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Methotrexate

"An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of TETRAHYDROFOLATE DEHYDROGENASE and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA." (MeSH 2013)

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Web Resources: Methotrexate
Latest Research Publications

Web Resources: Methotrexate (6 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Ejima-Yamada K, Oshiro Y, Okamura S, et al.
Epstein-Barr virus infection and gene promoter hypermethylation in rheumatoid arthritis patients with methotrexate-associated B cell lymphoproliferative disorders.
Virchows Arch. 2017; 470(2):205-215 [PubMed] Related Publications
We analyzed CpG-island hypermethylation status in 12 genes of paraffin-embedded tissues from 38 rheumatoid arthritis (RA) patients with methotrexate (MTX)-associated large B cell lymphoproliferative disorder (BLPD), 11 RA patients with non-MTX-associated BLPD (non-MTX-BLPD), 22 controls with diffuse large B cell lymphoma (DLBCL), and 10 controls with Epstein-Barr virus (EBV)(+) DLBCL. Among them, tumor cells from EBV(+) MTX-BLPD patients and control EBV(+) DLBCL patients had significantly lower median incidence of CpG island methylator phenotype (CIMP) than those from non-MTX-BLPD and control DLBCL groups (2.3 and 1.7 vs. 4.3 and 4.4; P < 0.01 for each). In the MTX-BLPD group, EBV(+) patients showed lower median CIMP than EBV(-) patients (2.3 vs. 3.2); they also had significantly lower hypermethylation incidence in four apoptosis-related genes, especially death-associated protein kinase (14 vs. 55 %), higher incidence of massive tumor necrosis (86 vs. 27 %), and lower BCL2 protein expression (19 vs. 86 %) than did the control DLBCL group (P < 0.01 for all). In all clinical stages, EBV(+) MTX-BLPD patients had better prognoses than the EBV(-) MTX-BLPD (P = 0.011), non-MTX-BLPD (P = 0.002), and control DLBCL groups (P = 0.015). MTX-BLPD patients without hypermethylated RAS-associated domain family-1A (RASSF1A) or O (6) -methyl guanine-DNA methyltransferase (MGMT) had significantly better prognosis than those with hypermethylation of those genes (P = 0.033). We conclude that in RA patients with MTX-BLPD, EBV infection is associated with a lower incidence of CIMP, apoptosis-related gene hypermethylation, and BCL2 expression, which can induce tumor regression by MTX withdrawal and lead to better prognoses.

Reiss SN, Buie LW, Adel N, et al.
Hypoalbuminemia is significantly associated with increased clearance time of high dose methotrexate in patients being treated for lymphoma or leukemia.
Ann Hematol. 2016; 95(12):2009-2015 [PubMed] Related Publications
As a weak acid, methotrexate (MTX) is bound to serum albumin and has variable protein binding. The purpose of this study was to assess serum albumin's relationship with MTX pharmacokinetics by comparing MTX clearance and toxicities between patients with normal serum albumin to those with hypoalbuminemia. This single-center retrospective study included adult patients with leukemia or lymphoma who received their first MTX at a dose ≥1 g/m(2). Hypoalbuminemia was defined as serum albumin ≤3.4 g/dL. MTX clearance was defined as the first documented time the MTX level ≤0.05 μM. Fisher's exact tests and Wilcoxon rank sum tests were used to examine differences in toxicities, and Cox proportional hazard regression was used to assess relationship with time to clearance. Of 523 patients identified, 167 patients were evaluable. One hundred thirty-five patients had normal serum albumin and 32 had hypoalbuminemia. Hypoalbuminemia was associated with a higher proportion of patients experiencing edema, ascites or pleural effusions (34 vs. 12 %, p = 0.006), and the concomitant use of nephrotoxic agents (41 vs. 20 %, p = 0.021). Hypoalbuminemia was associated with a significantly longer time to MTX clearance (median 96 vs. 72 h, p = 0.004). In addition, patients with hypoalbuminemia had a higher proportion of hyperbilirubinemia and significantly longer hospitalization (median 14 vs. 5 days, p < 0.001). In conclusion, hypoalbuminemia was associated with increased time to MTX clearance and increased length of hospitalization. High dose MTX is safe to administer in patients with low albumin levels, with appropriate leucovorin rescue, and good supportive care.

Hogan MP, Osborne J, Ulaner GA
FDG-Avid Intrathecal Inflammation Following Administration of Intrathecal Methotrexate.
Clin Nucl Med. 2016; 41(12):995-997 [PubMed] Related Publications
Intrathecal methotrexate is a standard option for central nervous system-directed therapy in patients with stage III and IV diffuse large B-cell lymphoma. We present a case of a 50-year-old man with stage IV diffuse large B-cell lymphoma with widespread lymphomatous involvement including the central nervous system, who received 7 doses of intrathecal methotrexate via Ommaya catheter. Posttherapy F-FDG-PET/CT imaging demonstrated diffuse, intense intrathecal FDG avidity, without correlative findings on MR spinal imaging. FDG avidity resolved on follow-up. These PET/CT findings are most consistent with methotrexate-induced thecal inflammation, which needs to be distinguished from intrathecal malignancy.

