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Sub-category:
Pharmacogenomics
Category:
Developmental Therapeutics - Molecular Therapeutics
Meeting:
2004 ASCO Annual Meeting
Abstract No:
3021
Citation:
Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 3021
Author(s):
L. Wojnowski, G. Schlueter, S. Vonhof, B. Kulle, H. Bickeboeller, M. Loeffler, M. Pfreundschuh, J. Brockmoeller, G. Hasenfuss, L. Trumper; University of Goettingen, Goettingen, Germany; University of Leipzig, Leipzig, Germany; University of Saarland, Homburg, Germany
Abstract:
Background: Anthracyclines are widely used in the treatment of many malignancies. Up to 5% patients develop chronic anthracyclin-induced cardiotoxicity (ACT) mostly presenting as arrhythmias or congestive heart failure. The involvement of the individual genetic makeup is suggested by mouse models, but there is a lack of data on pharmacogenomic predictors of ACT in humans. Patients and methods: We genotyped DNA samples from doxorubicin-treated participants of the prospective randomized phase III NHL-B-trial of the German High Grade lymphoma study group (DSHNHL), who were followed up for the development of heart failure for a median of more than 4 years. Patients were treated with CHOP or CHOP+etoposide (CHOEP) in 14- or 21-day intervals. Blood samples were drawn before the iniation of treatment. SNPs were selected from genes implicated in heart failure, in disposition of doxorubicin and in metabolism of reactive oxygen species (ROS). Results: Out of 1500 patients, 87 developed ACT. We detected two significant associations with inherited polymorphisms, each involving a pair of functionally related proteins. The tyrosine (His72Tyr) variant of the CYBA gene-encoded subunit of the NAD(P)H oxidase p22phox (OR: 2.0 95% CI: 1.2 - 3.6), and a SNP in the RAC2 gene, which is an activator of the same enzyme. Furthermore, we detected an association of ACT with the Gly671Val variant of the doxorubicin efflux transporter MRP1 (OR: 2.4, CI: 1.2 - 4.9) and with the haplotype Val1188Glu and Cys1515Tyr of the functionally similar MRP2 (OR: 2.0, CI: 1.0 - 3.9). These results suggest that genetic variants affecting transport of doxorubicin and the propensity to generate free oxygen radicals following exposure to this drug modulate the individual risk to doxorubicin-induced ACT.
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Educational Book Manuscripts by L. Wojnowski:
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