Pharmacogenetic analysis of high-dose methotrexate treatment in children with osteosarcoma.

Marta Hegyi,Monika Csoka,Csaba Szalai,Agnes F Semsei,Adam Arany,Daniel J Erdelyi,Katalin Csordas,Andras Gezsi,Oliver Eipel,Nora Kutszegi,Peter Antal,Gabor T Kovacs,Judit Muller

doi:10.18632/oncotarget.11543

Abstract

Inter-individual differences in toxic symptoms and pharmacokinetics of high-dose methotrexate (MTX) treatment may be caused by genetic variants in the MTX pathway. Correlations between polymorphisms and pharmacokinetic parameters and the occurrence of hepato- and myelotoxicity were studied. Single nucleotide polymorphisms (SNPs) of the ABCB1, ABCC1, ABCC2, ABCC3, ABCC10, ABCG2, GGH, SLC19A1 and NR1I2 genes were analyzed in 59 patients with osteosarcoma. Univariate association analysis and Bayesian network-based Bayesian univariate and multilevel analysis of relevance (BN-BMLA) were applied. Rare alleles of 10 SNPs of ABCB1, ABCC2, ABCC3, ABCG2 and NR1I2 genes showed a correlation with the pharmacokinetic values and univariate association analysis. The risk of toxicity was associated with five SNPs in the ABCC2 and NR1I2 genes. Pharmacokinetic parameters were associated with four SNPs of the ABCB1, ABCC3, NR1I2, and GGH genes, and toxicity was shown to be associated with ABCC1 rs246219 and ABCC2 rs717620 using the univariate and BN-BMLA method. BN-BMLA analysis detected relevant effects on the AUC0-48 in the following SNPs: ABCB1 rs928256, ABCC3 rs4793665, and GGH rs3758149. In both univariate and multivariate analyses the SNPs ABCB1 rs928256, ABCC3 rs4793665, GGH rs3758149, and NR1I2 rs3814058 SNPs were relevant. These SNPs should be considered in future dose individualization during treatment.

Highlights

Osteosarcoma is one of the most frequent primary malignant bone tumors that occurs in childhood [1]
Single nucleotide polymorphisms (SNPs) of the ABCB1, ABCC1, ABCC2, ABCC3, ABCC10, ABCG2, GGH, SLC19A1 and NR1I2 genes were analyzed in 59 patients with osteosarcoma
Pharmacokinetic parameters were associated with four SNPs of the ABCB1, ABCC3, NR1I2, and GGH genes, and toxicity was shown to be associated with ABCC1 rs246219 and ABCC2 rs717620 using the univariate and BN-BMLA method

Summary

Introduction

Osteosarcoma is one of the most frequent primary malignant bone tumors that occurs in childhood [1]. The treatment aims to reduce the initial tumor volume and to eliminate the potential of micrometastases [3]. The cytostatic drugs that are used in preoperative chemotherapy are doxorubicin, cisplatin, ifosphamide, and methotrexate (MTX) [4]. MTX, a folic acid antagonist, is used in high dosages to treat all osteosarcoma tumors. It penetrates into the cells and inhibits the production of metabolites essential for the synthesis of nucleotides [5]. MTX is very effective in the treatment of osteosarcoma; reduced elimination may induce side effects such as hepatotoxicity and myelotoxicity. MTX-serum levels after administration are routinely monitored together with hepatic and bone marrow function

Objectives

Methods

Results

Discussion

Conclusion