BIOCHEMICAL AND MECHANSIMS OF ACTION OF STUDIES WITH

根据本主协议发布的任何主协议订单的目的 协议将确定可能的作用机制， 开发人员感兴趣的潜在抗肿瘤药物 治疗计划（DTP）。 大多数待研究的化合物将 已通过DTP体外人肿瘤细胞系筛选鉴定。 显示特异性差异细胞毒性和/或生长的化合物 将考虑抑制作用以进行进一步评价。 阐发 这种药剂的生化作用机制将被用来帮助 为临床试验的化合物开发设定优先级。 化合物 也可根据其机械性能选择进行机械评价。 抗转移、光敏或放射增敏活性。 因此 所进行的特定生物化学研究可能因化合物而异， 化合物. 将尽可能进行机制评价 使用来自体外筛选的细胞谎言。 研究可以使用 培养的细胞、细胞提取物、纯化的细胞组分，和/或 完整动物和分离组织。 特定的生化效应 评估的可能包括诱导DNA损伤，干扰RNA 处理，核苷酸池大小的变化，DNA结合， 特定的细胞酶（例如，DNA聚合酶、引物酶和甲基化酶; 嘌呤和嘧啶从头合成酶;补救酶; 拓扑异构酶I和II;修复酶），抑制大分子 合成，对微管蛋白和有丝分裂纺锤体的影响， 自由基的形成和与细胞膜成分的相互作用， 蛋白激酶C、G蛋白和其他参与信号传导的受体 转导、生长调节、分化和癌基因表达。

The objective of any Master Agreement Orders issued under this Master Agreement will be to determine the probable mechanism(s) of action of potential antitumor agents which are of interest to the Developmental Therapeutics Program (DTP). The majority of compounds to be studies will have been identified by the DTP in vitro human tumor cell line screen. Those compounds demonstrating specific differential cytotoxic and/or growth inhibitory effects will be considered for further evaluation. Elucidation of the biochemical mechanism of action of such agents will be used to help set priorities for development of compounds to clinical trial. Compounds may also be selected for mechanistic evaluation on the basis of their antimetastatic, photosensitizing or radiosensitizing activities. Thus, the specific biochemical studies performed may vary greatly from compound to compound. Mechanistic evaluations will be conducted wherever possible using cell lies from the in vitro screen. Studies may be performed with cultured cells, cellular extracts, purified cellular components, and/or intact animals and isolated tissues. Specific biochemical effects to be evaluated may include induction of DNA damage, perturbation of RNA processing, changes in nucleotide pool sizes, DNA binding, inhibition of specific cellular enzymes (e.g., DNA polymerases, primases, and methylases; enzymes of de novo purine and pyrimidine synthesis; salvage enzymes; topoisomerases I and II; repair enzymes), inhibition of macromolecular synthesis, effects on tubulin and mitotic spindle, alterations in free radical formation and interactions with cell membrane components such as protein kinase C, G proteins and other receptors involved in signal transduction, growth regulation, differentiation, and oncogene expression.