How J, Blattner M, Fowler S, et al.
Chemotherapy-associated Posterior Reversible Encephalopathy Syndrome: A Case Report and Review of the Literature.
Neurologist. 2016; 21(6):112-117 [PubMed] Related Publications
INTRODUCTION: There are increasing reports of posterior reversible encephalopathy syndrome (PRES) associated with the use of chemotherapeutic agents. Recognition of PRES is crucial given its reversibility with appropriate supportive management. We report a patient presenting with PRES after treatment with Rituximab, Cyclophosphamide, Hydroxydaunorubicin/Adriamycin, Oncovin/Vincristine, Prednisone (R-CHOP) and intrathecal methotrexate. We also perform a systematic review of the literature on chemotherapy-associated PRES.
CASE REPORT: A 72-year-old man with recently diagnosed diffuse large B-cell lymphoma became unresponsive 4 days after initiation of R-CHOP and intrathecal methotrexate. Brain magnetic resonance imaging showed interval development of occipital and temporal fluid attenuation inversion recovery hyperintensities consistent with PRES. The patient's blood pressure was aggressively controlled and he received 5 days of high-dose methylprednisone. He subsequently regained consciousness and his mental status gradually improved. Repeat magnetic resonance imaging showed interval resolution of the bilateral fluid attenuation inversion recovery hyperintensities.
REVIEW SUMMARY: We performed a systematic review of the literature and included a total of 70 unique cases involving chemotherapy-associated PRES. Platinum-containing drugs, Cyclophosphamide, Hydroxydaunorubicin/Adriamycin, Oncovin/Vincristine, Prednisone/R-CHOP regimens, and gemcitabine were the agents most commonly used in patients who developed suspected chemo-associated PRES. Median onset of symptoms occurred 8 days after chemotherapy. Hypertension was the most commonly reported risk factor associated with the development of chemotherapy-associated PRES. In most cases, PRES improved with supportive management alone within 2 weeks.
CONCLUSIONS: Chemotherapy-associated PRES is an increasingly encountered syndrome. Both neurologists and non-neurologists should be familiar with the most commonly implicated agents, symptoms, risk factors, and clinical course of chemotherapy-associated PRES, given its favorable prognosis with appropriate management.

Akiyama H, Takase H, Kubo F, et al.
High-dose methotrexate following intravitreal methotrexate administration in preventing central nervous system involvement of primary intraocular lymphoma.
Cancer Sci. 2016; 107(10):1458-1464 [PubMed] Free Access to Full Article Related Publications
In order to prevent central nervous system (CNS) involvement and improve the prognosis of primary intraocular lymphoma (PIOL), we prospectively evaluated the efficacy of combined therapy using intravitreal methotrexate (MTX) and systemic high-dose MTX on treatment-naïve PIOL. Patients with newly diagnosed PIOL whose lymphoma was limited to the eyes were enrolled. The patients were treated with weekly intravitreal MTX until the ocular lesions were resolved, followed by five cycles of systemic high-dose MTX (3.5 g/m(2) ) every other week. Ten patients were enrolled in this study and completed the treatment. All patients achieved complete response for their ocular lesions with rapid decrease of intravitreal interleukin-10 concentration. Adverse events of intravitreal and systemic high-dose MTX were mild and tolerable. With a median follow-up of 29.5 months, four patients (40%) experienced the CNS disease development and the mean CNS lymphoma-free survival (CLFS) time was 51.1 months. Two-year CLFS, which was the primary end-point of the study, was 58.3% (95% confidence interval, 23.0-82.1%). In contrast, eight patients were treated with intravitreal MTX alone in our institute, and their 2-year CLFS was 37.5% (95% confidence interval, 8.7-67.4%). In conclusion, systemic high-dose MTX following intravitreal MTX is feasible and might be effective in preventing CNS involvement of PIOL. Further arrangements are worth considering in order to improve the effects. This study was registered with UMIN Clinical Trials Registry (UMIN000003921).

Ureshino H, Nishioka A, Kojima K, et al.
Subdural Hematoma Associated with Dasatinib and Intrathecal Methotrexate Treatment in Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia.
Intern Med. 2016; 55(18):2703-6 [PubMed] Related Publications
Dasatinib has been associated with an increased risk of bleeding, with the most prominent risk noted in patients with advanced-stage chronic myeloid leukemia and thrombocytopenia. We herein report two cases of Philadelphia chromosome-positive acute lymphoblastic leukemia in which a subdural hematoma developed in association with low-dose (40-50 mg/day) dasatinib treatment and lumbar puncture for intrathecal methotrexate injection. Both patients were in complete remission, with normal platelet counts and coagulation status. We suggest that dasatinib, even at a low dose, may impair platelet aggregation and that lumbar puncture may increase the risk of a subdural hematoma (occasionally bilateral) in patients receiving dasatinib.

Matsumoto R, Numata K, Doba N, et al.
A case of multiple hepatic lesions associated with methotrexate-associated lymphoproliferative disorder.
J Med Ultrason (2001). 2016; 43(4):545-51 [PubMed] Related Publications
Patients receiving methotrexate (MTX) for the treatment of autoimmune disease are at a high risk of developing lymphoproliferative disorders (LPD), the so-called methotrexate-associated lymphoproliferative disorders (MTX-LPD). We recently performed abdominal ultrasonography (US) in a patient with rheumatoid arthritis (RA) who had developed hepatic dysfunction during the course of MTX therapy; the examination revealed multiple well-demarcated hepatic tumors with slightly irregular borders, the largest one measuring 9 cm in diameter. In view of the finding of portal and hepatic veins perforating the tumor, we suspected a diagnosis of malignant lymphoma and performed a hepatic tumor biopsy. Histopathological examination of the biopsy specimens revealed a diagnosis of diffuse large B-cell lymphoma, and we made a final diagnosis of MTX-LPD. MTX treatment was discontinued, which resulted in rapid resolution of the lesions. Resolution of MTX-LPD can be obtained just by discontinuation of MTX treatment. In patients receiving MTX therapy who are found to have hepatic tumors perforated by the portal vein and/or hepatic vein on abdominal US, it is advisable to perform hepatic tumor biopsy to facilitate differential diagnosis of MTX-LPD and enable a definite diagnosis.

