Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human lung cancer cells treated with dasatinib, imatinib, nilotinib or PD0325901

ABSTRACT: Cell Line: This experiment was designed to measure the transcriptional responses to four kinase inhibitors across a five-logarithm dose range. The A549 human lung cancer cell line was treated with dasatinib, imatinib or nilotinib (4 hours and 20 hours) or PD0325901 (4 hours). Treatments used a 12-point dose range (30 uM with 3-fold dilutions down to 0.17 nM; 0.5% DMSO vehicle for all treatments). Experimental design prevented row or column handling effects being confounded with dose effect.

ORGANISM(S): Homo sapiens

SUBMITTER: Jian Cao

PROVIDER: E-TABM-585 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Transcriptional profiling of the dose response: a more powerful approach for characterizing drug activities.

Ji Rui-Ru RR de Silva Heshani H Jin Yisheng Y Bruccoleri Robert E RE Cao Jian J He Aiqing A Huang Wenjun W Kayne Paul S PS Neuhaus Isaac M IM Ott Karl-Heinz KH Penhallow Becky B Cockett Mark I MI Neubauer Michael G MG Siemers Nathan O NO Ross-Macdonald Petra P

PLoS computational biology 20090918 9

The dose response curve is the gold standard for measuring the effect of a drug treatment, but is rarely used in genomic scale transcriptional profiling due to perceived obstacles of cost and analysis. One barrier to examining transcriptional dose responses is that existing methods for microarray data analysis can identify patterns, but provide no quantitative pharmacological information. We developed analytical methods that identify transcripts responsive to dose, calculate classical pharmacolo ...[more]

PMID: 19763178

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Project description:High levels of hepcidin, the main regulator of systemic iron metabolism leads to various diseases. Targeting hepcidin and lowering its concentration is a possible form of intervention in order to treat these diseases. High turnover rate of hepcidin is a major drawback of therapies directly targeting this peptide. We developed two monoclonal antibodies (mAbs) ABT-207 and h5F9-AM8 which inhibit hemojuvelin also known as repulsive guidance molecule c (RGMc) and downregulate hepcidin. After a single application of these antibodies hepcidin expression in liver and its concentration in serum were reduced. Serum iron increased for several weeks. The RGMc antibodies show a pronounced dose response relationship in rats with h5F9-AM8 having an IC50 (UIBC) of ~80 fold higher than ABT-207. When hepcidin levels were downregulated iron deposition in the liver was visible histologically one week post application. The anitbody-mediated iron deposition was not associated with any toxicologically relevant effect at the doses and timepoints evaluate. Iron depositions seen after 14 weekly treatments with ABT-207 were partially reversible in rats and in cynomolgus monkeys. Due to their long-lasting effects and excellent safety profile, both RGMc-blocking antibodies ABT-207 and h5F9-AM8 are favorable clinical candidates for diseases characterized by high serum hepcidin levels like anemia of chronic disease. Female Sprague-Dawley rats [Crl:CD®(SD)IGS BR], weighing ~200 g at study initiation were obtained from Charles River Laboratories, Inc. Rats were housed singly in ventilated, stainless steel, wire-bottom hanging cages, fed non-certified Rodent Chow and water ad libitum and acclimated for at least 5 days after arrival. Rats were randomly assigned to various treatment groups (5 rats/group) and were dosed once weekly by IV injection via tail vein with vehicle (30mM Histidine, 8% w/v Sucrose, pH6.0, + 0.02% Tween 80) or with 0.02, 0.2, or 20 mg/kg of RGMc antibody for a total of 4 doses. All rats were sacrificed under isoflurane anesthesia 24 hours after final dose. Liver and spleen waere flash frozen in liquid nitrogen and stored at 80°C until processing for gene expression profiling on the Affymetrix platform. total of 12 samples, 3 biological replicates (rats) from each of 4 treatments groups 1. vehicle control (30mM Histidine, 8% w/v Sucrose, pH6.0, + 0.02% Tween 80) 2. 0.02 mg/kg RGMC Ab 3. 0.2 mg/kg RGMC Ab 4. 20 mg/kg RGMC Ab; rats were dosed by IV injection via tail vein once weekly for 4 total doses, dose volume 2mL/kg/week

Dataset Information

Transcription profiling of human lung cancer cells treated with dasatinib, imatinib, nilotinib or PD0325901

Publications

Transcriptional profiling of the dose response: a more powerful approach for characterizing drug activities.

Similar Datasets

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