23 



mithramycin. During the same period, some 35,000 plant samples were cx)llected from 

 mainly temperate regions in over 60 countries, including the United States, through a 

 collaborative agreement between NCI and the United States Department of Agriculture 

 (USD A), and yielded over 114,000 extracts. Clinically active agents which have been 

 developed through this program include Taxol* from the Pacific yew and other related 

 species, topotecan and CPT-11, semisynthetic derivatives of camptothecin from a tree native 

 to China, and homoharringtonine from another Chinese tree. In addition to Taxol* (whose 

 initial in vitro activity was first observed in 1964 through the early program), which was 

 approved by the Food and Drug Administration (FDA) in December 1992 for the treatment 

 of patients with ovarian cancer, commercially available plant-derived anticancer drugs include 

 the Vinca alkaloids vinblastine and vincristine, from the Madagascar periwinkle, and 

 etoposide and teniposide, semisynthetic derivatives of epipodophyllotoxin, an analog of 

 podophyllotoxin from the mayapple. The thorough investigation of marine organisms as 

 sources of antitumor agents only started in the mid-1970s, but by 1981 over 16,000 extracts 

 derived from 561 species representing 413 genera had been screened. Thus far, two marine 

 organism-derived agents, didemnin B and bryostatin 1, have advanced to clinical trials, and 

 the latter has shown promising early results. 



NCI NATURAL PRODUCTS ACQUISITION PROGRAM: 

 1986-PRESENT 



Despite the number of natural product-derived agents in clinical use or development, the NCI 

 natural products discovery and development program was discontinued in the early 1980s, 

 since it was perceived that few novel active leads were being isolated from natural sources. 

 Of particular concern was the failure to yield agents effective against the major human solid 

 tumors (breast, lung, colon). This apparent failure may have been due more to the limitations 

 of the primary mouse screens rather than a deficiency of nature, and, beginning in 1985, a 

 new in vitro screening strategy involving the use of 60 human tumors growing in cell culture 

 was developed. This led to the implementation of new natural products acquisition, 

 extraction, and isolation projects; further impetus and resources for these projects were 

 provided by the initiation of a major new program within NCI in 1987 for the discovery and 

 development of agents for the treatment of HIV-infection and its sequelae. 



Contracts for the cultivation and extraction of fungi and cyanobacteria from international 

 sources were established in 1985 and 1986, respectively; later contracts have focussed on the 

 investigation of marine bacteria and simple animals. Marine organism collections have 

 centered on the Indo-Pacific region since 1986, and collection contractors have included the 

 Australian Institute of Marine Science, Harbor Branch Oceanographic Institute in Florida, and 

 the Coral Reef Research Foundation based in Chuuk (TRUK Islands, Federated States of 

 Micronesia). Contracts for the collection of plants from tropical and subtropical regions of 

 Africa and Madagascar, Central and South America, and Southeast Asia were awarded to 

 Missouri Botanical Garden, New York Botanical Garden, and the University of Illinois at 

 Chicago (UIC) (assisted by the Arnold Arboretum at Harvard University and the Bishop 



