In 1937, the US NCI was founded in order to initiate and coordinate research related to cancer. In 1955, the NCI created the Cancer Chemotherapy National Service Center (CCNSC) with the aim of developing a program of screening chemical substances for anti-cancer activity. Initially envisioned as a voluntary cooperative cancer chemotherapy program, the CCNSC has gradually grown into a major drug research and development unit. CCNSC (now incorporated into NCI's Developmental Therapeutics Program) cooperates with academia and is heavily involved with the pharmaceutical industry in the acquisition and screening of potential anti-cancer agents.
In its efforts to find active anti-cancer agents, NCI has engaged in rational design and testing of synthetic anti-tumor agents, and the random screening of natural products. From the outset the natural products screening program included plants, microbial sources and animals (primarily marine organisms). Suffness and Douros (1982) report that by the end of the first phase of the natural products testing program, the NCI annual screening throughput had reached:
14000 crude natural product extracts of which: 8000 fermentation, 5000 plant, 1000 marine animal;
10000 new synthetic compounds; and
From its initiation, NCI has employed three different screening methodologies to test for anti-cancer activity in natural products and synthetic chemical compounds. The first NCI screening program, from 1958 to 1975, on the basis of an in-vivo screen using the murine leukemia cell line, L1210. In the second program, a modification of the original program, NCI used from 1975 to 1986 an in-vivo prescreen (against murine leukemia cell line P388), followed by in-vivo testing using a panel of murine tumors and human xenografts in mice. These two initial programs at NCI are described by Suffness et al. (1989) as compound oriented; the goal was to find cytotoxic agents with the ability to kill growing tumor cells in a rapid manner.
The third screening program, initiated in 1986, remains compound oriented, but emphasizes the search for compounds that can demonstrate selective cytotoxicity. Thus, the current program is disease-oriented because extracts are screened for activity against a panel of human tumor cell lines grown in vitro. Sixty different cancer cell lines, mostly human, are represented in the panel. The cell lines are divided among the following cancer types: lung, breast, colon, melanoma, renal, central nervous system, leukemia and ovarian (Suffness, 1992). Most recently, NCI has included AIDS in its research agenda by adding an anti-HIV screen to its stable of screening methodologies.
The screening of natural products begun in 1956 effectively ceased in 1981 because of two inter-related trends. First, the natural products program was perceived to have turned up only a few novel compounds useful in the battle against cancer. This apparent failure of the natural products program only reinforced the prevailing attitude at the National Institutes of Health (NCI's mother organization) that 'rational' and, therefore 'scientific' drug design was preferable to an 'empirical' approach to the random screening of natural products.
With the advent of the cheaper, in vitro, high throughput screening program in 1986, NCI nevertheless resuscitated its natural products acquisition and testing program. Natural product researchers at NCI suspected that the paucity of marketable discoveries during the first collection program was not because of a lack of bioactivity on the part of the natural products tested, but as a result of the failure of the initial two screening systems (Cragg et al., 1994a). This second phase of NCI's natural products acquisition and screening program offers its researchers and biodiversity a second chance to prove themselves. As the NCI program represents the single most comprehensive and longest-running effort at screening of plants for chemical activity we take a retrospective look at both the initial and renewed phases of NCI's plant screening program.
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