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Annals of Oncology Advance Access originally published online on February 17, 2009
Annals of Oncology 2009 20(4):736-740; doi:10.1093/annonc/mdn698
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

supportive care

Relationship between GSTP1 Ile105Val polymorphism and docetaxel-induced peripheral neuropathy: clinical evidence of a role of oxidative stress in taxane toxicity

O. Mir1,2,*, J. Alexandre1, A. Tran2, J.-P. Durand1, G. Pons2, J.-M. Treluyer2 and F. Goldwasser1

1 Department of Medical Oncology
2 Department of Clinical Pharmacology, Teaching Hospital Cochin, University Paris Descartes, Assistance Publique—Hôpitaux de Paris, Paris, France

* Correspondence to: Dr O. Mir, Department of Medical Oncology, Teaching Hospital Cochin, Université Paris Descartes, Assistance Publique—Hôpitaux de Paris, 27 rue du faubourg Saint-Jacques, 75679 Paris cedex 14, France. Tel: +33-6-30-73-90-79; Fax: +33-1-58-41-17-45; E-mail: olivier.mir{at}cch.aphp.fr

Background: Glutathione-S-transferases (GST) regulate the cellular response to oxidative stress. We previously highlighted the importance of oxidative stress in taxane toxicity and therefore investigated the relationship between the GST isoforms M1, T1 and P1 gene polymorphisms and docetaxel (Taxotere)-induced peripheral neuropathy (DIPN).

Patients and methods: The GSTM1 (null), GSTT1 (null) and GSTP1 (Ile105Val and Ala114Val) polymorphisms were determined in a cohort of cancer patients treated with docetaxel and entered in a clinical trial database. The relationship between GST polymorphisms and grade ≥2 DIPN as primary end point was studied.

Results: Fifty-eight patients (median age 61 years) received a total of 261 cycles of docetaxel given as single agent. Patients with GSTP1 105Ile/105Ile genotype had a higher risk of developing a grade ≥2 DIPN than did those with other GSTP1 genotypes (8 of 27 versus 2 of 31, respectively, odds ratio 6.11; 95% confidence interval 1.17–31.94; P = 0.03). In multivariate analysis, grade ≥2 DIPN was strongly correlated with GSTP1 105Ile/105Ile genotype (P = 0.01) and the number of cycles (P = 0.03).

Conclusion: We found a significant correlation between GSTP1 105Ile/105Ile genotype and the development of grade ≥2 DIPN. This finding strongly suggests a role of oxidative stress in the pathophysiology of DIPN.

Key words: docetaxel, GST, oxidative stress, peripheral neuropathy, pharmacogenetics, polymorphism

Received for publication February 11, 2008. Revision received October 5, 2008. Accepted for publication October 7, 2008.


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