Glutathione S-transferase genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin.
One of the side effects of cisplatin therapy in malignant neoplasms is ototoxicity. This effect shows a wide inter-individual range which is more variable than the pharmacokinetic parameters. Oxidative stress has been implicated in cisplatin ototoxicity. The glutathione S-transferase (GST) supergene family encodes isoenzymes that appear to be critical in protection against oxidative stress. Certain GST loci are polymorphic, demonstrating alleles that are null (GSTM1 and GSTT1), encode low-activity variants (GSTP1) or are associated with variable inducibility (GSTM3). The aim of our study was to investigate genetic risk factors involved in the ototoxicity of cisplatin and to determine whether the polymorphisms in five GST genes affect the individual risk of ototoxicity by cisplatin. Two groups of patients were analyzed in this study: group H, 20 patients early and highly sensitive to the ototoxicity of cisplatin; and group N, 19 patients with no hearing impairment under comparable doses of the drug. We found a protective effect for the GSTM3*B allele with a frequency of 0.18 in the group with normal hearing after therapy versus 0.025 in the group with hearing impairment. (chi2=5.37; p=0.02).
Peters
U
U
Institute for Human Genetics, University of Münster, Germany. petersul@uni-muenster.de
Preisler-Adams
S
S
Hebeisen
A
A
Hahn
M
M
Seifert
E
E
Lanvers
C
C
Heinecke
A
A
Horst
J
J
Jürgens
H
H
Lamprecht-Dinnesen
A
A
D000293:Adolescent; D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000009:adverse effects* / Q000627:therapeutic use; D003051:Cochlea / Q000187:drug effects*; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006315:Hearing Loss, Functional / Q000139:chemically induced* / Q000145:classification; D006801:Humans; D008297:Male; D012516:Osteosarcoma / Q000188:drug therapy; D018384:Oxidative Stress / Q000235:genetics*; D011110:Polymorphism, Genetic
D005982:Glutathione Transferase; D002945:Cisplatin