POTENTIAL ANTICANCER AGENTS FROM BASIDIOMYCETES

LifePharms, Inc.已经建立了一个拥有1,000,000种独特的担子菌/子囊菌的集合，而三角研究所的天然产物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。通过整合我们各自的能力，我们建议：1)筛选LifePharms Inc.（担子菌和子囊菌储存库）对9KB细胞的生物活性；2)根据活性再确认、文献、真菌可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更大样本，4)使用生物测定指导方法从这些更大样本中分离和纯化生物活性化合物；5)对纯生物活性化合物进行完整表征；6)在拓扑异构酶I抑制和DNA切口实验中评估纯化合物的生物活性，并测量与9KB细胞的EC50值；扩大分离程序，以便为体内研究提供足够数量的纯化合物。将研究生物活性化合物的总合成和模拟合成的合成方法。(二期);8)测试化合物的体内活性。(二期)。拟议的商业应用：美国国家癌症研究所估计，1998年有近130万新发癌症病例，超过50万人死亡。癌症的死亡率约为每10万人中有160人死亡，死亡率以每年约6%的速度增长。美国每年仅在癌症药物治疗上就花费约78亿美元。对于许多类型的癌症，5年生存率非常低。因此，迫切需要新的抗癌药物。

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.