II work will focus on the application of these endoscopic cryosurgical devices in a canine model. CMSI recognizes a need to explore the molecular biological mechanisms of cell death that occur as a consequence of hypothermic(15 to 4C) and freezing (0C to -196C) episodes. CMSI is using molecular biological research to develop improved cryosurgical protocols through an understanding freeze-related cell death and survival. Data from cryosurgeons in the past few years have indicated that cancer cells in the middle of a tissue iceball created during cryosurgical procedures die immediately due to necrosis; whereas many of the cells that die in the iceball periphery where temperatures approach 0C die several days subsequent to cryoablation. While some of the peripheral cells survive the freezing insult. In vitro and molecular genetic studies performed at CMSI show that cells frozen at -70C die by necrosis; whereas at least 25 percent of the cells that die at -15C succumb via apoptosis. These observations lead to CMSI's in vitro cryochemo adjunct therapy studies showing that the addition of non-toxic levels of the apoptosis initiator 5-fluorouracil (5-FU) to kidney, liver, prostate and most notably colon cancer cells enhances the efficacy of cryoablation. This Phase I grant will determine if (1) sub-lethal freezing of HT-29 and/or Caco-2 colon carcinoma cells results in the increase in synthesis of the cell death regulators, bcl-2, bax, Apaf 1, FADD, Fas and PARP; (2) sublethal freezing causes an up-regulation of caspase mRNA levels; (3) cell death due to freezing injury is cell cycle phase dependent and (4) modifications can be made to two prototype cryosurgical devices that are currently being designed for treating Barrett's esophagus and colon cancer to make them more useful and efficacious in the cryosurgical suite. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE