Discovery of cell cycle inhibitors from natural products

描述（由申请人提供）：迫切需要选择性靶向癌细胞并因此具有高得多的治疗指数的新的和有效的化疗剂。大多数化学治疗剂损害正常分裂细胞，这是这些药物的大部分副作用的原因。癌症选择性化疗的发现和发展是国家癌症研究所的主要目标。在第一阶段，我们发现了symlubricol A，一种从蘑菇中分离出来的癌症选择性化合物。该化合物的效力与我们的阳性对照喜树碱相似。值得注意的是，在多柔比星对增殖非癌细胞毒性具有5倍选择性（ED 50 MFC-7/ED 50 MCF 10A = 0.16）的测定中，它对癌细胞毒性的选择性也超过3倍（ED 50 MFC-7/ED 50 MCF 10A = 3.71）。在II期，我们将在1）细胞周期抑制研究，2）体内小鼠肿瘤模型和3）NCI 60细胞系毒性组中表征该化合物。如果结果证明需要进一步开发，我们将通过战略伙伴关系或与NCI合作继续这一开发。为了发现更多的选择性和有效的抗癌药物，我们将继续筛选LifePharms独特和专有的提取物库，这些提取物来自13，000多个现场收集的担子菌和子囊菌（蘑菇），以寻找选择性靶向癌细胞中细胞周期事件的抑制剂。天然产物是一种特别好的化合物来源，这些化合物是对细胞周期至关重要的靶标的优秀探针。我们提出在一组三种癌细胞系i）MFC-7、ii）NCI-H690和iii）SF-268中筛选提取物的毒性。将针对非致瘤细胞系MCF 10A筛选具有强效活性（IC 90等于或小于20 μ g/ml）的提取物，以确定选择性商数。将对含有癌症选择性化合物的提取物进行分级，并分离和鉴定活性化合物。将鉴定它们阻断细胞周期的阶段，并将进一步检查先导化合物在体内抗肿瘤模型和NCI 60细胞系组中的活性。通过利用增殖的正常细胞和癌细胞之间的这些差异，我们希望找到更多的新化合物，具有更高的肿瘤选择性和更低的毒性。

DESCRIPTION (provided by applicant): The need for new and effective chemotherapeutic agents that selectively target cancer cells and thus, would have a much higher therapeutic index is urgent. Most chemotherapeutic agents damage normal dividing cells which accounts for the majority of the side effects of these drugs. The discovery and development of cancer selective chemotherapy is a principal goal of the National Cancer Institute. During Phase 1, this project we identified symlubricol A, a cancer selective compound isolated from a mushroom. This compound is similar in potency to our positive control, camptothecin. Remarkably, it was also more than 3-fold selective for cancer cell toxicity (ED50 MFC-7/ED50 MCF10A = 3.71) in an assay that doxorubicin was 5-fold selective for proliferating noncancerous cells toxicity (ED50 MFC-7/ED50 MCF10A = 0.16). During Phase 2, we will characterize this compound in 1), cell cycle inhibition studies, 2), in vivo mouse tumor models and 3), the NCI 60 cell line toxicity panel. If the results justify additional development, we will continue this development either through strategic partnerships or in collaboration with the NCI. To discover additional selective and potent anticancer agents, we will continue screening LifePharms' unique and proprietary library of extracts from >13,000 field collected basidiomycetes and ascomycetes (mushrooms) for inhibitors that selectively target the cell cycle events in cancer cells. Natural products have been a particularly good source of compounds that are excellent probes for targets vital to the cell cycle. We propose to screen extracts for toxicity in a panel of three cancerous cell lines, i) MFC-7, ii) NCI-H690 and iii), SF-268. Those extracts with potent activity (IC90 is equal to or less than 20 ug/ml) will be screened against the nontumorigenic cell lines MCF10A, to determine a selectivity quotient. Extracts containing cancer selective compounds will be fractionated and the active compound(s) isolated and identified. The stage at which they block the cell cycle will be identified and lead compounds will be examined further for activity in in vivo antitumor models and NCI 60-cell line panel. By exploiting those differences between proliferating normal and cancer cells, we expect to find additional novel chemical compounds with increased tumor selectivity and reduced toxicity.