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Glutathione S-Transferase P1 Polymorphism (Ile¹⁰⁵Val) Predicts Cumulative Neuropathy in Patients Receiving Oxaliplatin-Based Chemotherapy

Authors' Affiliations: Departments of ¹ Gastroenterology and ² Biochemistry, Assistance Publique-Hôpitaux de Paris, European Georges Pompidou Hospital; and ³ Université Paris-Descartes, Faculté de Médecine, Institut National de la Sante et de la Recherche Medicale UMRS 775, Paris, France

Requests for reprints: Pierre Laurent-Puig, U775 Bases Moléculaires de la Réponse aux Xénobiotiques, 45 rue des Saints Pères, 75006 Paris, France. Phone: 33-1-428-62081; Fax: 33-1-428-62072; E-mail: pierre.laurent-puig{at}biomedicale.univ-paris5.fr.

Purpose: Glutathione S-transferases (GST) are xenobiotic metabolizing enzymes involved in the detoxification of a variety of chemotherapeutic drugs, including platinum derivatives. Genetic polymorphisms of GSTs have been associated with enzyme activity variations. Thus, a study was done to investigate the relationship between GST polymorphisms and oxaliplatin-related cumulative neuropathy in gastrointestinal cancer patients treated with oxaliplatin-based chemotherapy.

Experimental Design: Ninety patients were included. Clinical neurologic evaluation was done at baseline and before each cycle of treatment. We determined genetic variants for GSTP1 exon 5 (Ile¹⁰⁵Val), GSTP1 exon 6 (Ala¹¹⁴Val), GSTM1 (homozygous deletion), and GSTT1 (homozygous deletion). We conducted analyses in a subgroup of 64 patients receiving a minimal cumulative dose of 500 mg/m² of oxaliplatin to examine whether the GST polymorphisms are associated with oxaliplatin-related cumulative neuropathy.

Results: Among patients receiving a minimal cumulative dose of 500 mg/m² of oxaliplatin, 15 patients showed clinically evident oxaliplatin-related cumulative neuropathy scored grade 3 according to an oxaliplatin-specific scale. The oxaliplatin-related cumulative neuropathy scored grade 3 was significantly more frequent in patients homozygous for the GSTP1 ¹⁰⁵Ile allele than in patients homozygous or heterozygous for the GSTP1 ¹⁰⁵Val allele (odds ratio, 5.75; 95% confidence interval, 1.08-30.74; P = 0.02). No association was found with respect to any of the GSTM1, GSTT1, or GSTP1 exon 6 genotypes.

Conclusions: The results of the current study suggest that the ¹⁰⁵Val allele variant of the GSTP1 gene at exon 5 confers a significantly decreased risk of developing severe oxaliplatin-related cumulative neuropathy.

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