EFFICACY STUDIES OF CHEMOPREVENTIVE AGENTS IN ANIMAL MOD

拟议研究的目标将是在4NQO模型中调查一系列四种化合物的化学预防活性。被检测的四种药物中至少有两种(iNOS抑制剂、抗血管生成剂、COX-2抑制剂，TBA)的MTDS是已知的。因此，目前仅对两种制剂进行了初步毒性研究。5周龄雄性F344大鼠随机给予饮水中20ppm的4NQO。大鼠连续灌服含水4NQO 10周。在这段时间结束时，给大鼠常规的水。从4NQO停止后的两天开始，大鼠再接受22周的化学预防药物治疗。在这段时间结束时，大鼠将被二氧化碳窒息而处死。4NQO治疗32周后处死大鼠。在尸检时，其他各种组织，特别是口腔组织，正在进行大体检查。大鼠的舌头固定在福尔马林中。口腔的其他组织用福尔马林固定。对于组织病理学确认，组织和大体病变应固定在10%缓冲福尔马林中，石蜡包埋，并采用常规组织学方法进行H&E染色。

The objectives of the proposed studies will be to investigate a series of four compounds for chemopreventive activity in the 4NQO model. The MTDs of at least two of the four agents to be examined (iNOS inhibitor, antiangiogenic agent, Cox-2 inhibitor, TBA) are known. Therefore preliminary toxicity studies are being performed on only two agents. Five week old male F344 rats are scheduled for administration 20 ppm 4NQO in the drinking water ad libitum. Rats are being maintained continually on 4NQO containing water for a period of 10 weeks. At the end of this time period rats regular water is given. Starting 2 days following the cessation of 4NQO rats are being given chemopreventive agents for an additional 22 weeks. At the end of this time period rats are being sacrificed by CO2 asphyxiation. All rats are sacrificed 32 weeks following the initiation of treatment with 4NQO. At necropsy various other tissues, particularly of the oral cavity, are being examined grossly. Tongues of rats are fixed in formalin. Other tissues of the oral cavity are fixed in formalin. For histopathologic confirmation, tissues and gross lesions shall be fixed in 10% buffered formalin, embedded in paraffin blocks and processed by conventional histologic methods using H&E staining.