CELL BIOLOGY

3.3-细胞生物学是项目的一部分，题为：“DNA拓扑异构酶- 结肠癌的靶向治疗。 该计划将使用3-4个组织 人类结肠癌的培养细胞系，通过它们的DNA 拓扑异构酶I（topo-I）的含量、生长模式和形态 测试针对Topo-I的新类似物。 topo-I的水平， 形态进行了评价和比较1）标本 从患者获得的结肠癌和正常粘膜，2）异种移植物 和3）结肠癌的组织培养系和代表性系 选择。 这项研究将有助于该项目选择最有效的 以及用于体内测试的充分表征的化合物。 目标是 以下内容： 1.在无细胞系统中通过筛选选择的化合物将被 通过克隆形成试验检测细胞毒性，并检测 拓扑-I-DNA可切割复合物。 这些研究将通过测试来扩展 针对“静止”或常氧/缺氧细胞，并通过测量 药物吸收和代谢，比较有效的亲脂性和水- 可溶性同系物。 2.类似物对具有mdrl的结肠癌细胞系的疗效 表型将被确定，并且获得对初始 有效的类似物研究。 3.将使用（a）评价联合治疗的优点 临床有效的化疗剂，或（B）放射治疗， 与Topo-I抑制剂相继或同时给药。 对细胞杀伤的加和与协同与拮抗作用将 建立。

PROGRAM 3-CELL BIOLOGY is part of the project entitled: 'DNA Topoisomerase- I-Targeted Therapy of colonic Cancer'. The program will use 3-4 tissue culture lines of human colon cancer, well defined by their DNA topoisomerase I (topo-I) content, growth pattern and morphology for the testing of new analogs directed against topo-I. The level of topo-I and morphology has been evaluated and compared among 1) the specimens of colonic carcinoma and normal mucosa obtained from patients, 2) xenograft and 3) tissue-culture lines, and representative lines of colonic cancer chose. The research will aid the Project in selecting the most effective and well characterized compounds for in-vivo testing. the aims are the following: 1. The compounds, selected by screens in the cell-free system, will be tested for cytotoxicity by the clonogenic assay, and for the formation of topo-I-DNA cleavable complexes. The studies will be expanded by tests against 'quiescent' or euoxic/hypoxic cells, and by the measurement of drug-uptake and metabolism, comparing effective lipophilic and water- soluble congeners. 2. The efficacy of analogs against lines of colonic cancer with the mdrl phenotype will be determined, and an acquired resistance to initially effective analogs studied. 3. The merits of combination treatments will be evaluated, using (a) clinically effective chemotherapeutic agents, or (b) radiation treatment, either sequentially to or concomitantly with an inhibitor of topo-I. Additive versus synergistic versus antagonistic effects on cell kill will be established.