Treating Cancer of the GI using Cryomolecular Biology

描述（由申请人提供）：Cryomedical Sciences Inc.（CMSI）联手 德克萨斯大学医学中心和约翰霍普金斯医学中心 建议开发冷冻外科手术治疗 胃肠道（GI）癌症。这项1期研究将侧重于分子 生物学研究和原型冷冻外科设备的开发;而 第二阶段的工作将集中在这些内窥镜的应用， 冷冻外科设备在犬模型中的应用。CMSI认识到有必要探讨 细胞死亡的分子生物学机制， 低温（15至4 ℃）和冷冻（0 ℃至-196 ℃）发作。CMSI正在使用 分子生物学研究，以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。数据从 冷冻外科医生在过去的几年中指出， 在冷冻手术过程中产生的组织冰球的中间 由于坏死而立即死亡;而在冰球中死亡的许多细胞 温度接近0摄氏度的外围在几天后死亡， 冷冻消融术同时一些外周细胞在冷冻损伤中存活。 在CMSI进行的体外和分子遗传学研究表明， 在-70 ℃时，至少有25%的细胞因坏死而死亡;而在-70 ℃时， -15C通过凋亡而死亡。这些观察结果导致CMSI在体外 冷冻化疗辅助治疗研究显示， 凋亡引发剂5-氟尿嘧啶（5-FU）对肾脏、肝脏、前列腺和 最显著的是结肠癌细胞增强了冷冻消融的功效。这 第一阶段拨款将确定（1）HT-29和/或Caco-2的亚致死冷冻 结肠癌细胞导致细胞死亡的合成增加 调节因子bcl-2、bax、Apaf 1、FADD、Fas和PARP;（2）亚致死冷冻 导致caspase mRNA水平上调;（3）由于冷冻导致的细胞死亡 损伤是细胞周期时相依赖性的，以及（4）可以对两个 目前正在设计的用于治疗 巴雷特食管和结肠癌，使他们更有用和有效 在冷冻手术室里 拟议商业应用：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