التفاصيل البيبلوغرافية
| العنوان: |
Correlation of aldo-ketoreductase ( AKR) 1C3 genetic variant with doxorubicin pharmacodynamics in Asian breast cancer patients. |
| المؤلفون: |
Voon, Pei Jye, Yap, Hui Ling, Ma, Cho‐Yee‐Thu, Lu, Fan, Wong, Andrea L. A., Sapari, Nur Sabrina, Soong, Richie, Soh, Thomas I. P., Goh, Boon‐Cher, Lee, How‐Sung, Lee, Soo‐Chin |
| المصدر: |
British Journal of Clinical Pharmacology; Jun2013, Vol. 75 Issue 6, p1497-1505, 9p, 3 Charts, 1 Graph |
| مصطلحات موضوعية: |
DOXORUBICIN, BREAST cancer patients, DRUG metabolism, PHARMACOKINETICS, DISEASE progression |
| مستخلص: |
Aims Aldo-ketoreductases have been implicated in the metabolism of doxorubicin. We sought to assess the influence of AKR1C3 genetic variants on doxorubicin metabolism. Methods We sequenced AKR1C3 exon 5 and genotyped seven functional single nucleotide polymorphisms in CBR3, ABCB1 and SLC22A16 involved in doxorubicin pharmacology in 151 Asian breast cancer patients treated with doxorubicin-containing chemotherapy, and correlated these genotypes with doxorubicin pharmacokinetics and pharmacodynamics. Results Two previously reported AKR1C3 intronic variants, IVS4-212 C> G and IVS4+218 G> A, were detected. The AKR1C3 IVS4-212 GG genotype was associated with significantly lower cycle 1 day 15 leucocyte (mean leucocytes 2.49 ± 1.57 × 109 vs. 3.85 ± 3.42 × 109 l−1, P = 0.007) and neutrophil counts (mean neutrophils 0.70 ± 1.01 × 109 vs. 1.56 ± 2.80 × 109 l−1, P = 0.008) and significant improvement of progression-free survival [PFS, mean PFS 49.0 (95% confidence interval 42.2-55.8) vs. 31.0 (95% confidence interval 20.7-41.2) months, P = 0.017] and overall survival [ OS; mean OS 64.4 (95% confidence interval 58.3-70.5) vs. 46.3 (95% confidence interval 35.1-57.5) months, P = 0.006] compared with those carrying at least one C allele. There was no significant association between AKR1C3 IVS4-212 C>G and doxorubicin pharmacokinetics. Of the other seven single nucleotide polymorphisms genotyped, CBR3 G11A correlated with doxorubicinol area under the concentration-time curve and OS, ABCB1 G2677T/ A correlated with doxorubicin clearance and platelet toxicity, while ABCB1 IVS26+59 T> G correlated with OS. The AKR1C3 IVS4-212 C< G genotype remained significantly correlated with both PFS and OS on multivariate analysis with clinical prognosticators. Conclusions The AKR1C3 IVS4-212 GG genotype was associated with greater haematological toxicity and longer progression-free survival and overall survival after doxorubicin-based therapy, suggesting potential interaction of this variant with doxorubicin metabolism. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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