SK3 polyglutamine tract polymorphism and acute oxaliplatin neurotoxicity: A translational study

Abstract

21076 Background: Acute neurotoxicity of l-oxaliplatin (l-OHP), characterized by cold-induced paresthesias, muscle cramps and tightness, seems electrophysiologically related to an abnormal nerve hyperexcitability (NHE) resembling neuromyotonia, an autoimmune disease caused by autoantibodies directed against voltage-gated potassium channels (VGKC). This l-OHP-related channelopathy seems to be reversible, but there is no agreement about the channel involved, most investigators favouring voltage-gated sodium channels. SK3 VGKC are mainly located in the peripheral nervous system and are characterized by an highly polymorphic CAG motif. We hypothesized that SK3 potassium channel dysfunction might be responsible for nerve hyperexcitability in patients treated with l-OHP. Methods: Pts eligible for an l-OHP-containing regimen were enrolled. Detailed neurological examination, nerve conduction studies (NCS) and needle electromyography (EMG) were performed before and after l-OHP administration. Furthermore, a venous blood sample was obtained from each pt in order to perform genetic analysis. Genomic DNA was extracted from pts’ leukocytes and PCR-mediated amplification of the second polyglutamine CAG tract of SK3 gene was carried out; PCR products were analyzed on polyacrylamide gel stained with Ethidium Bromide. Results: We evaluated 20 pts (14M, 6F); mean age was 59 yrs. According to neurophysiologic data it was possible to divide pts into 3 groups: G0 (no symptoms or signs of NHE), 7 pts; G1 (cold induced paresthesias-mild NHE), 8 pts; G2 (muscle cramps-severe NHE), 5 pts. Genetic analysis showed different alleles ranging from 125 to 225 bp. In particular, 75% of pts carrying a 175 bp allele experienced severe acute toxicicy (G2 group), and 15% mild toxicity (G1 group). The 175 bp allele was found only in 1/7 G0 pts (15%); in these pts the alleles distribution was diffusely scattered. Conclusions: Acute and reversible NHE observed in some pts treated with l-OHP might be produced either by an increased sodium conductance or by a decreased activity of VGKC. The high percentage of the 175 bp allele, that we found in the G2 group, induces us to think that the polymorphism at CAG locus of SK3 may be responsible for l-OHP toxicity. Sequence analysis of PCR gene products is ongoing. No significant financial relationships to disclose.