Tumor Models and the Discovery and Secondary Evaluation of Solid Tumor Active Agents

Abstract

Each independently arising tumor is a separate and unique biologic entity with its own unique histologic appearance, biologic behavior, and drug response profile. Thus, in drug discovery, no single tumor has been a perfect predictor for any other tumor. For this reason, new agents are evaluated in a variety of tumor models which is known as breadth of activity testing. In recent years, human tumors implanted in athymic nude mice and SCID mice have also become available for breadth of activity testing. In studies carried out in these laboratories, it was found that 10 human tumors metastasized in the SCID mice, but failed to metastasize in nude mice. In addition, tumor growth and tumor takes were superior in the SCID mice. The strengths and weaknesses of xenograft model systems are discussed. For example, most human tumor xenograft models are excessively sensitive to alkylating agents as well as to a new class of DNA binders (XE840 and XP315). Using human tumor models that are the least sensitive to these classes of agents is suggested. A drug discovery screen using a disk-diffusion-soft-agar-colony formation assay is presented. This assay employs leukemia cells, normal cells, and cells, from solid tumors of mouse and human origin. The goal is to find agents with greater cytotoxicity for solid tumor cells than for leukemic or normal cells. Over 50,000 materials of synthetic and natural product origin have been tested in this disk-assay which identijied a variety of agents. In-vivo breadth of activity testing is presented for several agents that fit the desired cellular selectivity in-vitro. Three of these agents are currently in Phase-1,2 clinical trials [PZA (NSC366140), Acetyldinaline (C1994), and WlN333771. Three others are in clinical development (XK469, Nanoparticle-Piposuljan, and Cryptophycin-8). All of these agents are highly active and broadly active against a variety of solid tumors.