Clinical aspects of the GGH -401C>T polymorphism apropos of the chemotherapy of children with osteosarcoma
  Márta Zubreczki-Hegyi1, Karolina Nemes2, Ágnes Semsei2, Edit Cságoly2, Csaba Szalai2, Dániel Erdélyi 2, Gábor Kovacs1
1 2nd Department of Pediatrics
2 Department of Genetics, Cell- and Immunobiology Semmelweis University, Budapest, Hungary

Introduction: According to previous results, the human gamma-glutamyl hydrolase (GGH) plays an important role in antifolate-resistance in tumour cells. The presence of the GGH 401T allele causes increased gene expression in leukemic cell lines. During this study, we examined the association of this GGH promoter polymorphism with the kinetics and toxicity of methorexate in children with osteosarcoma.

Patients and methods: We examined the data of 319 methotrexate blocks of 49 patients treated by COSS 86 or 96 protokoll between 1987 and 2004. From the medical records we collected the following values: the serum drug levels 4, 24, 36, 48 hours after the inducement of the methorexate infusion, and the highest serum GPT, GGT and bilirubine values on the first two week after the treatment. The GGH -401C>T promoter-polymorphism was determined by a PCR-RFLP method from DNA extracted from peripherical blood.

Results: There was no difference in the 4 hours serum methotrexate levels (p=0,48) and the 24 hours serum drug levels (p=0,09) between the group with GGH -401CC/CT genotype and the patients homozygous for T allele. . However, drug serum levels were significantly lower in the cellular elimination phase (p=0.01 at 48 hours). The incidence of grade IV. acute hepatotoxicity was also less frequent (p=0,018) in this genotype group.

Conclusion: Patients homozygous for the GGH -401T allele had faster methotrexate-elimination and less hepatotoxicity compared to those with -401CC/CT genotype. Our results raise the possibility of future GGH-genotype based dose individualization.