title: Cisplatin-induced ototoxicity in pediatric solid tumors: the role of glutathione S-transferases and megalin genetic polymorphisms.
abstract: Cisplatin-induced ototoxicity, an important dose-limiting side effect, has proven high interindividual variability. Glutathione S-transferases (GSTs) are isoenzymes involved in cellular detoxification processes. Megalin has been demonstrated to bind aminoglycosides, known to be similar to cisplatin for their ototoxicity. The GSTs and megalin expression is genetically polymorphic, which might be responsible for the variability in cisplatin-induced ototoxicity. The genotyping of GSTM1, GSTT1 polymorphisms, and 2 nonsynonymous single nucleotide polymorphisms (SNPs) at megalin genes, rs2075252 and rs2228171, were performed in 68 children diagnosed with solid tumors who received cisplatin-based chemotherapy. After the end of treatment, audiometry demonstrated hearing loss in 79.4% of patients according to Brock classification. The cumulative cisplatin dose >400 mg/m is associated with increased risk of cisplatin-induced ototoxicity [odds ratio (OR), 17.5; 95% confidence interval (CI), 3.09-98.62]. GSTT1 wild genotype and C-allele of rs2228171 SNPs of megalin gene occurred with higher frequency in patients with ototoxicity (P=0.023; OR, 10; 95% CI, 1.80-56.00 and P=0.034; OR, 2.67; 95% CI, 1.22-5.82, respectively). In conclusion, our results suggested that GSTT1 wild genotype and C-allele of rs2228171 SNPs might be risk factors for ototoxicity. The cumulative cisplatin dose <400 mg/m should be beneficial in order to ameliorate ototoxicity.
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Bangkok, Thailand.
authors.forename: Worawut
authors.initials: W
authors.lastname: Choeyprasert
authors.forename: Rachchadol
authors.initials: R
authors.lastname: Sawangpanich
authors.forename: Krisna
authors.initials: K
authors.lastname: Lertsukprasert
authors.forename: Umaporn
authors.initials: U
authors.lastname: Udomsubpayakul
authors.forename: Duantida
authors.initials: D
authors.lastname: Songdej
authors.forename: Usanarat
authors.initials: U
authors.lastname: Unurathapan
authors.forename: Samart
authors.initials: S
authors.lastname: Pakakasama
authors.forename: Suradej
authors.initials: S
authors.lastname: Hongeng
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics*; D034381:Hearing Loss / Q000139:chemically induced* / Q000235:genetics*; D006801:Humans; D007223:Infant; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics*; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D005982:Glutathione Transferase; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C413545:glutathione S-transferase T1