POTENTIAL ANTICANCER AGENTS FROM BASIDIOMYCETES

LifePharms，Inc.已经建立了超过12，000种独特的担子菌/子囊菌的集合，三角研究所的天然产品实验室在从天然来源分离有效的抗肿瘤药物方面有着悠久而成功的历史。通过合作我们各自的能力，我们建议1）筛选生命制药公司，针对9 KB细胞的生物活性的担子菌和子囊菌的储存库; 2）基于活性的再确认、文献、真菌的可获得性等，对样品进行优先排序; 3)获得确认的生物活性真菌物种的较大样品，4）使用生物测定引导的方法从这些较大样品中破碎和纯化生物活性化合物; 5）完全表征纯生物活性化合物; 6）在拓扑异构酶I抑制和DNA切口测定中评价纯化合物的生物活性，以及测量相对于9 KB细胞的EC 50值; 7）扩大分离程序，以便为体内研究提供足量的纯化合物。生物活性化合物的全合成和类似物合成都将采用合成方法。（阶段II）; 8）测试化合物的体内活性。（第二阶段）。拟议的商业应用：国家癌症研究所估计，1998年有近130万新的癌症病例，50多万人死亡。癌症的死亡率为每10万人中约160人死亡，并且死亡率每年以约6%的速度增加。美国每年仅在药物癌症治疗上就花费约70 - 80亿美元。对于许多类型的癌症，5年生存率非常低。因此，迫切需要新型抗癌药物。

LifePharms, Inc. has established a collection of >12,000 unique species of basidiomycetes/ascomycetes, and the Natural Products Laboratory of Research Triangle Institute has a long and successful history of isolating potent antitumor agents from natural sources. By teaming our respective capabilities, we propose to 1) screen the LifePharms Inc., repository of basidiomycetes and ascomycetes for bioactivity against 9KB cells; 2) prioritize the samples based upon reconfirmation of activity, literature, availability of fungi, etc.; 3) obtain larger samples of the confirmed bioactive fungal species, 4) fractionate and purify the bioactive compounds from these larger samples using a bioassay guided approach; 5) characterize the pure bioactive compounds completely; 6) evaluate the bioactivity of the pure compounds in topoisomerase I inhibition and DNA nicking assays, as well as, measure EC50 values vs. 9KB cells; 7) scale up the isolation procedures in order to provide an ample quantity of pure compound for in vivo studies. Synthetic methodologies will be pursued for both total and analog synthesis of the bioactive compounds. (Phase II); 8) test the compounds for in vivo activity. (Phase II). PROPOSED COMMERCIAL APPLICATIONS: The National Cancer Institute estimated nearly 1.3 million new cases of cancer in 1998 and over one-half million deaths. Cancer has a mortality rate of about 160 deaths per 100,000 population, and the death rates are increasing at about 6% annually. The United States spends approximately $7-8 billion annually on pharmacological cancer therapies alone. For many forms of cancer, the 5-year survival rate is very low. Consequently, novel anticancer agents are needed urgently.