Advances in individual prediction of methotrexate toxicity: a review

Abstract

SummaryAs the cure rates for haematological malignancies have improved, the exploration of the balance between efficacy and side effects has become a major research target. The antifolate methotrexate is widely used in the treatment of acute lymphoblastic leukaemia, non-Hodgkin lymphoma, and osteosarcoma. Even when given identical methotrexate doses, patients vary significantly in their response and pattern of toxicities. This diversity can, to some extent, be linked to sequence variations in genes involved in drug absorption, metabolism, excretion, cellular transport, and effector targets or target pathways. In the coming years pharmacogenomics is expected to change our approaches to individualised therapy with methotrexate. However, genetic polymorphisms affect the pharmacokinetics and dynamics of all the drugs a patient receive as well as the normal tissues tolerance to a given drug exposure. Thus, although high-throughput techniques will allow mapping of tens of thousands of genetic polymorphisms in one run, it will be a major challenge to dissect out which of these have the strongest impact on efficacy and toxicity and hence should be the targets for intervention. This paper discusses the pharmacology of methotrexate and reviews studies on haematological malignancies that have attempted to predict the risk of toxicity by specific clinical or genetic features.

Germline genetic polymorphisms may influence chemotherapy response and disease outcome in osteosarcoma

“…Adverse survival in childhood acute lymphoblastic leukemia (ALL) is associated with several single nucleotide polymorphisms (SNPs), including MTHFR c.677C>T p.Ala 222 Val, also known to enhance methotrexate toxicity in both ALL and solid tumors. 2,3,6,[13][14][15][16] In osteosarcoma, MTHFR c.677C>T p.Ala 222 Val increased hematological toxicity but did not influence survival. 17 Cisplatin and doxorubicin form helix-distorting DNA adducts resulting in strand breakage and inhibition of replication.…”

Metabolic Markers of MG-63 Osteosarcoma Cell Line Response to Doxorubicin and Methotrexate Treatment: Comparison to Cisplatin

“…These three agents (often together with ifosfamide) are the components of one of the most commonly adopted preoperative chemotherapy regimen for the treatment of nonmetastatic high grade OS, 4,5 a frequent type of malignant bone tumor in pediatric and adolescent age groups. 6 Although much knowledge is available on the specific mechanisms of action of DOX (cytostatic, intercalates with DNA thus preventing replication), 7 MTX (cytostatic, interferes with the natural folate-homocysteine cycle and with purine de novo synthesis), 8 and cDDP (cytotoxic, forms intra-and interstrand DNA cross-links), 9−12 relatively little is known on the metabolic adaptations of tumor cells to each drug and on the occurrence of possible metabolic markers of drug efficacy. In this respect, cDDP has been more extensively investigated by metabolomics, mainly NMR-based, in several cancer cells: lung, 13,14 brain, 15−17 liver, 18 and OS, 19 the latter by our own group.…”

Impacto de polimorfismos genéticos de la vía metabólica del metotrexato sobre la sobrevida de niños mexicanos con leucemia linfoblástica aguda (LLA)

“…El metotrexato (MTX), antifolato que forma parte del tratamiento de elección en todas las etapas de quimioterapia de los pacientes con LLA, por su semejanza con el folato, usa la misma vía metabólica a partir de su paso por la FPGS (8). Adicionalmente, el MTX es inhibidor selectivo de la XO(9) altamente tóxico (10).…”