The response to cyclophosphamide in steroid-sensitive nephrotic syndrome is influenced by polymorphic expression of glutathion-S-transferases-M1 and -P1.
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.
Vester
Udo
U
Clinic of Pediatric Nephrology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany. udo.vester@medizin.uni-essen.de
Kranz
Birgitta
B
Zimmermann
Stephanie
S
Büscher
Rainer
R
Hoyer
Peter F
PF
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*
D003520:Cyclophosphamide; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D013256:Steroids; C496556:GSTP1 protein, human
Blood. 2000 Feb 15;95(4):1222-8
10666194
Biochem J. 1994 May 15;300 ( Pt 1):271-6
8198545
Cancer Res. 2001 Oct 1;61(19):7130-5
11585745
Proc Natl Acad Sci U S A. 1988 Oct;85(19):7293-7
3174634
Kidney Int. 2000 Nov;58(5):2186-93
11044240
Lancet. 1979 Feb 24;1(8113):401-3
84259
Carcinogenesis. 1996 Apr;17(4):881-4
8625505
Cancer Res. 1994 Aug 15;54(16):4313-20
8044778
Lancet. 1996 Feb 3;347(8997):295-7
8569364
Br J Cancer. 1996 Jan;73(1):44-8
8554981
J Clin Oncol. 1997 May;15(5):1885-96
9164199
Cancer Epidemiol Biomarkers Prev. 1997 Jul;6(7):511-5
9232338
Carcinogenesis. 1997 Apr;18(4):641-4
9111193
Clin Cancer Res. 1998 Oct;4(10):2439-45
9796976
Drug Metab Dispos. 1991 May-Jun;19(3):625-9
1680629
Pediatr Nephrol. 2003 Jul;18(7):661-4
12750975
N Engl J Med. 1982 Feb 25;306(8):451-4
7035953
Pharmacogenetics. 2000 Nov;10(8):715-26
11186134
Eur J Biochem. 1994 Sep 15;224(3):893-9
7925413
Pediatr Nephrol. 1997 Feb;11(1):16-9
9035165
Carcinogenesis. 1998 Feb;19(2):275-80
9498276
Cancer. 1991 Mar 15;67(6):1608-13
2001549
Pediatr Nephrol. 2001 Mar;16(3):271-82
11322378