New Approaches to Cancer Chemotherapy with Methotrexate

Bleich, Howard L.; Boro, Emily S.; Frei, Emil; Jaffe, Norman; Tattersall, Martin H. N.; Pitman, Susan W.; Parker, Leroy M.

doi:10.1056/nejm197504172921607

Cited by 193 publications

(10 citation statements)

References 20 publications

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“…Several investigators have reported alterations in MTX pharmacokinetics due to presence of fluid collections or third spaces [17–18, 32–34]. Using a physiologically-based pharmacokinetic model, Li and Gwilt assessed factors related to the extent to which methotrexate is sequestered into physiologic third spaces [19].…”

Section: Discussionmentioning

confidence: 99%

Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections

Wright

Panetta

Onar‐Thomas

et al. 2014

Cancer Chemother Pharmacol

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Purpose High-dose methotrexate (HD-MTX) has been used to treat children with central nervous system tumors. Accumulation of MTX within pleural, peritoneal, or cardiac effusions has led to delayed excretion and increased risk of systemic toxicity. This retrospective study analyzed the association of intracranial post-resection fluid collections with MTX plasma disposition in infants and young children with brain tumors. Methods Brain MRI findings were analyzed for postoperative intracranial fluid collections in 75 pediatric patients treated with HD-MTX and for whom serial MTX plasma concentrations ([MTX]) were collected. Delayed plasma excretion was defined as [MTX] ≥1μM at 42 hours (h). Leucovorin was administered at 42 h and then every 6 h until [MTX] <0.1μM. Population and individual MTX pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling. Results Fifty-eight patients had intracranial fluid collections present. Population average (inter-individual variation) MTX clearance was 96.0 ml/min/m2 (41.1 CV%) and increased with age. Of the patients with intracranial fluid collections, 24 had delayed excretion; only 2 of the 17 without fluid collections (p<0.04) had delayed excretion. Eleven patients had grade 3 or 4 toxicities attributed to HD-MTX. No significant difference was observed in intracranial fluid collection, total leucovorin dosing, or hydration fluids between those with and without toxicity. Conclusions Although an intracranial fluid collection is associated with delayed MTX excretion, HD-MTX can be safely administered with monitoring of infants and young children with intracranial fluid collections. Infants younger than one year may need additional monitoring to avoid toxicity.

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Section: Discussionmentioning

confidence: 99%

Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections

Wright

Panetta

Onar‐Thomas

et al. 2014

Cancer Chemother Pharmacol

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“…However, it was MTX that was introduced to clinical application in RA since the mid-1980s [4,5]. Currently, MTX is commonly applied in combination with other drugs for the treatment of many neoplasms (acute lymphoblastic leukaemia, acute myeloid leukaemia, meningeal leukaemia and lymphoma, osteosarcomas, non-Hodgkin's lymphoma, also breast, bladder and number of other cancers) [6][7][8][9][10][11][12][13], severe and resistant forms of autoimmune diseases (rheumatoid arthritis, psoriasis, myasthenia gravis, Crohn's disease, multiple sclerosis, polyarticular juvenile idiopathic arthritis) [4][5][6][7][14][15][16][17][18][19], or even an ectopic pregnancy [20].…”

Section: Introductionmentioning

confidence: 99%

Overview of Dual-Acting Drug Methotrexate in Different Neurological Diseases, Autoimmune Pathologies and Cancers

Koźmiński

Halik

Chesori

et al. 2020

IJMS

207

120

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Methotrexate, a structural analogue of folic acid, is one of the most effective and extensively used drugs for treating many kinds of cancer or severe and resistant forms of autoimmune diseases. In this paper, we take an overview of the present state of knowledge with regards to complex mechanisms of methotrexate action and its applications as immunosuppressive drug or chemotherapeutic agent in oncological combination therapy. In addition, the issue of the potential benefits of methotrexate in the development of neurological disorders in Alzheimer’s disease or myasthenia gravis will be discussed.

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“…MTX could inhibit dihydrofolate reductase (DHFR) activity and stop FA cycle, and in turn inhibit the DNA synthesis and cell proliferation, and finally drives cells to death [16-18]. Recently, MTX has been developed to target to FA receptor-overexpressing cancer cells in vitro [19-21].…”

Section: Introductionmentioning

confidence: 99%

Validation of a Janus role of methotrexate-based PEGylated chitosan nanoparticles in vitro

Luo

Jia

et al. 2014

Nanoscale Res Lett

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Recently, methotrexate (MTX) has been used to target to folate (FA) receptor-overexpressing cancer cells for targeted drug delivery. However, the systematic evaluation of MTX as a Janus-like agent has not been reported before. Here, we explored the validity of using MTX playing an early-phase cancer-specific targeting ligand cooperated with a late-phase therapeutic anticancer agent based on the PEGylated chitosan (CS) nanoparticles (NPs) as drug carriers. Some advantages of these nanoscaled drug delivery systems are as follows: (1) the NPs can ensure minimal premature release of MTX at off-target site to reduce the side effects to normal tissue; (2) MTX can function as a targeting ligand at target site prior to cellular uptake; and (3) once internalized by the target cell, the NPs can function as a prodrug formulation, releasing biologically active MTX inside the cells. The (MTX + PEG)-CS-NPs presented a sustained/proteases-mediated drug release. More importantly, compared with the PEG-CS-NPs and (FA + PEG)-CS-NPs, the (MTX + PEG)-CS-NPs showed a greater cellular uptake. Furthermore, the (MTX + PEG)-CS-NPs demonstrated a superior cytotoxicity compare to the free MTX. Our findings therefore validated that the MTX-loaded PEGylated CS-NPs can simultaneously target and treat FA receptor-overexpressing cancer cells.

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New Approaches to Cancer Chemotherapy with Methotrexate

Cited by 193 publications

References 20 publications

Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections

Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections

Overview of Dual-Acting Drug Methotrexate in Different Neurological Diseases, Autoimmune Pathologies and Cancers

Validation of a Janus role of methotrexate-based PEGylated chitosan nanoparticles in vitro

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