[Increased urinary excretion of the neurotoxic side-chain metabolites of ifosphamide in children with polymorphism of the glutathione S-transferases genes].
From 5% to 30% of children treated with ifosphamide (IF) develop symptoms of neurotoxicity due to toxic metabolites of the drug: 2- and 3- dechloroifosphamide (2- and 3-DCIF) and chloracetaldehyde (CAA), which cause glutathione depletion in cells. The aim of the study is to establish the influence of polymorphism of genes encoding for glutathione S-transferases classes pi (GSTP1), mi (GSTM1) and theta (GSTT1) on frequency of neurotoxicity of IF and amounts of toxic metabolites of the drug excreted in urine.


METHODS
Neurotoxicity of IF was assessed in 76 children (38 girls and 38 boys), aged 9 to 210 months with diffrent kinds of neoplasms. They were treated with IF in 3-hours infusion in doses from 1.5 g/m2 to 3 g/m2 for 3 to 5 days. Before chemotherapy, deletions of GSTT1, GSTM1 genes and transition at +313 A-G in GSTP1 gene were identified with PCR and PCR-FRLP method, respectively. Daily urine excretion of 2-DCIF, 3-DCIF and unmetabolised IF was assessed with nuclear magnetic resonance (31P NMR).


RESULTS
Symptoms of neurotoxicity were observed in 14 (18%) of 76 examined children treated with IF Comparing to children without neurological symptoms, in children with encephalopathy urinary excretion of unchanged ifosphamide was lower (p=0.055) and 2DCIF and 3DCIF was increased. Concomitantly, in children with transition at 313 A-->G GSTP1 gene concentrations of 2DCIF and 3DCIF were increased. Excretion of unmetabolised IF was statistically significantly higher in children with deletion of GSTT1 gene (p=0.02). Moreover, no correlation was found between the GSTM1 genotype and the excretion of ifosphamide and its metabolites.


CONCLUSIONS
The results suggest that ifosphamide can be the substrate for glutathione S-transferases. Polymorphism of genes coding for glutathione S-transferases can influence individual reactions to iphosphamide.
Zielińska
Elzbieta
E
Klinika Chorób Dzieci Uniwersytetu Medycznego w Lodzi.
Zubowska
Małgorzata
M
Misiura
Konrad
K
D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000652:urine*; D002648:Child; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects* / Q000652:urine*; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000652:urine*; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length
D018906:Antineoplastic Agents, Alkylating; C413545:glutathione S-transferase T1; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007069:Ifosfamide