Fig 1.
Overview of the folate pathway with separate folate isoforms and converting enzymes. Leucovorin (5-formyl THF) rescue therapy bypasses the action of DHFR. SAM: S-adenosylmethionine; SAH: S-adenosylhomocysteine; DHF: dihydrofolate; THF: tetrahydrofolate; TS: thymidylate synthase; DHFR: dihydrofolate reductase; MTHFD1: methylenetetrahydrofolate dehydrogenase 1; MTHFR: methylenetetrahydrofolate reductase; MTX: methotrexate; LV: Leucovorin.
Fig 2.
Abbreviations: ALL, acute lymphoblastic leukemia; HD-MTX, high-dose methotrexate; DCOG, Dutch Childhood Oncology Group; SNP, single-nucleotide polymorphism; n = number of patients; * 1 patient had neurological damage before start HD-MTX treatment, 1 patients was transferred to another hospital, 1 patient had an adjusted protocol due to a SPINKS mutation and 1 patient was initially treated otherwise due to another diagnosis.
Fig 3.
One carbon metabolism metabolite levels before (T0) and after (T1) high-dose MTX therapy.
One carbon metabolism metabolite levels before (T0) and after (T1) of high-dose MTX therapy: erythrocyte 5-methyl THF (a, p<0.0001), erythrocyte non-methyl THF (b, p = 0.676) sum erythrocyte folate isoforms (c, p<0.0001), serum folate (d, p <0.0001), plasma homocysteine (d, p<0.0001), serum vitamin B12 (e, p = 0.134). The red lines depict the median levels and the blue lines depict the 95% confidence interval.
Table 1.
One-carbon metabolism metabolite levels at T0 and T1 (n = 67).
Table 2.
Estimated linear regression coefficients with 95% confidence intervals.
Table 3.
Delta one-carbon metabolism levels in relation to MTX-induced oral mucositis (n = 67).