Methotrexate: clinical pharmacology, current status and therapeutic guidelines

Bleyer, W. Archie

doi:10.1016/s0305-7372(77)80007-8

Cited by 193 publications

(115 citation statements)

References 48 publications

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“…The cornerstone of successful treatment for patients with HDMTX-induced renal dysfunction includes early recognition of this toxicity and prompt institution of increased doses of LV. 9,20 However, patients are at greater risk for the development of lifethreatening MTX toxicities if MTX renal excretion is delayed and plasma MTX concentrations remain elevated, even though they are receiving high doses of LV. The large number of publications describing invasive methods that attempt to address the underlying problem of impaired MTX elimination (Table 2) reflects the necessity to provide an alternative route of MTX elimination in patients with renal dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…However, the development of HDMTX-induced acute renal dysfunction, which is mediated by the precipitation of MTX and its metabolites in the renal tubules, 6 -8 is a potentially life-threatening complication. MTX is cleared primarily by renal excretion, 9 and renal dysfunction results in delayed MTX excretion and sustained, elevated plasma MTX concentrations, which may lead to a marked enhancement of the other toxicities of MTX, especially myelosuppression, mucositis, hepatitis, and dermatitis. 2,3,9 -11 Nephrotoxicity secondary to HDMTX was responsible primarily for its morbidity and mortality observed during the 1970s.…”

mentioning

confidence: 99%

“…Conventional treatment for HDMTX-induced renal dysfunction includes a prompt increase in the LV dose based on plasma MTX concentrations 9,20 and the continuation of hydration and alkalinization, provided adequate urine output can be maintained. Hemodialysis-based methods of MTX removal have been described for over 20 years.…”

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confidence: 99%

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High‐dose methotrexate‐induced nephrotoxicity in patients with osteosarcoma

Widemann

Balis

Kempf-Bielack

et al. 2004

Cancer

265

224

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BACKGROUNDHigh‐dose methotrexate (HDMTX)‐induced renal dysfunction can be life threatening, because it delays methotrexate (MTX) excretion, thereby exacerbating the other toxicities of MTX. HDMTX‐induced nephrotoxicity has been managed with high‐dose leucovorin, dialysis‐based methods of MTX removal, thymidine, and with the recombinant enzyme, carboxypeptidase‐G2 (CPDG2), which cleaves MTX to inactive metabolites. The objectives of the current study were to estimate the current incidence of HDMTX‐induced renal dysfunction in patients with osteosarcoma and to compare the efficacy and recovery of renal function for dialysis‐based methods of MTX removal with treatment using CPDG2.METHODSThe literature was reviewed for osteosarcoma trials, use of dialysis‐based methods for MTX removal, and reports of MTX‐induced nephrotoxicity, including information regarding recovery of renal function. Clinical trial databases of select osteosarcoma studies were reviewed. The efficacy of CPDG2 and renal recovery after CPDG2 rescue was obtained from the database of a compassionate‐release trial.RESULTSApproximately 1.8% of patients with osteosarcoma (68 of 3887 patients) who received HDMTX developed nephrotoxicity Grade ≥ 2. The mortality rate among those patients was 4.4% (3 of 68 patients). Dialysis‐based methods of MTX removal were used frequently but had limited effectiveness in removing MTX compared with the rapid reductions > 98% in plasma MTX concentrations achieved with CPDG2. CPDG2 did not appear to increase the time to recovery of renal function compared with supportive treatment that included dialysis‐based methods.CONCLUSIONSHDMTX‐induced renal dysfunction continues to occur in approximately 1.8% of patients with osteosarcoma who are treated on clinical protocols with optimal supportive care. For patients with delayed MTX excretion and high plasma MTX concentrations, CPDG2 should be considered over hemodialysis to lower plasma MTX concentrations rapidly and efficiently. Cancer 2004. © 2004 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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High‐dose methotrexate‐induced nephrotoxicity in patients with osteosarcoma

Widemann

Balis

Kempf-Bielack

et al. 2004

Cancer

265

224

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“…Mechanisms including elevated DHFR, decreased thymidylate synthase, impaired folate/antifolate transportation, and decreased polyglutamylation on MTX have been proposed to contribute to the development of MTX resistance (Asai et al, 2003). It is also postulated that the excessive use of leucovorin makes tumor cells refractory to subsequent MTX therapy (Bleyer, 1977;Sirotnak et al, 1978). Nevertheless, what causes the emergence of MTX-resistant tumor cells and the reason why high concentrations of leucovorin might affect cell survival or even support MTX resistance remain to be answered.…”

Section: Introductionmentioning

confidence: 99%

Serine Hydroxymethyltransferase Isoforms Are Differentially Inhibited by Leucovorin: Characterization and Comparison of Recombinant Zebrafish Serine Hydroxymethyltransferases

et al. 2007

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ABSTRACT:Serine hydroxymethyltransferase (SHMT) provides activated onecarbon units required for the biosynthesis of nucleotides, protein, and methyl group by converting serine and tetrahydrofolate to glycine and N 5 ,N 10 -methylenetetrahydrofolate. It is postulated that SHMT activity is associated with the development of methotrexate resistance and the in vivo activity of SHMT is regulated by the binding of N 5 -CHO-THF, the rescue agent in high-dose methotrexate chemotherapy. The aim of this study is to advance our understanding of the folate-mediated one-carbon metabolism in zebrafish by characterizing zebrafish mitochondrial SHMT. The cDNA encoding zebrafish mitochondrial SHMT was cloned, overexpressed in Escherichia coli, and purified with a three-step purification protocol. Similarities in structural, physical, and kinetic properties were revealed between the recombinant zebrafish mitochondrial SHMT and its mammalian orthologs. Surprisingly, leucovorin significantly inhibits the aldol cleavage of serine catalyzed by zebrafish cytosolic SHMT but inhibits to a lesser extent the reaction catalyzed by the mitochondrial isozyme. This is, to our knowledge, the first report on zebrafish mitochondrial folate enzyme as well as the differential inhibition of leucovorin on these two SHMT isoforms. Western blot analysis revealed tissue-specific distribution with the highest enrichment present in liver for both cytosolic and mitochondrial SHMTs. Intracellular localization was confirmed by confocal microscopy for both mitochondrial and cytosolic SHMTs. Unexpectedly, the cytosolic isoform was observed in both nucleus and cytosol. Together with the previous report on zebrafish cytosolic SHMT, we suggest that zSHMTs can be used in in vitro assays for folate-related investigation and antifolate drug discovery.Folates carry the chemically activated single carbons at N 5 and/or N 10 positions and are required for the biosynthesis and metabolism of nucleic acid, protein, amino acid, methyl group, neurotransmitter, and vitamins. Its vital role in nucleotide biogenesis has led to the development of many anticancer drugs targeting folate-requiring enzymes. Among them, methotrexate (MTX) is one of the most widely used anticancer agents to date. It blocks de novo nucleotide synthesis by depleting reduced tetrahydrofolates mainly through inhibition of dihydrofolate reductase (DHFR) and thymidylate synthase (Fig. 1, enzymes 2 and 3, respectively). However, resistance to MTX often emerges and becomes the major impediment to its curative potential.To overcome this obstacle and prevent MTX-associated toxicity, high-dose MTX combined with leucovorin rescue is administered and has become an important regimen in the treatment of a variety of cancers (Frei et al., 1980). Despite these preventive measures, MTXinduced resistance and toxicity continue to occur, although infrequently. Mechanisms including elevated DHFR, decreased thymidylate synthase, impaired folate/antifolate transportation, and decreased polyglutamylation on MTX have been pr...

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“…It irreversibly binds and inhibits dihydrofolate reductase enzyme and impairs the ability of the DNA to replicate. Being the first chemotherapeutic agent shown to have a response in cancer treatment, it changed the world of chemotherapy as we know it and led to the development of many standard cancer treatments used today [1-3]. The role of MTX has evolved as an immunological agent in autoimmune diseases such as rheumatoid arthritis, psoriasis, and systemic lupus erythematosus, etc.…”

Section: Introductionmentioning

confidence: 99%

A deadly prescription: combination of methotrexate and trimethoprim-sulfamethoxazole

Hamid

Lashari

Ahsan

et al. 2018

Journal of Community Hospital Internal Medicine Perspectives

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Methotrexate (MTX) is a chemotherapeutic synthetic(s) phase cell cycle inhibitor, and its role has evolved as an immunological agent in autoimmune diseases like rheumatoid arthritis, psoriasis, and systemic lupus erythematosus, etc. Trimethoprim-sulfamethoxazole (TS) is one of the most widely prescribed antibiotics commonly used for urinary tract infections, exacerbations of chronic bronchitis, traveler’s diarrhea, and pneumocystis pneumonia. Both MTX and TS can have significantly overlapping side effects involving dermatologic, renal, and hematological systems, and the combination of these can be deadly. Our case is about the combination of MTX and TS that leads to mucocutaneous ulceration, leukopenia, and renal insufficiency. The purpose of this case is to increase awareness of potentially significant toxicity from the combination of MTX with TS. Abbreviations: MTX: methotrexate; TS: trimethoprim-sulfamethoxazole; ED: emergency department; IV: intravenous; GI: gastrointestinal; NSAIDs: nonsteroidal anti-inflammatory drugs.

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Methotrexate: clinical pharmacology, current status and therapeutic guidelines

Cited by 193 publications

References 48 publications

High‐dose methotrexate‐induced nephrotoxicity in patients with osteosarcoma

High‐dose methotrexate‐induced nephrotoxicity in patients with osteosarcoma

Serine Hydroxymethyltransferase Isoforms Are Differentially Inhibited by Leucovorin: Characterization and Comparison of Recombinant Zebrafish Serine Hydroxymethyltransferases

A deadly prescription: combination of methotrexate and trimethoprim-sulfamethoxazole

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