Shan W, Zhang X, Li M, et al.
Over expression of miR-200c suppresses invasion and restores methotrexate sensitivity in lung cancer A549 cells.
Gene. 2016; 593(2):265-71 [PubMed] Related Publications
MicroRNAs have become recognized as key players in the development of malignancy. MiR-200c can function as a tumor suppressor gene. However, the effect of miR-200c on methotrexate resistance remains unclear to date. This study aims to evaluate the function of miR-200c in lung cancer A549 cells. The data presented in our study demonstrated that the expression of miR-200c was down-regulated in methotrexate-resistant A549 cells. Over expression of miR-200c could significantly inhibit cell proliferation, induce G0/G1 cell cycle arrest and induce cell apoptosis. RT-PCR and Western blot assays showed that the expression of P53 and P21 were significantly increased with miR-200c overexpression. These results indicated that over expression of miR-200c might enhance the sensitivity of A549 cells to methotrexate through the P53/P21 pathway. Furthermore, miR-200c overexpression significantly inhibited cell migration and invasion with increasing the expression of E-cad and decreasing the expression of EZH2. In consequence, we provide a mechanism of acquired resistance to methotrexate that is caused by the loss of miR-200c in lung cancer cells. Along with this, our study demonstrates the complex network of microRNA mediated chemoresistance.

Ferrazzi A, Russo I, D'Amore ES, Alaibac M
A Case of Angioinvasive Cutaneous Anaplastic Large Cell Lymphoma Completely Regressed After Low-dose Systemic Methotrexate.
Acta Derm Venereol. 2017; 97(2):281-282 [PubMed] Related Publications
is missing (Short communication).

Lawrie TA, Alazzam M, Tidy J, et al.
First-line chemotherapy in low-risk gestational trophoblastic neoplasia.
Cochrane Database Syst Rev. 2016; (6):CD007102 [PubMed] Related Publications
BACKGROUND: This is the second update of a Cochrane review that was first published in 2009, Issue 1, . Gestational trophoblastic neoplasia (GTN) is a rare but curable disease arising in the fetal chorion during pregnancy. Most women with low-risk GTN will be cured by evacuation of the uterus with or without single-agent chemotherapy. However, chemotherapy regimens vary between treatment centres worldwide and the comparable benefits and risks of these different regimens are unclear.
OBJECTIVES: To determine the efficacy and safety of first-line chemotherapy in the treatment of low-risk GTN.
SEARCH METHODS: We electronically searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase in September 2008, February 2012, and January 2016. In addition, we searched online trial registers for protocols and ongoing trials.
SELECTION CRITERIA: For the original review, we included randomised controlled trials (RCTs), quasi-RCTs and non-RCTs that compared first-line chemotherapy for the treatment of low-risk GTN. For this updated versions of the review, we included only RCTs.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and extracted data to a pre-designed data extraction form. Meta-analysis was performed using the random-effects model.
MAIN RESULTS: We included seven RCTs (667 women) in this updated review. Most studies were at a low or moderate risk of bias and all compared methotrexate with actinomycin D. Three studies compared weekly intramuscular (IM) methotrexate with bi-weekly pulsed intravenous (IV) actinomycin D (393 women), one study compared five-day IM methotrexate with bi-weekly pulsed IV actinomycin D (75 women), one study compared eight-day IM methotrexate-folinic acid (MTX-FA) with five-day IV actinomycin D (49 women), and one study compared eight-day IM MTX-FA with bi-weekly pulsed IV actinomycin D. One study contributed no data. Moderate-certainty evidence indicates that actinomycin D is probably more likely to lead to primary cure than methotrexate (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.57 to 0.75; six trials, 577 participants; I(2) = 26%), and first-line methotrexate treatment is probably more likely to fail than actinomycin D treatment (RR 3.55, 95% CI 1.81 to 6.95; six trials, 577 participants; I(2) = 61%; moderate-certainty evidence) Low-certainty evidence suggests that there may be little or no difference between methotrexate and actinomycin D treatment with respect to nausea (four studies, 466 women; RR 0.61, 95% CI 0.29 to 1.26) or any of the other individual side-effects reported, although data for all of these outcomes were insufficient and too inconsistent to be conclusive. Low-certainty evidence suggests that there may be little or no difference in the risk of severe adverse events (SAEs) between the groups overall (five studies, 515 women; RR 0.35, 95% CI 0.08 to 1.66; I² = 60%); however, the direction of effect favours methotrexate and more evidence is needed. Furthermore, evidence from subgroup analyses suggests that actinomycin D may be associated with a greater risk of SAEs than methotrexate (low-certainty evidence). We found no evidence on the effect of these treatments on future fertility.
AUTHORS' CONCLUSIONS: Actinomycin D is probably more likely to achieve a primary cure in women with low-risk GTN, and less likely to result in treatment failure, than a methotrexate regimen. There may be little or no difference between the pulsed actinomycin D regimen and the methotrexate regimen with regard to side-effects. However, actinomycin D may be associated with a greater risk of severe adverse events (SAEs) than a methotrexate regimen. Higher-certainty evidence is still needed on treating low-risk GTN and the four ongoing trials are likely to make a significant contribution to this field. Given the variety of treatment regimens, findings from these trials could facilitate a network meta-analysis in the next version of this review to help women and clinicians determine the best treatment options for low-risk GTN.

