Identification of platform-independent gene expression markers of cisplatin nephrotoxicity.
Within the International Life Sciences Institute Committee on Genomics, a working group was formed to focus on the application of microarray technology to preclinical assessments of drug-induced nephrotoxicity. As part of this effort, Sprague-Dawley rats were treated with the nephrotoxicant cisplatin at doses of 0.3-5 mg/kg over a 4- to 144-hr time course. RNA prepared from these animals was run on a variety of microarray formats at multiple sites. A set of 93 differentially expressed genes associated with cisplatin-induced renal injury was identified on the National Institute of Environmental Health Sciences (NIEHS) custom cDNA microarray platform using quadruplicate measurements of pooled animal RNA. The reproducibility of this profile of statistically significant gene changes on other platforms, in pooled and individual animal replicate samples, and in an independent study was investigated. A good correlation in response between platforms was found among the 48 genes in the NIEHS data set that could be matched to probes on the Affymetrix RGU34A array by UniGene identifier or sequence alignment. Similar results were obtained with genes that could be linked between the NIEHS and Incyte or PHASE-1 arrays. The degree of renal damage induced by cisplatin in individual animals was commensurate with the number of differentially expressed genes in this data set. These results suggest that gene profiles linked to specific types of tissue injury or mechanisms of toxicity and identified in well-performed replicated microarray experiments may be extrapolatable across platform technologies, laboratories, and in-life studies.
Thompson
Karol L
KL
Center for Drug Evaluation and Research, Division of Applied Pharmacology Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Life Sciences Building 64, Silver Spring, MD 20993, USA. Thompsonk@cder.fda.gov
Afshari
Cynthia A
CA
Amin
Rupesh P
RP
Bertram
Timothy A
TA
Car
Bruce
B
Cunningham
Michael
M
Kind
Clive
C
Kramer
Jeffrey A
JA
Lawton
Michael
M
Mirsky
Michael
M
Naciff
Jorge M
JM
Oreffo
Victor
V
Pine
P Scott
PS
Sistare
Frank D
FD
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D020869:Gene Expression Profiling / Q000379:methods*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results
D000970:Antineoplastic Agents; D002945:Cisplatin