Toxic and therapeutic effects of methotrexate-folinic acid (leucovorin) in advanced cancer and leukemiaWriting committee for the southeastern cancer study group

Vogler, William R.; Jacobs, Julian

doi:10.1002/1097-0142(1971)28:4<894::aid-cncr2820280412>3.0.co;2-i

Cited by 36 publications

(4 citation statements)

References 14 publications

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“…Further, 5-fluorouracil (5-FU), a uracil analog that inhibits TS, also disrupts the folate cycle and DNA synthesis and is used to treat several types of cancers [170]. Leucovorin, also known as folinic acid, is a derivative of the metabolically active THF that is often administered with MTX as it has been shown to mitigate toxicity and increase efficacy by providing a substrate to restore the folate cycle [169,171].…”

Section: Folate and Methionine-cycle Targeted Therapiesmentioning

confidence: 99%

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease

et al. 2020

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Vitamins B9 (folate) and B12 are essential water-soluble vitamins that play a crucial role in the maintenance of one-carbon metabolism: a set of interconnected biochemical pathways driven by folate and methionine to generate methyl groups for use in DNA synthesis, amino acid homeostasis, antioxidant generation, and epigenetic regulation. Dietary deficiencies in B9 and B12, or genetic polymorphisms that influence the activity of enzymes involved in the folate or methionine cycles, are known to cause developmental defects, impair cognitive function, or block normal blood production. Nutritional deficiencies have historically been treated with dietary supplementation or high-dose parenteral administration that can reverse symptoms in the majority of cases. Elevated levels of these vitamins have more recently been shown to correlate with immune dysfunction, cancer, and increased mortality. Therapies that specifically target one-carbon metabolism are therefore currently being explored for the treatment of immune disorders and cancer. In this review, we will highlight recent studies aimed at elucidating the role of folate, B12, and methionine in one-carbon metabolism during normal cellular processes and in the context of disease progression.

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Section: Folate and Methionine-cycle Targeted Therapiesmentioning

confidence: 99%

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease

et al. 2020

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“…Nevertheless, oral methotrexate in weekly doses of between 100 and 300 mg/M2 achieved no complete remissions in nine patients in another series. 3 The use of colaspase as a rescue rather than folinic acid may be preferable, since colaspase is cytotoxic to leukaemic cells, but does not affect normal dividing cells. Our excellent results suggest possible therapeutic synergy between the two agents, and the minimal toxicity suggests that colaspase given sequentially provides relative protection from methotrexate toxicity.…”

Section: Discussionmentioning

confidence: 99%

Refractory acute leukaemia in adults treated with sequential colaspase and high-dose methotrexate

Yap¹,

McCredie²,

Benjamin³

et al. 1978

BMJ

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BRITISH MEDICAL JOURNAL 16 SEPTEMBER 1978 791 out of 25); the possible benefit of relatively high doses of asparaginase and cytosine arabinoside (cytarabine) given' early in UKALL I; and the relative merits of the different schedules of methotrexate and mercaptopurine. Journal, 1978, 2, 791-793 Summary and conclusions Thirty-nine adults with acute leukaemia who had relapsed when receiving extensive chemotherapy were treated with a combination of methotrexate and colaspase (L-asparaginase) given sequentially. Patients initially received 50-80 mg/M2 methotrexate, followed three hours later by intravenous colaspase, 40 000 lU/M2. Seven days later intravenous methotrexate, 120 mg/M2 was given. Each dose of methotrexate was followed 24 hours later by colaspase, and the two-day course of treatment was repeated every 7-14 days. The methotrexate dose was increased to tolerance by increments of 40 mg/M2 with each course, while the colaspase dose remained constant unless abnormal liver function developed, when it was reduced by half.Overall, 18 out of 39 patients achieved complete remission (46%). Of these, 13 out of 21 (62%) had acute lymphoblastic leukaemia, three out of seven (43%) acute undifferentiated leukaemia, and two out of 11 (18%) acute myeloblastic leukaemia. The median duration of complete remission was 20 weeks and the median duration of survival in complete responders was 45 weeks. The median number of courses needed to achieve complete remission was three. The maximum tolerated dose of methotrexate was 400 mg/M2 (median 200 Mg/m2).Major side effects were due to colaspase. Methotrexate in doses of up to 400 mg/mi caused minimal myelosuppression and stomatitis, which suggested that colaspase

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“…Methotrexate (4-amino-10-methyl folic acid, MTX) is a competitive irreversible inhibitor of dihydrofolate reductase (DHFR) [ 9 ] that is effectively used in the treatment of cancer, rheumatoid arthritis, and other inflammatory diseases [ 10 – 12 ]. However, the efficacy of this drug is associated with adverse effects, especially on the liver [ 13 – 16 ].…”

Section: Introductionmentioning

confidence: 99%

Combination Treatment of Omega‐3 Fatty Acids and Vitamin C Exhibited Promising Therapeutic Effect against Oxidative Impairment of the Liver in Methotrexate‐Intoxicated Mice

Alorabi

Mohammed

Mostafa‐Hedeab

et al. 2022

BioMed Research International

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Drug-induced liver injury (DILI) is the main cause of liver damage mediated by the excretion of toxic active drug metabolites. Omega-3 fatty acids and vitamin C have potent antioxidant, anti-inflammatory, and antiapoptotic effects that could offer protection against oxidative stress and liver damage. This study evaluated the hepatoprotective effect of omega-3 and vitamin C alone as well as in a combined form in methotrexate- (MTX-) induced acute liver injury in mice. Male ICR mice of seven groups (7 mice per group) were used. Groups 1 (control group) and 2 (MTX) received 0.9% saline/day (po) for 9 days. Groups 3 and 4 received 100 and 200 mg/kg bw/day omega-3 (po), respectively, for 9 days. Groups 5 and 6 received 100 and 200 mg/kg bw/day vitamin C (po), respectively, for 9 days, while group 7 received omega-3 (100 mg/kg bw/day) and vitamin C (100 mg/kg bw/day) (po) for 9 days. All animals in groups 2 to 7 received 20 mg/kg/day MTX (I.P.) once on the 10th day. Our results revealed that MTX significantly induced the elevation of transaminases, alkaline phosphates (ALP), lactate dehydrogenase (LDH), and malonaldehyde (MDA) while depleting the levels of superoxide dismutase (SOD) and glutathione (GSH) when compared to the control group. Treatment with omega-3 fatty acids or vitamin C significantly attenuated the antioxidants and biochemical alterations in a dose-independent manner. Our molecular docking study of ligand-receptor interaction revealed that both ascorbic acid and omega-3 docked well to the binding cavity of LDH with high binding affinities of –5.20 and –4.50 kcal/mol, respectively. The histopathological features were also improved by treatment with omega-3 and vitamin C. The combined form of omega-3 and vitamin C showed a remarkable improvement in the liver enzymes, oxidative stress biomarkers, and the histopathological architecture of the mice. Conclusively, the combination of omega-3 and vitamin C demonstrated a synergistic therapeutic effect against MTX-intoxicated mice, hence representing a potential novel strategy for the management of drug-induced liver disorders.

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Toxic and therapeutic effects of methotrexate-folinic acid (leucovorin) in advanced cancer and leukemiaWriting committee for the southeastern cancer study group

Cited by 36 publications

References 14 publications

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease

Refractory acute leukaemia in adults treated with sequential colaspase and high-dose methotrexate

Combination Treatment of Omega‐3 Fatty Acids and Vitamin C Exhibited Promising Therapeutic Effect against Oxidative Impairment of the Liver in Methotrexate‐Intoxicated Mice

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