Predictive factors of oxaliplatin neurotoxicity: the involvement of the oxalate outcome pathway.
OBJECTIVE
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.


METHODS
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 pi, 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 pi nor ABCC2 single nucleotide polymorphisms we looked for were linked to neurotoxicity.


CONCLUSIONS
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.
Gamelin
Laurence
L
Laboratory of Oncopharmacology-Pharmacogenetics, Institut National de Sante et de Recherche Medicale U564, Angers, France.
Capitain
Olivier
O
Morel
Alain
A
Dumont
Agnes
A
Traore
Sory
S
Anne
Le Bouil
le B
Gilles
Simard
S
Boisdron-Celle
Michele
M
Gamelin
Erick
E
D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity; D002118:Calcium / Q000378:metabolism; D005838:Genotype; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008274:Magnesium / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D000089762:Multidrug Resistance-Associated Protein 2; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D009498:Neurotoxins / Q000737:chemistry*; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D010070:Oxalates / Q000737:chemistry / Q000378:metabolism*; D000077150:Oxaliplatin; D011237:Predictive Value of Tests; D017422:Sequence Analysis, DNA; D015222:Sodium Channels / Q000737:chemistry
C000715087:ABCC2 protein, human; D000970:Antineoplastic Agents; D000089762:Multidrug Resistance-Associated Protein 2; D009498:Neurotoxins; D009944:Organoplatinum Compounds; D010070:Oxalates; D015222:Sodium Channels; D000077150:Oxaliplatin; D005982:Glutathione Transferase; D008274:Magnesium; D002118:Calcium