Garg NK, Singh B, Jain A, et al.
Fucose decorated solid-lipid nanocarriers mediate efficient delivery of methotrexate in breast cancer therapeutics.
Colloids Surf B Biointerfaces. 2016; 146:114-26 [PubMed] Related Publications
The present study is designed to engineer fucose anchored methotrexate loaded solid lipid nanoparticles (SLNs) to target breast cancer. The developed nano-carriers were characterized with respect to particle size, PDI, zeta potential, drug loading and entrapment, in-vitro release etc. The characterized formulations were used to comparatively assess cellular uptake, cell-viability, apoptosis, lysosomal membrane permeability, bioavailability, biodistribution, changes in tumor volume and animal survival. The ex-vivo results showed greater cellular uptake and better cytotoxicity at lower IC50 of methotrexate in breast cancer cells. Further, we observed increased programmed cell death (apoptosis) with altered lysosomal membrane permeability and better rate of degradation of lysosomal membrane in-vitro. On the other hand, in-vivo evaluation showed maximum bioavailability and tumor targeting efficiency with minimum secondary drug distribution in various organs with formulated and anchored nano-carrier when compared with free drug. Moreover, sizeable reduction in tumor burden was estimated with fucose decorated SLNs as compared to that seen with free MTX and SLNs-MTX. Fucose decorated SLNs showed promising results to develop therapeutic interventions for breast cancer, and paved a way to explore this promising and novel nano-carrier which enables to address breast cancer.

Purkait R, Dolai TK, Lath C, Das B
Intracranial Hemorrhage Following Intrathecal Methotrexate Therapy for Acute Lymphoblastic Leukaemia.
Indian Pediatr. 2016; 53(5):423-4 [PubMed] Related Publications
BACKGROUND: Acute toxic leukoencephalopathy following intrathecal methotrexate administration is well documented but intracranial haemorrhage is extremely rare.
CASE CHARACTERISTICS: A 2-year-6 months old girl with acute lymphoblastic leukemia developed sudden onset neurological deterioration following intrathecal methotrexate.
OBSERVATIONS: Computed tomography scan of brain demonstrated intraventricular and subarachnoid hemorrhage.
OUTCOME: Child improved gradually on conservative management. Follow-up neuroimaging showed resolution of hemorrhage.
MESSAGE: Intracranial haemorrhage is a rare but serious complication of intrathecal methotrexate.

Yap SM, MacEneaney P, Ryan C, O'Toole O
Alternating hemiparesis and orolingual apraxia as manifestations of methotrexate neurotoxicity in a paediatric case of acute lymphoblastic leukaemia.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
A 15-year-old girl with a recent diagnosis of acute lymphoblastic leukaemia was admitted to hospital with pancytopaenia after having received high-dose intrathecal methotrexate 1 day prior. During the next week she had intermittent episodes of alternating hemiparesis associated with speech arrest lasting minutes to hours at a time. The episodes were not associated with altered level of consciousness or headache. MRI of the brain showed features consistent with methotrexate encephalopathy. This report discusses the typical clinical and radiological features of methotrexate neurotoxicity in addition to differential diagnoses and the proposed pathophysiological mechanisms.

Oudart JB, Marquet B, Feliu C, et al.
Analytical interference in the therapeutic drug monitoring of methotrexate.
Ann Biol Clin (Paris). 2016; 74(3):333-7 [PubMed] Related Publications
High-dose of methotrexate chemotherapy is used in the treatment of some tumors. It presents several side effects that required therapeutic drug monitoring, which is commonly performed on 24, 48 and 72h after the beginning of the methotrexate infusion. Treatment of overexposure to methotrexate is based on injection of carboxypeptidase G2, which specifically degrades methotrexate into inactive metabolite: DAMPA. FPIA immunoassay on TDx automated analyzer (Abbott™) was used for therapeutic drug monitoring of methotrexate. This immunoassay presented a significant cross-reactivity between methotrexate and DAMPA, which widely overestimate the residual concentration compared to the gold standard HPLC/MS. TDx automated analyzer was substituted by a new immunoassay on Architect automated analyzer (Abbott™). However, this immunoassay has the same cross-reactivity, which needs to be careful when monitoring methotrexate after an injection of carboxypeptidase G2. In order to determine the most suitable assay for the therapeutic drug monitoring of methotrexate, the knowledge of injection of carboxypeptidase G2 remains essential.

Gurion R, Mehta N, Migliacci JC, et al.
Central nervous system involvement in T-cell lymphoma: A single center experience.
Acta Oncol. 2016; 55(5):561-6 [PubMed] Related Publications
Background We characterized the incidence of central nervous system (CNS) involvement, risk factors and outcome in a large single institution dataset of peripheral T-cell lymphoma (PTCL). Methods Retrospective review of the PTCL database at Memorial Sloan Kettering Cancer Center. We identified 231 patients with any subtype of PTCL between 1994-2011 with a minimum six months of follow-up or an event defined as relapse or death. Results Histologies included peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) (31.6%), angioimmunoblastic (16.9%), anaplastic large cell lymphoma (ALCL), ALK- (12.1%), ALCL, ALK + (6.1%), extranodal NK/T-cell lymphoma (7.4%), adult T-cell leukemia/lymphoma (ATLL) (7.4%), and transformed mycosis fungoides (8.7%). Seventeen patients had CNS disease (7%). Fifteen had CNS involvement with PTCL and two had diffuse large B-cell lymphoma and glioblastoma. Median time to CNS involvement was 3.44 months (0.16-103.1). CNS prophylaxis was given to 24 patients (primarily intrathecal methotrexate). Rates of CNS involvement were not different in patients who received prophylaxis. Univariate analysis identified stage III-IV, bone marrow involvement, >1 extranodal site and ATLL as risk factors for CNS disease. On multivariate analysis, >1 extranodal site and international prognostic index (IPI) ≥ 3 were predictive for CNS involvement. The median survival of patients with CNS involvement was 2.63 months (0.10-75). Conclusions Despite high relapse rates, PTCL, except ATLL, carries a low risk of CNS involvement. Prognosis with CNS involvement is poor and risk factors include: >1 extra nodal site and IPI ≥3.

