Drug development for cancer: implications for chemical modifiers.

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 sources, but the responsibility for preclinical development and clinical trial was shared by industry and the National Cancer Institute. Drugs from both academic and private sources entered the NC1 pipeline at any point in the process, and, once sufficient clinical promise was established and if the agent had a clear patent status, it could be licensed and marketed by industry. In particular, the Bristol-Myers Company has been successful in licensing bleomycin, cisplatin, carboplatin, VP16, and VM-26, and has built a highly profitable cancer drug division as an important part of its pharmaceutic operation. The sources and licensing of currently marketed anticancer cytotoxic drugs in the United States are shown in Table 1; this information illustrates the interplay of the pharmaceutics industry, the NC1 and academia in drug discovery and development (1). Also shown are so-called Group C agents, a group of drugs with proven antitumor activity in specific diseases, but not yet approved for marketing. For some drugs, lack of approval has resulted from the lack of commercial sponsorship and a limited potential for profit, while for other agents, such as the nitrosoureas, problems related to toxicity have discouraged the licensee from pursuing marketing approval. Not only does the NC1 drug development effort offer important preclinical and clinical resources, but it also offers a flexibility of approach not often found in private industry. The primary objective of commercial firms is to obtain New Drug Approval (NDA) (marketing status), at which point the agent can be sold for profit. This goal is pursued with singular determination, the strategy often being to define a single specific use or indication. Ancillary studies of drug action in highor low-dose schedules, or other clinical trials of an exploratory nature in combination with the other experimental agents, or even for non-malignant diseases, have secondary priority or, in