Antagonist Vs Agonist

The costs of publication of this article were defrayed in part by the payment of page charges.Whereas geldanamycin showed promising preclinical activity in vitro, it was found to be too hepatotoxic in animal models and could not be tested in humans. AAG is structurally similar to geldanamcyin, maintains its antitumor activity, and has a better toxicity profile and therapeutic index.Early evaluation of the new generation of molecularly targeted therapies requires the assessment of pharmacodynamic biomarkers that provide proof of concept for molecular target inhibition and facilitate the rational selection of the dose and schedule for phase II trials. Understanding the 5-hydroxytryptophan pharmacokineticpharmacodynamic relationship is particularly important, allowing the construction of a pharmacologic audit trail that links pharmacokinetic and pharmacodynamic variables to target modulation, biological responses, and potentially, to clinical outcome. Inclusion of pharmacodynamic end points in phase I trials of molecular targeted agents and their incorporation into the decisionmaking is disappointingly infrequent. HSP is a known cochaperone of HSP that is regulated by the transcription factor HSF and is induced when HSP is inhibited. The simultaneous upregulation of HSP expression and downregulation of HSP client proteins represents a molecular signature of HSP inhibition that can be incorporated into pharmacokineticpharmacodynamic investigations. Although effects of AAG on client proteins have been described in various tumor models, there has been no detailed description of the pharmacokineticpharmacodynamic relationships that are required to underpin a pharmacokineticallypharmacodynamically driven clinical trial.The aim of the present study was to validate pharmacodynamic markers for HSP inhibition in vitro and subsequently in established human ovarian cancer xenograft models with the aim of establishing pharmacokineticpharmacodynamic relationships for AAG.Both tumor and peripheral blood leukocytes were investigated.The former are more directly informative of the molecular response in target tissue, whereas the latter are more easily assessable in the clinic.Both lines were grown as monolayers in DMEM, mmolL glutamine, and nonessential amino acids in CO.Isolation of human and murine peripheral blood leukocytes.Mobile phase consisted of a gradient of acetonitrile in water.Following a wash with mL of water, samples were eluted with formic acid in water, evaporated to dryness, reconstituted in AL mobile phase, and AL were injected.Tumor and liver samples were homogenized at gmL and AL extracted with mL ethyl acetate.Following sample drying, the residue was dissolved in AL mobile phase and AL injected onto the system.Calibration curves were produced from to, ngmL for plasma and to, ngmL for tissues by spiking AAG and AG into control plasma or tissue homogenate.Acceptance criteria were established according to published guidelines. Tumor growth was assessed thrice weekly and tumor volumes were calculated according to the formula: volume, where a andbare orthogonal diameters and a is the longest diameter.Tumor volumes were then Cefadroxil expressed as a proportion of the volume at the start of treatment, the relative tumor volume at the start of the experiment is, by definition, unity.The efficacy of the drug was then determined by the growth delay difference in time, in days, for treated versus control tumor volumes to reach pretreatment volume.In addition, to correct for the differences in growth rate between the two tumors, specific growth delays were calculated by dividing the growth delays in days by the tumor doubling time.

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