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

Abstract

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 oxaliplatininduced 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 k, 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 k 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 AGXTgenotyping as a pretherapeutic screening test to predict individual susceptibility to neurotoxicity.Oxaliplatin, a platinum-based chemotherapeutic agent with a 1,2-diaminocyclohexane (DACH) carrier ligand, displays a characteristic pattern of neurotoxicity, which is the most frequent dose-limiting toxicity, with an acute onset of distal dysesthesia and/or paresthesia, induced or exacerbated by cold and prolonged muscular contraction after a voluntary contraction. Although these symptoms that occur during or short after infusion are transient and generally mild, when treatment is continued, a persistent sensory peripheral neuropathy can develop, eventually causing superficial and deep sensory loss, sensory ataxia, and functional impairment (1). The mechanism of chronic neurotoxicity evoked by some authors is close to that of cisplatin-being the progressive accumulation of a heavy metal, the DACH platin, in neurons and the implication of the detoxication system of glutathione (2).However, clinical neurophysiologic examinations and nerve biopsy studies have shown that patients displaying sensory symptoms have no signs or very mild signs of axonal degeneration (1). Oxaliplatin has a direct ''pharmacologic'' effect on the excitability of sensory neurons and muscle cells that has not previously been described with other platinum agents (3). Furthermore, the acute symptoms induced by oxaliplati...

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