title: Applications of quantitative pharmacodynamic effect markers in drug target identification and therapy development.
abstract: Genome-wide transcriptional profiling is now feasible, and profiling of the proteome, although technically challenging, is advancing rapidly. Expression profiling provides a tool to accelerate discovery in a broad range of sciences, but its greatest impact on human health may be on the process of drug discovery and therapy development, and investigation of the functional networks underlying drug responses of diseased and normal tissue. For anticancer agents in particular, antitumor effects and toxicities to critical normal tissues may rest in a delicate balance that is governed by complex pharmacokinetic (PK) and pharmacodynamic (PD) inter-relationships. Recent advances in the development of mechanistic computational PD models promise to promote an understanding of these interrelationships, provided suitable quantitative PD effect markers will be identified. Here we describe both advances toward the unsupervised application of PD models to complex expression profiling datasets, as well as approaches to address the technical requirement of these models for quantitative assessment of protein expression levels. Together, these models and analytical approaches may contribute to the rational design of more effective pharmacotherapies.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, NY 14260-1200, USA. rms@Buffalo.edu
authors.forename: Robert M
authors.initials: RM
authors.lastname: Straubinger
authors.forename: Wojciech
authors.initials: W
authors.lastname: Krzyzanski
authors.forename: Crystal M
authors.initials: CM
authors.lastname: Francoforte
authors.forename: Jun
authors.initials: J
authors.lastname: Qu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D020869:Gene Expression Profiling; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D010599:Pharmacokinetics; D010600:Pharmacology / Q000379:methods; D014176:Protein Biosynthesis; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents