The role of 7-hydroxymethotrexate during methotrexate anti-cancer therapy

Lankelma, J.; Klein, E; Ramaekers, Frans C. S.

doi:10.1016/0304-3835(80)90117-2

Cited by 98 publications

(32 citation statements)

References 8 publications

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“…Ch~mat~graphy of plasma from I patient showed trace, amoun~ of 7-OH-MTX (19). This is surprising and seems to ~ in-contrast with data from Lankelma e t aL, who reported a stepwise rise in plasma concentrations of T-OI-/-MTX during 3 sequential MTX infusions (65).…”

Section: T~ ~I N~!a Ne and Reve~al Of Metlhotrexate Toxicitycontrasting

confidence: 83%

Is there a role for thymidine in cancer chemotherapy?

Schornagel

Leyva

Pinedo

1982

Cancer Treatment Reviews

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Section: T~ ~I N~!a Ne and Reve~al Of Metlhotrexate Toxicitycontrasting

confidence: 83%

Is there a role for thymidine in cancer chemotherapy?

Schornagel

Leyva

Pinedo

1982

Cancer Treatment Reviews

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“…The pathogenesis of MTX-induced renal dysfunction is not clear, although it is believed to be mediated via the precipitation of MTX and its metabolites in the renal tubules [19][20][21] . Hydration of the patient and alkalinization of urine only reduces the renal damage and does not prevent it completely, suggesting that other mechanisms may also be involved in the pathogenesis of MTX-induced renal damage.…”

Section: Discussionmentioning

confidence: 99%

“…Routine monitoring of serum creatinine and MTX is being done for management of MTX-induced renal dysfunction [18] . The pathogenesis of MTX-induced renal dysfunction is not clear, although it is believed to be mediated via the precipitation of MTX and its metabolites in the renal tubules [19,20] or by a direct toxic effect of MTX on the renal tubules [21] . Hydration of the patient and alkalinization of urine only reduces the renal damage and does not prevent it completely, suggesting that other mechanisms may also be involved in MTX-induced renal damage.…”

Section: Introductionmentioning

confidence: 99%

Neutrophil Infiltration and Oxidative Stress May Play a Critical Role in Methotrexate-Induced Renal Damage

Kolli¹,

Abraham²,

Isaac

et al. 2009

Chemotherapy

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Background: Nephrotoxicity is one of the adverse side effects of methotrexate (MTX) chemotherapy. The mechanism of renotoxicity of MTX is not fully understood. It is essential to understand the mechanism of nephrotoxicity of MTX in order to diminish the side effects and hence maximize the benefits of chemotherapy. Objectives: The aim of the study was to verify whether oxidative stress and neutrophil infiltration play a role in MTX-induced renal damage using a rat model. Methods: Adult male rats were administered MTX at the dose of 7 mg/kg body weight intraperitoneally for 3 consecutive days and sacrificed 12 or 24 h after the last dose. Vehicle-treated rats served as controls. The kidneys were removed and used for light microscopic and biochemical studies. Myeloperoxidase activity, a marker of neutrophil infiltration was measured in kidney homogenates along with the markers of oxidative damage including protein carbonyl content, protein thiol and malondialdehyde. The activities of the antioxidant enzymes, namely glutathione peroxidase, glutathione S-transferase, superoxide dismutase and catalase, were also assayed. Results: MTX treatment induced damage to the glomeruli and tubules. Plasma creatinine levels in the MTX-treated rats were significantly elevated compared with controls. A significant increase in myeloperoxidase activity (p < 0.05) was observed in the kidneys of MTX-treated rats. Protein carbonyl content and malondialdehyde, sensitive and reliable markers of oxidative damage to proteins and lipids, respectively, were significantly elevated (p < 0.01) in the kidneys of MTX-treated rats compared with controls. The activities of the antioxidant enzymes, namely, superoxide dismutase and glutathione peroxidase, were significantly elevated (p < 0.01 and p < 0.05, respectively) in kidneys of rats following MTX treatment. Conclusion: The results of the present study provide evidence for the role of neutrophil infiltration and oxidative stress in MTX-induced renal damage. Administration of inhibitors of myeloperoxidase or scavenging hypochlorous acid, the product of myeloperoxidase, by supplementation with antioxidants as an adjuvant therapy may be promising in alleviating the renal side effect of MTX.

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“…MTX is metabolized to MTX polyglutamate (6), 7-hydroxymethotrexate (7-OH-MTX) (7)(8)(9)(10), and 2,4-diamino-N 10 -methylpteroic acid (11) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Variation of Hepatic Methotrexate 7‐Hydroxylase Activity in Animals and Humans

et al. 1999

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SummaryThis study deals with individual and species variations in the converting activity of methotrexate (MTX) to 7-hydroxymethotrexate in animals and humans. When MTX 7-hydroxylase was assayed in six human liver cytosols, a 48-fold range of intersubject variation of the activity was observed. The variations were correlated to the concentrations of aldehyde oxidase activity in human subjects assayed with benzaldehyde as a substrate. Species differences of liver MTX 7-hydroxylase activity were also observed. The activity was highest in rabbits, followed by rats, hamsters, and monkeys but was undetectable in dogs. Strain differences of MTX 7-hydroxylase activity based on aldehyde oxidase activity were also observed in rats and mice. The results suggest that aldehyde oxidase functions as MTX 7-hydroxylase in livers of animals and humans, and the observed differences of MTX 7-hydroxylase activity are due to variations in the amount of aldehyde oxidase present. IUBMB Life, 48: 607-611, 1999

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The role of 7-hydroxymethotrexate during methotrexate anti-cancer therapy

Cited by 98 publications

References 8 publications

Is there a role for thymidine in cancer chemotherapy?

Is there a role for thymidine in cancer chemotherapy?

Neutrophil Infiltration and Oxidative Stress May Play a Critical Role in Methotrexate-Induced Renal Damage

Variation of Hepatic Methotrexate 7‐Hydroxylase Activity in Animals and Humans

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