Figure 1 National Institutes of Health/classical cytotoxic preclinical drug screening process. *Cellular screens are usually performed on permanent cell lines using some type of growth inhibition or cytotoxicity assay (e.g., methylthiazolidiphenyl tetrazolium (MTT), sulforhodamine B (SRB)). **In vivo models can include xenografts/immuno-suppressed mice, murine tumors/ mice, other species (e.g., rats) with syngeneic or spontaneous tumors in companion animals (e.g., dogs), hollow fiber assays, etc. w Aspects of mechanism of action, metabolism, PK/PD, and toxicology can be addressed at any point or concurrently with earlier testing. (Source: http://dtp.nci.nih.gov.)
syngeneic leukemia/lymphoma models that were typically conducted as an intraperitoneal inoculation of mouse tumor cells, with subsequent development of ascitic disease. In their most simplistic forms, efficacy was evaluated as a treatment-associated delay in the development of morbidity.12 These model systems were used quite successfully to develop effective therapies for the treatment of childhood leukemia.13'14 With the utilization of methods to suppress immune function in mice and, more importantly, the discovery and characterization of immunocompromised strains of mice (e.g., Foxn1nuUnu (nude) and Prkdcscldlsad (scid)), numerous solid tumor lines of human origin were added to the tumor model repertoire (xenograft models).15,16 These early solid tumor models were usually rapidly growing, sub-cutaneously implanted tumors that often required in vivo propagation to maintain the line. Today, dozens of human tumor cell lines are commonly used to evaluate efficacy of experimental agents.17 Although some of these lines still require in vivo propagation, many can be easily maintained in cell culture, thus allowing for potentially more direct in vitro/in vivo correlates of activity.
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