BIOLOGICAL EVALUATION

癌症是一种具有巨大社会经济重要性的恶性疾病。 尽管在过去的治疗中已经实现了一些改进， 几年来，仍然需要有效的药物来治疗全身性疾病。 转移性疾病的治疗。植物是一种被证明有用的 化学治疗剂，以及发现这种化学治疗剂的最集中的方法。 制剂是通过生物测定引导的分级分离的过程。在 国家合作天然产物药物发现框架 本项目将提供生物测定支持。上一 项目期间，我们开发了一组人类肿瘤细胞系 包括BC 1（乳腺）、Col 2（结肠）、Lu 1（肺）、HT-1080（肉瘤）， Mel 2（黑色素瘤）、KB、多药耐药KB-V1、ZR-75-1（乳腺）、LNCaP （前列腺）和A431（鳞状）细胞。KB-V1细胞用 在存在和不存在长春碱的情况下的植物提取物和分离物 以确定逆转多药耐药性的潜力， 表型。此外，抗有丝分裂潜力已被常规地 用培养的ASK细胞监测。我们在这些方面取得了成功， 程序和产生的数据与信息很好地结合在一起， 通过由其他成员进行的基于机制的测定获得 国家天然产物药物发现协作组。此外，本发明还提供了一种方法， 用这组细胞系获得的活性谱是有价值的 在考虑活性分离物的更先进的发展。因此，在本发明中， 这些细胞系将继续用于即将进行的项目中， 期已添加到面板中的另一个细胞系是 税2-4。该细胞系的生长依赖于添加 紫杉醇的存在，所以紫杉醇样化合物的存在可以是 在粗混合物中辨别，并且细胞系可用于 活性先导化合物的生物测定定向分级分离。此外，由于 很明显，需要某种作用机制的指示， 正确评估新的植物分离物， 更先进的发展，机械评价将进行， 这个项目的一部分这些机制研究将在 根据化学结构和内部结构保证的程度 体外活性曲线。作为额外贡献，所有分离株 将在试验中对联合体其他成员获得的数据进行评估 系统管理，所有产生的数据将被输入 一个共同的数据库。总体而言，该项目将继续侧重于 提供临床上有用的癌症化疗剂 通过国家自然资源合作组织的综合努力， 产品药物发现组。

Cancer is a recalcitrant disease of enormous socioeconomic importance. Although some improvements in therapy have been realized over the past several years, efficacious drugs are still needed for the systemic treatment of metastatic disease. Plants are one proven source of useful chemotherapeutic agents, and the most focussed method of uncovering such agents is by the process of bioassay-guided fractionation. In the framework of this National Collaborative Natural Product Drug Discovery Group, this project will provide bioassay support. In the previous project period, we have developed a panel of human tumor cell lines comprised of BC1 (breast), Col2 (colon), Lu1 (lung), HT-1080 (sarcoma), Mel 2 (melanoma), KB, multidrug-resistant KB-V1, ZR-75-1 (breast), LNCaP (prostate), and A431 (squamous) cells. KB-V1 cells are evaluated with plant extracts and isolates in the presence and absence of vinblastine to establish the potential of reversing the multidrug-resistance phenotype. In addition, antimitotic potential has been routinely monitored with cultured ASK cells. We have had success with these procedures and the resulting data integrate well with the information obtained with mechanism-based assays performed by other members of the National Collaborative Natural Product Drug Discovery Group. In addition, the activity profile obtained with this panel of cell lines is of value in considering the more advanced development of active isolates. Thus, these cell lines will continue to be employed in the upcoming project period. One additional cell line that has been added to the panel is designated Tax 2-4. Growth of this cell line is dependent on the addition of taxol to the medium, so the presence of taxol-like compounds can be discerned in crude mixtures, and the cell line can be used for the bioassay-directed fractionation of active leads. In addition, since it is clear the some indication of mechanism of action is required in order to properly assess novel plant isolates and to appraise the validity of more advanced development, mechanistic evaluations will be performed as part of this project. These mechanistic studies will be performed to the extent that is warranted on the basis of chemical structure and the in vitro activity profile. As an additional contribution, all isolates obtained by other members of the consortium will be evaluated in the test systems managed by this project, and all resulting data will be entered into a common database. Overall, this project will remained focussed on the provision of a clinically useful cancer chemotherapeutic agent through the consolidated effort of the National Collaborative Natural Product Drug Discovery Group.