Drug development for cancer: Implications for chemical modifiers

Abstract

Cancer drug development has, for many years, differed from the traditional patterns previously established by successful industrial ventures into the fields of antibiotics, psychoactive agents, and cardiovascular drugs. In the latter areas, preclinical model systems allowed the identification of new classes of compounds, the chemical modification of which led to highly effective and marketable agents. The problem of cancer treatment defied easy solutions; malignant cells differed only quantitatively from normal proliferating cells. Further, the successful treatment of cancer required total eradication of a subset of host cells, not simply a transient or reversible modification of cellular metabolism or function. The genetic instability of the target population led to heterogeneity of tumor population and rapid development of drug resistance, further complicating efforts to treat cancer with drugs. In this setting, the private sector chose not to make the considerable investment required to undertake the search for cancer drugs through the traditional process of preclinical screening, chemical modification of active lead compounds, and preclinical and clinical drug develop ments. The discovery of active antitumor agents-nitrogen mustard (Yale University) and methotrexate (Lederle)-prompted the Federal Government of the United States to set up a complrehensive drug screening and development system in 1955. This system contained all necessary components to procure and screen new compounds, to derive analogs of active leads, and to perform the necessary toxicology, formulation, and pharmacokinetic evaluation prior to testing in man. The contractsupported efforts in screening and preclinical development are complemented by grant-supported research in all phases of drug discovery and preclinical pharmacology. This federal drug development effort currently operates with a budget of $425 million per year, a sum that exceeds the expenditure of any private concern in cancer research; only Bristol-Myers, Upjohn, Eli Lilly, Warner-Lambert, and Burroughs-Wellcome among the major pharmaceutical companies support substantial targeted investments in the traditional activities of preclinical cancer drug development. In the 1960s and 1970s a balance evolved between industry, government, and academia in which the discovery of new agents emanated from a variety of