Cancer Treatment Reports February 1976 [antikvár]

History and Development of DTIC (NSC-45388)1 Saul A. Schepartz2'* The National Cancer Institute's Drug Research and Development Program becomes involved with drugs in a variety of ways and at various stages of development. In some cases, the NCI may not become involved until the drug is already in clinical trial in this or another country. In other cases, preliminary data may have been obtained by the investigator who discovered the drug and the NCI may become involved heavily in the preclinical development and eventual clinical evaluation. In still other cases, the NCI may be provided with a new compound of unknown biologic activity to evaluate in its screening systems. The majority of such compounds are submitted without charge by chemists in the chemical and pharmaceutic industry or in academic and other institutes throughout the world. A relatively small proportion of the total comppunds submitted to the NCI come from within its own contract-supported research programs. .DTIC is one of these rare compounds. It serves as a good example of the collaboration of the NCI with its contractors in academic, industrial, and research institutes as well as with clinical and other investigators throughout the world. The details relating to the collaborative development of this drug will become clear in the papers presented in this issue. It might be of interest, however, to trace very briefly the chronology of the development of DTIC from its original synthesis to the present. This chronology is summarized in table 1. The compound was first synthesized in 1959 by investigators at Southern Research Institute under an NCI contract. It was tested in the NCI in vivo screen shortly after that and in the course of testing, activity was observed in L1210 leukemia. Over the next 3 years, a great deal of additional biologic testing was carried out to establish fully the parameters of activity of this new compound. ¦DTIC: CAS reg. No. 4342-03-4; imidazole-4-carboxamide, 5-(3,3-dimethyl-l-triazeno)-. 2Drug Research and Development Program (DR&DP), Division of Cancer Treatment (DCT), National Cancer Institute (NCI), Bethesda, Md. 'Reprint requests to: Dr. Saul A. Schepartz, DR&DP, DCT, NCI, 8300 Colesville Road, Blair Bldg, Rm 5A07, National Institutes of Health, Silver Spring, Md 20910. Finally, in April 1964 a decision was made to develop DTIC toward preclinical toxicology testing and clinical trial. This further development involved increasing the production of the drug so that it could be produced on a scale sufficient for toxicologic and clinical evaluation, developing a suitable formulation so that the drug could be administered appropriately to patients, and finally, designing the large animal toxicology studies. Toxicology studies tested the drug by both the oral and iv routes. An Investigational New Drug Application (IND) was filed in March 1966 for oral use and a supplement was filed in September 1966 for iv use. Over the next several years, extensive clinical studies were carried out, finally leading the NCI to the conclusion that DTIC was indeed an active drug and worthy of being put on the market. Early in 1973 efforts were initiated to develop a contract for processing a New Drug Application (NDA) which would eventually lead to the marketing of this drug. A contract to carry out this activity was signed in September 1973, the NDA was filed in February 1974, and 1 year later the so-called Table 1.—Chronology of DTIC development Date 10/59 First sample synthesized by Southern Research Insti- tute 2/60 Submitted to NCI screen 3/61 Activity in L1210 leukemia first observed 4/64 Accepted for development toward clinical trial 12/64-3/66 Formulation development 3/66-9/66 First large production batches prepared 11/64 Oral toxicology studies started 7/65 Oral toxicology studies completed 3/66 IND application filed 5/65 Iv toxicology studies started 4/66 Iv toxicology studies completed 9/66 IND amendment filed 1/73 RFP issued for marketing 9/73 Marketing contract signed 2/74 NDA filed 2/75 "Approvable" letter received Cancer Treatment Reports Vol. 60, No. 2, February 1976 123