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.

Resistance to Chemotherapy in Cancer: A Complex and Integrated Cellular Response

“…Conjugation of CPA metabolites involves several GST isoforms, some of which display increased levels in tumours. Enhanced detoxification of CPA metabolites would conceivably reduce the efficacy of chemotherapy; however, the clinical data available thus far do not provide supporting evidence of a correlation [114,115] . Aldehyde dehydrogenase isoforms are also involved in the detoxification of CPA and IFO metabolites [108] , and their overexpression in cultured cells decreases the sensitivity of cells to CPA and the related mafosamide [116,117] .…”

Do glutathione-S-transferase polymorphisms influence response to intravenous cyclophosphamide therapy in idiopathic nephrotic syndrome?

“…We observed a significant association of GSTP1 Ile105 polymorphism with a combination of GSTM1 null and GSTT1 null genotype and response to CP therapy in our study population. Studies by Vester et al have shown a significant effect of polymorphic expression of GST on the long-term remission rate after CP treatment in SSNS [18]. This study evaluated only 26 children with SSNS.…”

“…This study evaluated only 26 children with SSNS. It was observed that GSTM1 null genotype was shown to increase the efficacy of CP and that GSTP1 polymorphism was related to enhanced susceptibility to further relapses [18]. It was suggested that polymorphic expression of GSTM1 and P1 significantly influences the long-term remission rate, whereas GSTT1 genotype did not influence the outcome after CP treatment.…”

The GSTA1 polymorphism and cyclophosphamide therapy outcomes in lupus nephritis patients

“…In fact, in one study, the GSTP1 polymorphism (A>G) was associated with longer survival in breast cancer patients [17]. In contrast, children with steroid-sensitive nephrotic syndrome heterozygous or homozygous for GSTP1 variants, had worse remission than those with wild-type GSTP1 [18]. The latter observation is consistent with our results that patients with GSTP1 gene variants (heterozygous or homozygous) had a less remission (77.4% vs.84.4%, P =0.31)…”