Toxicology studies are one of the final steps required in the preclinical development of new drugs for potential clinical use. The purpose of this contract is to develop, in healthy intact animals, the profile of possible organ toxicities of experimental antineoplastic compounds. The toxicology studies of potential oncolytic agents that will be investigated under this contract are designed to meet this intent and involve four objectives: 1. Determination and safety assessment of an initial dose for clinical use. 2. Determination of the primary organ systems adversely affected by drug administration. 3. Determination of the reversibility of the adverse effects. 4. Determination of schedule dependent toxicity. A secondary objective is acquisition and use of pharmacokinetic information to reliably extrapolate toxic effects across species by relating plasma drug levels (peak and steady state) to the time of appearance and severity of toxicity. Integration of these two areas (toxicity:plasma drug levels) permits a more rational evaluation of the influence of schedule dependency on drug efficacy and drug toxicity. Data obtained from these studies of new drugs and evaluated in the light of potential human toxicity comprise a major portion of the information required by the Food and Drug Administration for an Investigational New Drug Application. Additionally, the data enable clinical investigations to proceed smoothly in dosing regimen and escalation procedures in initial clinical trials.
