17 groups had been formed. The Eastern Cooperative Group, the first of the cooperative groups, carried out a trial comparing two drugs in breast cancer, Hodgkin’s disease, and melanoma that was designed by an NCI Clinical Panel. The Panel also assessed the early principles of clinical trials in cancer chemotherapy and reviewed trial data coming from an emerging number of cooperative groups around the country (Zubrod, 1984). This was the first active, prospective involvement of NCI in large-scale cancer clinical trials.

In 1976, the CCNSC was incorporated into NCFs Developmental Therapeutics Program (DTP), the current locus of federally funded preclinical drug discovery and development. The heart of DTP was to become a large-scale in vivo drug screening operation that, by the late 1970s, tested up to 40,000 compounds per year in a variety of mouse leukemia models (Chabner, 1990). More than 500,000 chemicals were tested in laboratory animals in this program, and several hundred were tested in clinical trials. By the late 1970s, some 45 chemicals had been found effective in various cancers. Overall, DTP has had a role in the discovery or development of approximately 40 percent of the current U.S.-licensed chemotherapeutic agents (Sausville and Feigal, 1999), with the rest coming directly from the domestic or international pharmaceutical industry.

Evolving Screening Approaches

Preclinical models used by NCI to select new drugs for cancer clinical trials have evolved over time due to improved understanding of the biologic factors that affect the success of treatment, such as the relationship of tumor cell growth kinetics to drug responsiveness, to retrospective analyses of correlations between clinical and preclinical efficacy, and to the development of the NCI Drug Information System, a computer inventory of compound structure and activity in the mouse models, that limits the screening of analogues and directs the focus to novel structures (Schabel, 1969; Skipper et al., 1970. Venditti, 1981, Venditti et al., 1984).

In the 1940s, the S37 tumor was used to screen 300 chemicals and plant extracts, but by 1955 mouse leukemia models were selected as the initial systems for large-scale screening because they were relatively inexpensive and allowed for high throughput of compounds (Monks et al., 1997; Vendetti, 1981, Venditti et al., 1984, Zubrod, 1984). From its inception, therefore, until the mid 1970s the mouse screen would be used to process more than 400,000 compounds (Khleif and Curt, 2000). There are examples where this appeared to predict well for the clinic, but there was concern that screening against animal leukemia may have created a bias toward drugs that were active only against rapidly growing tumors. While treatment of human leukemias and lymphomas had improved during this period, lesser improvements in the chemotherapy of most human solid tumors were achieved (Venditti, 1981, Venditti et al., 1984).

The 1970s

In the 1970s, the availability of the athymic nude mouse, a model with a defective immune system that accepted transplanted foreign (non-mouse) tumors (Giovanella et al., 1974), permitted inclusion of human tumor grafts in a screening panel to identify agents in addition to those selected by mouse tumor screens. Candidate agents were screened



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