Whereas the goal of Core C is the discovery of new anticancer agents, this Project determines how good the discovery is and develops the candidate agent. In this project, decisions are made to: move the agent toward clinical development; carry out further analog search and synthesis efforts to find superior analogs or, drop the agent from further consideration. In order to be entered into this project, the agent must be selectively cytotoxic for a solid tumor compared to the leukemia or normal cell in vitro (Core C). In addition, the agent must also be active in vivo (T/C less than or equal to 42%) against that same tumor (also Core C). In this project, the following series of in vivo tests are carried out: (a) breadth of activity against a variety of solid tumors of mouse and human origin, including multidrug resistant (MDR) tumors; (b) optimal schedule determination, which includes identifying the schedule category; (c) acute and chronic patterns of toxicity assessment and host recovery time from maximum tolerated dosages; (d) cross-resistance patterns with selected standard agents. For an active series, """"""""head-to-head"""""""" analog comparison trials will be carried out in vivo, against selected tumor, and in the in vitro against a wide variety of tumors and normal cells. Also tumor model development and characterization will continue. All of these studies are planned to evaluate the following Central Hypothesis that the selective cytotoxicity for solid tumor cells in culture (compared to leukemias or normal cells) in the primary in vitro assays will predict for in vivo efficacy against the same tumors (Core C), as well as other solid tumors (Project 2), and human solid tumors in humans (Project 4). As more agents enter the clinic from this program, the correlations with clinical activity and the predictive worth of specific tumor models, mouse and human, will also be evaluated.
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