Investigation of gene expression and polymorphisms involved in the folate pathway, related to events of toxicity in Osteosarcoma

Abstract

Osteosarcoma (OS) is a primary malignant bone tumor of mesenchymal origin that is more frequent in childhood and adolescence. The etiology of OS still remains unknown; however, its genesis and progression might be determined by genetic factors. Methotrexate (MTX) belongs to the group of drugs classified as antimetabolites, the first successful class of drugs for the treatment of cancer. The profile of the side effects of MTX varies according to the dose. Regarding the use of MTX in the treatment of OS, the regime of high-dose MTX is the most commonly used. Despite the observed efficacy in the control of tumor size and metastasis, MTX is a drug-associated with the incidence of toxic effects, many of these limiting the life quality of patients. The understanding of the toxicity mechanisms and factors that enhance the toxic effects are very important aspects to be considered during treatment. Even when given identical methotrexate doses, patients vary significantly in their response and pattern of toxicities. These variations may be a result of polymorphisms, and single nucleotide polymorphisms (SNPs), are the most common type of the human genome. Genetic polymorphisms have been described in all the enzymes and pathways that are involved in the cellular disposition of MTX and natural folates. However there are little concrete information about the association between polymorphisms in the folate pathway enzymes genes (such as SLC19A1, MTHFR, TYMS e MTR) and the evolution of OS treatment or toxicity by the administration of MTX in OS. Thus, this study aims to investigate polymorphisms and the expression of genes involved in the folate pathway and correlates them with the toxicity profile of OS patients undergoing treatment with MTX. (AU)