Mna AB, Souissi A, Halouani S, et al.
Methotrexate-induced necrolysis in tumoral-stage mycosis fungoides: a challenging diagnosis.
Dermatol Online J. 2016; 22(1) [PubMed] Related Publications
Methotrexate-induced cutaneous ulceration is a rare but potentially serious drug adverse reaction. This adverse reaction of methotrexate therapy has been initially described in psoriasis patients and is unusual in patients with cutaneous T-cell lymphoma. In 1978, Mc Donald et al reported the first three cases of cutaneous ulcerations in patients treated for a mycosis fungoides with intravenous infusions of methotrexate. Since then, few cases of methotrexate-induced skin ulcers in patients with mycosis fungoides have been published. We report an additional patient with erythrodermic mycosis fungoides who developed cutaneous ulcerations as a sole manifestation of methotrexate toxicity.

Lucchesi M, Guidi M, Fonte C, et al.
Pharmacokinetics of high-dose methotrexate in infants aged less than 12 months treated for aggressive brain tumors.
Cancer Chemother Pharmacol. 2016; 77(4):857-64 [PubMed] Related Publications
PURPOSE: In infants aged less than 12 months, there are few data on pharmacokinetics of high-dose methotrexate (MTX) for brain tumors at the dose of 8 g/m(2). Consolidated knowledges are present only with the dose of 5 g/m(2) in acute lymphoblastic leukemia.
METHODS: We collected data on 8 infants at the time of their first treatment with high-dose MTX, 8 g/m(2), to evaluate the pharmacokinetic profile. All children had a dose adjustment with a weight-based prescription (1 m(2) = 30 kg).
RESULTS: The median age was 4.5 months (range 0-9). The median weight was 5.63 kg (range 3.12-9.0). The median steady-state MTX concentration at the end of 6-hr infusion was 486 µM/L (range 227-790). The median systemic MTX clearance was 4.14 L/h/m(2) (range 1.98-9.35). The median MTX concentration after 24 h from the beginning of infusion was 3.29 µM/L (range 1.14-100.44). Three (37.5 %) patients had a delayed elimination of MTX (delayed early, delayed late, or total delayed: one for each). These altered elimination occurred principally in children weighing less than 4 kg (p: 0.0179). Moreover, a systemic MTX clearance at the end of infusion minor than 3 L/h/m(2) can predict a delayed elimination (p: 0.0179). Patients with altered elimination underwent rescue measures (leucovorin supplement and/or exchange transfusion).
CONCLUSIONS: Our data suggest that a higher dose of MTX for the treatment of aggressive brain tumors in early infants had an acceptable pharmacokinetic profile. Greater attention must be used in the treatment of children weighing less than 4 kg.

Böhme D, Krieghoff J, Beck-Sickinger AG
Double Methotrexate-Modified Neuropeptide Y Analogues Express Increased Toxicity and Overcome Drug Resistance in Breast Cancer Cells.
J Med Chem. 2016; 59(7):3409-17 [PubMed] Related Publications
Bioconjugates containing the neuropeptide Y (NPY) analogue [F(7),P(34)]-NPY as targeting moiety are able to deliver toxic agents specifically to breast cancer cells that overexpress the human Y1-receptor (hY1R). To increase their activity, multiple toxophores can be attached to one peptide. Herein, synthesis and characterization of [F(7),P(34)]-NPY conjugates containing two methotrexate (MTX) molecules are presented. First, carboxytetramethylrhodamine was linked to [F(7),P(34)]-NPY by amide or enzymatic linkage. The conjugate containing the enzymatic cleavage site showed high extracellular stability and fast intracellular release. Then, MTX was introduced at positions four and 22 of [F(7),P(34)]-NPY, connected by enzymatic or amide linkage. The toxicity of the analogues on breast cancer cells was hY1R-mediated and dependent on the used linkage and amount of toxophores. Furthermore, conjugates revealed higher potency than MTX on MTX-resistant cells. These results emphasize that peptide-drug conjugates can overcome drug resistance and that the attachment of multiple cleavable toxophores enhances the efficiency of this smart delivery system.

Shao S, Sun PH, Satherley LK, et al.
Reduced RanBPM Expression Is Associated with Distant Metastasis in Gastric Cancer and Chemoresistance.
Anticancer Res. 2016; 36(3):1295-303 [PubMed] Related Publications
AIM: Ran binding protein M (RanBPM) is a ubiquitous, nucleocytoplasmic protein that serves as a scaffolding molecule. This study aimed to investigate the role of RanBPM in gastric cancer.
MATERIALS AND METHODS: RanBPM expression in human gastric cancer tissue samples was analyzed using real-time polymerase chain reaction. The effect of RanBPM on cellular functions was examined in RanBPM-knockdown gastric cells and with in vitro cell functional assays.
RESULTS: Gastric tumors with distant metastases expressed lower levels of RanBPM transcripts compared to tumours without detectable metastases (p=0.036). RanBPM knockdown in gastric cancer cells reduced adhesion and promoted survival of gastric cancer cells after exposure to methotrexate and fluorouracil.
CONCLUSION: RanBPM levels were reduced in gastric tumors with distant metastases. This suggests that loss of RanBPM expression may play an important role in gastric cancer tumor development and metastasis. Reduced RanBPM expression is also associated with chemoresistance of gastric cancer cells.

