Glutathione S-transferase P1 polymorphism (Ile105Val) predicts cumulative neuropathy in patients receiving oxaliplatin-based chemotherapy.

Abstract

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.

• Authors: Thierry Lecomte, Bruno Landi, Philippe Beaune, Pierre Laurent-Puig, Marie-Anne Loriot
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 10 Pg. 3050-6 (May 15 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16707601 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Organoplatinum Compounds
• Oxaliplatin
• glutathione S-transferase T1
• GSTP1 protein, human
• Glutathione S-Transferase pi
• Glutathione Transferase
• glutathione S-transferase M1

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Gastrointestinal Neoplasms (drug therapy)
• Genetic Predisposition to Disease
• Glutathione S-Transferase pi (genetics, metabolism)
• Glutathione Transferase (genetics, metabolism)
• Humans
• Male
• Middle Aged
• Nervous System Diseases (chemically induced, genetics)
• Organoplatinum Compounds (administration & dosage, adverse effects, therapeutic use)
• Oxaliplatin
• Polymorphism, Genetic
• Retrospective Studies