Polymorphism of CAG motif of SK3 gene is associated with acute oxaliplatin neurotoxicity

Polymorphism of CAG motif of SK3 gene is associated with acute oxaliplatin neurotoxicity,10.1007/s00280-010-1466-y,Cancer Chemotherapy and Pharmacolog

Polymorphism of CAG motif of SK3 gene is associated with acute oxaliplatin neurotoxicity   (Citations: 2)
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Purpose  There is no agreement on which channel is involved in oxaliplatin neurotoxicity, most investigators favouring voltage-gated sodium channels. However, the small conductance Ca++ activated K+ channels, encoded by the SK1–3 genes, are also involved in membrane excitability, playing a role in after-hyperpolarization at the motor nerve terminal. As the SK3 gene is characterized in Caucasians by a highly polymorphic CAG motif within the exon 1, we hypothesize that SK3 gene polymorphism may influence the development of acute nerve hyperexcitability in oxaliplatin-treated patients. Methods  Patients eligible for an oxaliplatin-containing regimen were enrolled. Detailed neurological examination, nerve conduction studies and needle electromyography were performed before and after oxaliplatin administration. DNA was extracted by polymerase chain reaction, and each allele was isolated and sequenced. Results  We evaluated 40 patients. After oxaliplatin administration, 28 patients developed symptoms of neurotoxicity, which were severe in 11. Patients were divided into three groups according to neurophysiological data: G0 (normal peripheral nerve excitability [PNE]), 16 patients; G1 (mild PNE), 15 patients; G2 (severe PNE), 9 patients. Genetic analysis showed different alleles ranging from 13 to 23 CAG repeats. Patients carrying alleles containing 13–15 CAG repeats experienced a significantly higher incidence of severe nerve hyperexcitability (chi-square 48.6; df 16; P = 0.0001). Conclusion  The results suggest that OXA-neurotoxicity may be related to distribution of the polymorphic CAG motif of the SK3 gene, which might modulate nerve after-hyperpolarization. The 13–14 CAG repeat allele could mark patients susceptible to acute OXA neurotoxicity.
Journal: Cancer Chemotherapy and Pharmacology - CANCER CHEMOTHER PHARMACOL , vol. 67, no. 5, pp. 1179-1187, 2011
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    • ...We read with interest the manuscript by Basso and colleagues recently published in Cancer, Chemotherapy and Pharmacology [1] regarding the association between polymorphisms in K + channel genes and acute oxaliplatin-...

    Susanna B. Parket al. The contribution of SK3 polymorphisms to acute oxaliplatin-induced neu...

    • ...In our study, we found a signiWcant association between the occurrence of acute oxaliplatin neurotoxicity and the presence of a shorter CAG repeat polymorphism of SK3 gene [1]...
    • ...This means that a single nerve stimulation generates a CMAP closely followed by a high number of extra-discharges producing repeated oscillations arising in the distal portion of the peripheral nerve [1, 10, 11]...

    Michele Bassoet al. In reply

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