Fodor T, Szántó M, Abdul-Rahman O, et al.
Combined Treatment of MCF-7 Cells with AICAR and Methotrexate, Arrests Cell Cycle and Reverses Warburg Metabolism through AMP-Activated Protein Kinase (AMPK) and FOXO1.
PLoS One. 2016; 11(2):e0150232 [PubMed] Free Access to Full Article Related Publications
Cancer cells are characterized by metabolic alterations, namely, depressed mitochondrial oxidation, enhanced glycolysis and pentose phosphate shunt flux to support rapid cell growth, which is called the Warburg effect. In our study we assessed the metabolic consequences of a joint treatment of MCF-7 breast cancer cells with AICAR, an inducer of AMP-activated kinase (AMPK) jointly with methotrexate (MTX), a folate-analog antimetabolite that blunts de novo nucleotide synthesis. MCF7 cells, a model of breast cancer cells, were resistant to the individual application of AICAR or MTX, however combined treatment of AICAR and MTX reduced cell proliferation. Prolonged joint application of AICAR and MTX induced AMPK and consequently enhanced mitochondrial oxidation and reduced the rate of glycolysis. These metabolic changes suggest an anti-Warburg rearrangement of metabolism that led to the block of the G1/S and the G2/M transition slowing down cell cycle. The slowdown of cell proliferation was abolished when mitotropic transcription factors, PGC-1α, PGC-1β or FOXO1 were silenced. In human breast cancers higher expression of AMPKα and FOXO1 extended survival. AICAR and MTX exerts similar additive antiproliferative effect on other breast cancer cell lines, such as SKBR and 4T1 cells, too. Our data not only underline the importance of Warburg metabolism in breast cancer cells but nominate the AICAR+MTX combination as a potential cytostatic regime blunting Warburg metabolism. Furthermore, we suggest the targeting of AMPK and FOXO1 to combat breast cancer.

Chung SR, Choi YJ, Kim HS, et al.
Tumor Vascular Permeability Pattern Is Associated With Complete Response in Immunocompetent Patients With Newly Diagnosed Primary Central Nervous System Lymphoma: Retrospective Cohort Study.
Medicine (Baltimore). 2016; 95(6):e2624 [PubMed] Free Access to Full Article Related Publications
A dynamic contrast-enhanced MR imaging (DCE-MRI) could provide the information about tumor drug delivery efficacy. We investigated the potential utility of the permeability pattern of DCE-MRI for predicting tumor response to high dose-methotrexate treatment and progression-free survival (PFS) in patients with primary CNS lymphoma (PCNSL). Clinical and conventional imaging parameters were assessed as potential predictors of tumor response in 48 immunocompetent PCNSL patients in a preliminary study. Fifty additional immunocompetent patients (27 men and 23 women; mean age, 60.6 years) with PCNSL underwent DCE-MRI before starting first-line treatment with high dose-methotrexate. The DCE-MRI pattern was categorized as diffuse or nondiffuse. After 4 courses of high dose methotrexate, patients underwent follow-up brain MR imaging to identify their complete response (CR). Predictors of CR and PFS were analyzed using clinical parameters, conventional MRI, and DCE-MRI. CR was noted in 20 (74.1%) of 27 patients with diffuse DCE-MRI pattern and in 4 (17.4%) of 23 patients with nondiffuse DCE-MRI pattern. The diffuse DCE-MRI pattern showed a significantly higher association with CR than the nondiffuse pattern (P < 0.001). Multivariate Cox proportional hazards model revealed that the DCE-MRI pattern (hazard ratio = 0.70; P = 0.045), age (hazard ratio = 1.47; P = 0.041), and adjuvant autologous stem-cell transplantation (hazard ratio = 6.97; P = 0.003) tended to be associated with a PFS. The pretreatment diffuse DCE-MRI pattern can be used as a potential imaging biomarker for predicting CR and a longer PFS in patients with newly diagnosed PCNSLs.

Choi G, Piao H, Alothman ZA, et al.
Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model.
Int J Nanomedicine. 2016; 11:337-48 [PubMed] Free Access to Full Article Related Publications
Methotrexate (MTX), an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco's Modified Eagle's Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection.

Mack F, Baumert BG, Schäfer N, et al.
Therapy of leptomeningeal metastasis in solid tumors.
Cancer Treat Rev. 2016; 43:83-91 [PubMed] Related Publications
Leptomeningeal metastasis (LM), i.e. the seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges, is a devastating and mostly late-stage complication of various solid tumors. Clinical signs and symptoms may include cranial nerve palsies, radicular symptoms, signs of increased intracranial pressure such as headache, nausea and vomiting, and cognitive dysfunction. In cases of suspected LM, the highest diagnostic sensitivity is provided by the combination of CSF cytology and contrast-enhanced MRI (cranial as well as complete spine). The therapeutic spectrum includes radiotherapy of the clinically involved region as well as systemic and intrathecal chemotherapy. The choice of treatment modalities depends on the type of LM (non-adherent tumor cells in the CSF vs. nodular contrast-enhancing tumor growth), additional systemic involvement (uncontrolled vs. controlled systemic disease) and additional involvement of the CNS parenchyma (LM as the only CNS involvement vs. LM+parenchymal CNS metastases). Larger contrast-enhancing nodular LM or symptomatic lesions of the spine may be treated with radiotherapy. In case of uncontrolled systemic disease, the treatment regimen should include systemic chemotherapy. The choice of systemic treatment should take into account the histology of the primary tumor. Intrathecal chemotherapy is most important in cases of LM of the non-adherent type. There are three substances for routine use for intrathecal chemotherapy: methotrexate, cytarabine, and thiotepa. Liposomal cytarabine shows advantages in terms of longer injection intervals, a sufficient distribution in the entire subarachnoid space after lumbar administration and improved quality-of-life. The role of new agents (e.g. rituximab and trastuzumab) for intrathecal therapy is still unclear.

