Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human cell lines under bioreductive prodrug PR-104A

ABSTRACT: A variety of human cell lines, were grown, RNA was extracted, and gene expression quantified using Affymetrix hgu133plus2 arrays. Expression of genes was compared to the rate of metabolism of the bioreductive prodrug PR-104A, and genes with expression shown to be statistically significantly correlated to pro-drug metabolic rate were chosen for further investigation.

ORGANISM(S): Homo sapiens

SUBMITTER: Rob Pollock

PROVIDER: E-TABM-767 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

The bioreductive prodrug PR-104A is activated under aerobic conditions by human aldo-keto reductase 1C3.

Guise Christopher P CP Abbattista Maria R MR Singleton Rachelle S RS Holford Samuel D SD Connolly Joanna J Dachs Gabi U GU Fox Stephen B SB Pollock Robert R Harvey Justin J Guilford Parry P Doñate Fernando F Wilson William R WR Patterson Adam V AV

Cancer research 20100209 4

PR-104, currently in phase II clinical trials, is a phosphate ester pre-prodrug which is converted in vivo to its cognate alcohol, PR-104A, a prodrug designed to exploit tumor hypoxia. Bioactivation occurs via one-electron reduction to DNA crosslinking metabolites in the absence of oxygen. However, certain tumor cell lines activate PR-104A in the presence of oxygen, suggesting the existence of an aerobic nitroreductase. Microarray analysis identified a cluster of five aldo-keto reductase (AKR) f ...[more]

PMID: 20145130

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Project description:In this study, we employ high-density oligonucleotide microarrays to characterize the MutaMouse FE1 cell line at various stages of cell growth, in primary MutaMouse lung epithelial cell cultures, and in whole lung. Global transcriptional analysis and real-time RT-PCR was applied to (1) further define the cellular origin of the FE1 cell line and its responses under different culture conditions (media and substratum), (2) provide insight into the transcriptional differences in cellular processes between FE1 cultures compared to whole lung tissues, more specifically in toxicological response, and (3) preliminarily examine FE1 culture response to exposure of benzo(a)pyrene compared to whole animals. Total RNA samples from 3 cell culture types (50% FE1, %100 FE1, and Primary lung) or MutaMouse lung were labeled with Cyanine 5-CTP, and universal reference total RNA (Stratagene, CA, USA) was labeled with Cyanine 3-CTP (Perkin Elmer Life Sciences, Woodbridge, ON, Canada) using Agilent linear Amplification kits (Agilent Tech. Inc. Mississauga, ON, Canada) following the manufacturer's instruction. Briefly, double-stranded cDNA was synthesized using MMLV-RT with T7 promoter primer, starting with 5 ug total RNA. Cyanine-labeled cRNA targets were in vitro transcribed using T7 RNA polymerase. The synthesized cRNA was precipitated by LiCl and fragmented at 60 degrees C for 30 min with fragmentation solution. Cy5- sample cRNA and Cy3- reference cRNA were hybridized to Agilent mouse development microarrays (containing ~20,000 unique 60 mer oligonucleotides; Agilent Tech. Inc. Mississauga, ON, Canada) at 60 degrees C overnight with Agilent hybridization solution and washed according to manufacturer's instruction. Arrays were scanned on a VersArray ChipReader (BioRad Laboratories Ltd., Waterloo, Ontario, Canada), and data were acquired with ImaGene 5.5 (BioDiscovery, Inc. CA, USA). Present calls were determined as signals that were greater than the mean plus three times the standard deviation of the average of the negative control spots.

Dataset Information

Transcription profiling of human cell lines under bioreductive prodrug PR-104A

Publications

The bioreductive prodrug PR-104A is activated under aerobic conditions by human aldo-keto reductase 1C3.

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