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Predictive Factors of Oxaliplatin Neurotoxicity: The Involvement of the Oxalate Outcome Pathway

Authors' Affiliations: ¹ Laboratory of Oncopharmacology-Pharmacogenetics, Institut National de la Sante et de la Recherche Medicale U564 and ² Unit of Biostatistics, Anticancer Centre Paul Papin; ³ Gastrointestinal-Tract Oncology Unit, Regional Institute of Cancer Anjou-Maine; ⁴ Antipoison-Toxicovigilance Centre, ⁵ Laboratory of Pharmacology-Toxicology, and ⁶ Laboratory of Biochemistry, University Hospital Larrey, Angers, France

Requests for reprints: Erick Gamelin, Anticancer Centre Paul Papin, 2 rue Moll, 49933 Angers, France. Phone: 33-241352700; Fax: 33-241483190; E-mail: e.gamelin{at}unimedia.fr.

Purpose: Oxaliplatin displays a frequent dose-limiting neurotoxicity due to its interference with neuron voltage-gated sodium channels through one of its metabolites, oxalate, a calcium chelator. Different clinical approaches failed in neurotoxicity prevention, except calcium-magnesium infusions. We characterized oxalate outcome following oxaliplatin administration and its interference with cations and amino acids. We then looked for genetic predictive factors of oxaliplatin-induced neurotoxicity.

Experimental Design: We first tested patients for cations and oxalate levels and did amino acid chromatograms in urine following oxaliplatin infusion. In the second stage, before treatment with FOLFOX regimen, we prospectively looked for variants in genes coding for the enzymes involved (a) in the oxalate metabolism, especially glyoxylate aminotransferase (AGXT), and (b) in the detoxification glutathione cycle, glutathione S-transferase , and for genes coding for membrane efflux proteins (ABCC2).

Results: In the first 10 patients, urinary excretions of oxalate and cations increased significantly within hours following oxaliplatin infusion, accompanied by increased excretions of four amino acids (glycine, alanine, serine, and taurine) linked to oxalate metabolism. In a further 135 patients, a minor haplotype of AGXT was found significantly predictive of both acute and chronic neurotoxicity. Neither glutathione S-transferase nor ABCC2 single nucleotide polymorphisms we looked for were linked to neurotoxicity.

Conclusion: These data confirm the involvement of oxalate in oxaliplatin neurotoxicity and support the future use of AGXT genotyping as a pretherapeutic screening test to predict individual susceptibility to neurotoxicity.