Audet-Walsh É, Papadopoli DJ, Gravel SP, et al.
The PGC-1α/ERRα Axis Represses One-Carbon Metabolism and Promotes Sensitivity to Anti-folate Therapy in Breast Cancer.
Cell Rep. 2016; 14(4):920-31 [PubMed] Related Publications
Reprogramming of cellular metabolism plays a central role in fueling malignant transformation, and AMPK and the PGC-1α/ERRα axis are key regulators of this process. The intersection of gene-expression and binding-event datasets for breast cancer cells shows that activation of AMPK significantly increases the expression of PGC-1α/ERRα and promotes the binding of ERRα to its cognate sites. Unexpectedly, the data also reveal that ERRα, in concert with PGC-1α, negatively regulates the expression of several one-carbon metabolism genes, resulting in substantial perturbations in purine biosynthesis. This PGC-1α/ERRα-mediated repression of one-carbon metabolism promotes the sensitivity of breast cancer cells and tumors to the anti-folate drug methotrexate. These data implicate the PGC-1α/ERRα axis as a core regulatory node of folate cycle metabolism and further suggest that activators of AMPK could be used to modulate this pathway in cancer.

Zeremski V, Koehler M, Fischer T, Schalk E
Characteristics and outcome of patients with primary CNS lymphoma in a "real-life" setting compared to a clinical trial.
Ann Hematol. 2016; 95(5):793-9 [PubMed] Related Publications
We aimed to compare the characteristics and outcome of patients treated within the multi-centre German Primary CNS Lymphoma Study Group 1 trial (G-PCNSL-SG-1; TRIAL group) and patients treated outside this clinical trial ("real-life" setting, R-LIFE group). Therefore, we conducted a retrospective single-centre study in order to analyse all patients with newly diagnosed primary CNS lymphoma (PCNSL) treated consecutively in our institution between November 2000 and June 2015. Altogether, 86 patients were analysed (median 68 years). Twenty patients were treated within (TRIAL) and 66 patients outside the clinical trial (R-LIFE), respectively. The majority (n = 75; 87 %) received high-dose methotrexate as the first-line treatment. Thirty-eight of 66 patients (57.6 %) responded to the first-line therapy. The R-LIFE patients were older (median age 70 vs. 62 years; p = 0.005) and had more frequently a worse performance status (ECOG score 2-4: 59.1 vs. 20.0 %; p = 0.004; median Karnofsky index 70 vs. 80 %; p = 0.003) and less frequently a low prognostic score (IELSG score 0-1: 19.7 vs. 45.0 %; p = 0.038), than the TRIAL patients. Median overall survial (OS) was shorter for the R-LIFE patients (9.3 months [95 % CI 1.9-16.7] vs. 33.4 months [95 % CI 17.6-49.2]; p = 0.065). Median progression-free survival (PFS) was significantly inferior for the R-LIFE patients (3.4 months [95 % CI 2.4-4.4] vs. 24.8 months [95 % CI 4.6-45.0]; p = 0.037). Our data indicate that the outcome of PCNSL patients treated outside, but about analogous to the G-PCNSL-SG-1 trial, was poor. This is likely explained by more unfavourable prognostic factors in patients being treated off trial.

Kanda PA, Kanda RG, Mei PA, Cury IJ
Extreme Spindles and Leukoencephalopathy after Acute Lymphoblastic Leukemia Treatment: An Undescribed Association.
Neurodiagn J. 2015; 55(4):235-42 [PubMed] Related Publications
We report a case of a child whose EEG demonstrated extreme spindles (ES) after acute lymphoblastic leukemia treatment. This finding has not been reported previously. In 1962, Gibbs and Gibbs described the ES EEG pattern due to its high amplitude (200 to 400 μV). ES are a rare spindle variant that is found in EEGs of 0.05% of normal children (average age, 3 years, with a range of 1 to 12 years), and are even rarer after 11 years. Moreover due to changes in the white matter of the frontal lobe, ES have been associated with such conditions as cerebral palsy and mental retardation, residual brain damage, undefined infections, infantile neuroaxonal dystrophy, Menkes' kinky-hair syndrome, congenital muscular dystrophy, hydrocephalus, porencephaly, epilepsy, progressive cerebellar degeneration, and mycoplasma encephalitis. Methotrexate has a notably toxic effect on the central nervous system, with leukoencephalopathy being the most common form. In our case, frontocentral ES were associated with hyperintense lesions in the white matter of the frontal lobe. Lesional deafferentation can be the substrate for an almost continuous ES, since both initiation and termination of spindle oscillations are thought to originate in thalamocortical neurons. Thus, we postulate that in some cases a partial functional cortical differentiation could generate ES.

