title: The response to cyclophosphamide in steroid-sensitive nephrotic syndrome is influenced by polymorphic expression of glutathion-S-transferases-M1 and -P1.
abstract: Glutathione-S-transferases (GST) play a central role in the inactivation of toxic drugs like cyclophosphamide (CP). These enzymes depict several polymorphisms with altered activity, and it has been shown that different polymorphisms influence the risk of malignancies and the outcome after chemotherapy. To prove the hypothesis that CP efficacy in children with nephrotic syndrome is influenced by polymorphic expression of GSTs, the genotype of 26 patients was analyzed and correlated with the outcome after CP treatment. All 26 children with steroid-sensitive nephrotic syndrome and frequent relapses or steroid dependency were treated with CP at a mean age of 6.7+/-4.0 years. CP was given in a dose of 2 mg/kg/day for 12+/-1 week. GST-M1, GST-P1 and GST-T1 polymorphisms were detected by PCR. In patients with GST-M1 null polymorphism, a significantly better rate of sustained remission was seen than in patients with the heterozygous or homozygous GST-M1 wildtype (0 versus 29%, P <0.01). In contrast, children with GST-P heterozygous or homozygous polymorphism had a significantly lower rate of sustained remission compared to homozygous wildtype (7 versus 38%, P <0.02). The GST-T1 genotype did not influence the outcome after CP treatment (P =0.32). Patients with the combination of GST-M1 null and GST-P1 wildtype did not relapse in 50%, compared to 6% in other children (P <0.01). We conclude that the polymorphic expression of GST-M1 and -P1 did significantly influence the long-term remission rate after CP treatment of steroid-sensitive nephrotic syndrome in children. Whereas GST-M1 null will increase cyclophosphamide efficacy, GST-P1 polymorphism seems to be related to enhanced susceptibility to further relapses.
authors.affiliation: Clinic of Pediatric Nephrology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. udo.vester@medizin.uni-essen.de
authors.forename: Udo
authors.initials: U
authors.lastname: Vester
authors.forename: Birgitta
authors.initials: B
authors.lastname: Kranz
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zimmermann
authors.forename: Rainer
authors.initials: R
authors.lastname: Büscher
authors.forename: Peter F
authors.initials: PF
authors.lastname: Hoyer
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000627:therapeutic use*; D005260:Female; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D009404:Nephrotic Syndrome / Q000188:drug therapy* / Q000235:genetics*; D011110:Polymorphism, Genetic; D012074:Remission Induction; D013256:Steroids / Q000627:therapeutic use*
chemical_list: D003520:Cyclophosphamide; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D013256:Steroids; C496556:GSTP1 protein, human
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