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


CONCLUSIONS
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.
Basso
Michele
M
Medical Oncology, Department of Internal Medicine, Catholic University of Sacred Heart, Largo Agostino Gemelli n. 8, 00168 Rome, Italy.
Modoni
Anna
A
Spada
Daniele
D
Cassano
Alessandra
A
Schinzari
Giovanni
G
Lo Monaco
Mauro
M
Quaranta
Davide
D
Tonali
Pietro Attilio
PA
Barone
Carlo
C
D000368:Aged; D020816:Amino Acid Motifs; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001661:Biliary Tract Neoplasms / Q000188:drug therapy / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics; D004576:Electromyography; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009431:Neural Conduction / Q000187:drug effects; D009460:Neurologic Examination; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D011110:Polymorphism, Genetic; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics
D000970:Antineoplastic Agents; C406328:KCNN3 protein, human; D009944:Organoplatinum Compounds; D051640:Small-Conductance Calcium-Activated Potassium Channels; D000077150:Oxaliplatin