Xu M, Jiang D, Shen J, et al.
Distinct characterization of two vinorelbine-resistant breast cancer cell lines developed by different strategies.
Oncol Rep. 2016; 35(4):2355-63 [PubMed] Related Publications
Resistance to chemotherapy is a major obstacle to the successful treatment of breast cancer patients. Recently, we successfully established two vinorelbine-resistant sublines, BC-DS and BC-TS, from the human breast cancer cell line BCap37, with different 'two-stage screening methods'. Interestingly, though BC-DS and BC-TS were developed from the same BCap37 cell line with the same drug, they showed remarkable differences. Compared with the parental BCap37 cells both BC-DS and BC-TS had resistance to vinorelbine, but the resistant characterizations are both unstable. BC-DS showed increased migration capability while BC-TS showed reduced migration capability. When investigating their multidrug resistance, we found BC-DS became more sensitive to methotrexate, which suggested that combination of MTX and vinorelbine could be a new treatment strategy. Moreover, BC-DS and BC-TS overexpressed P-glycoprotein at different levels. Our research also showed that the present clinical usage of vinorelbine is reasonable. These findings suggest that the vinorelbine-induced multiple drug resistance (MDR) sublines may be used as an in vitro model not only to further elucidate possible mechanisms of MDR involved in the human breast cancer, but also to find methods to optimize the curative effect of vinorelbine in clinic.

Mikami Y, Nagai T, Gomi Y, et al.
Methotrexate and actinomycin D chemotherapy in a patient with porphyria: a case report.
J Med Case Rep. 2016; 10:9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Despite their broadly recommended use as chemotherapeutic agents, the porphyrogenicity of methotrexate and actinomycin D have not been confirmed. Accordingly, it is not known whether these agents are safe for use in patients with porphyria.
CASE PRESENTATION: In this report, we present a case of an invasive mole with lung metastasis in a 49-year-old Japanese woman who had previously been diagnosed with acute intermittent porphyria at 27 years of age but had no recent history of acute intermittent porphyria attacks. Her serum human chorionic gonadotropin level was elevated 1 month after hysterectomy, and she was referred to our center for chemotherapy. After she received 100 mg of methotrexate, drug eruptions were observed starting on day 3 and grew progressively worse. Erythema and mucosal erosion spread throughout her body, whereupon she was administered prednisolone. In addition, our patient experienced febrile neutropenia and required granulocyte colony- stimulating factor treatment. No changes in our patient's urinary coproporphyrin or uroporphyrin levels were detected during this entire episode. Methotrexate was replaced by actinomycin D (0.5 mg/body intravenously on days 1-5 every 2 weeks). After five uneventful cycles of actinomycin D, our patient achieved and maintained a normal serum human chorionic gonadotropin level for 3 years.
CONCLUSIONS: Methotrexate and actinomycin D did not induce acute porphyric attacks in this patient with acute intermittent porphyria; however, severe adverse effects were noted with methotrexate. Although further investigation is required, our data suggest that these agents are nonporphyrinogenic and can therefore be used to treat patients with comorbid porphyria.

Ikeda K, Nakamura T, Kinoshita T, et al.
Methotrexate-related lymphoproliferative disorder of the stomach in a patient with rheumatoid arthritis: a case of disease regression after methotrexate cessation.
Clin J Gastroenterol. 2016; 9(1):17-21 [PubMed] Free Access to Full Article Related Publications
We report the case of a 78-year-old woman with methotrexate-related gastric lymphoproliferative disorder (LPD). The patient had a history of rheumatoid arthritis (RA) and had been treated with methotrexate (MTX). Endoscopic examination revealed round elevated lesions in the stomach, and a biopsy specimen showed atypical lymphoid cell proliferation. Immunohistological study found these atypical cells to be positive for L-26 but not for CD3 or EBER. Therefore, we made a diagnosis of MTX-related LPD showing features of diffuse large B-cell lymphoma. Combined positron emission tomography-computed tomography (PET-CT) using 18F-fluorodeoxyglucose (FDG) showed increased avidity in the stomach in addition to slightly increased FDG-avidity in the mediastinum and left chest wall. We decided not to start chemotherapy but to discontinue administration of MTX, with follow-up using endoscopy and PET-CT. The endoscopic examinations after cessation of MTX demonstrated gradual regression of the elevated lesions. PET-CT 6 months after cessation showed no increased FDG avidity in the stomach. While disease regression was observed in the stomach, the other FDG-avid spots remained unchanged on PET-CT. Therefore, we performed chemotherapy as additional therapy. On PET-CT after chemotherapy, the FDG-avid spots remained unchanged for more than 1 year, and we eventually concluded that they were RA-related inflammatory lesions. In patients with MTX-related LPD, cessation of MTX may be a therapeutic option, but careful follow-up and chemotherapy in accordance with the clinical course are essential.

Ma WL, Hou HA, Hsu YJ, et al.
Clinical outcomes of primary intraocular lymphoma patients treated with front-line systemic high-dose methotrexate and intravitreal methotrexate injection.
Ann Hematol. 2016; 95(4):593-601 [PubMed] Related Publications
A standard treatment for patients with primary intraocular lymphoma (PIOL) remains unclear. This study retrospectively analyzed the clinical features and outcomes of 19 patients with PIOL who were treated with a first-line therapy comprising combined intravenous high-dose methotrexate and intravitreal methotrexate between January 2003 and December 2013. Thirteen (68.4 %) patients were female, and the median age at diagnosis was 57 (39-77 years). Diagnoses were based on the identification of abnormal lymphoid cells in vitreous fluid. Ten (52.6 %) patients had bilateral eye involvement, and six had concurrent central nervous system (CNS) involvement. All 19 patients achieved complete remission (CR) as confirmed by cytological examination of vitreous and cerebrospinal fluid and brain imaging if CNS was involved. Patients with concurrent brain involvement required a longer time to achieve CR. However, the duration of complete remission did not differ between patients with and without CNS involvement. The 5-year overall survival rate was 55.8 % for the total cohort and was higher (68.8 %) in patients with isolated PIOL than in those with concurrent CNS involvement. In all patients, methotrexate treatment was well tolerated, with manageable side effects. We conclude that combined intravitreal methotrexate and systemic high-dose methotrexate treatment is effective in patients with PIOL.

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