Disease relevance of methotrexate

• Seven patients in the methotrexate group and three patients in each of the other two groups discontinued treatment because of drug toxicity [1].
• METHODS: We studied 350 women with tubal ectopic pregnancies who were treated with methotrexate intramuscularly according to a single-dose protocol [2].
• Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect [3].
• Brief report: reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis [4].
• We conclude that the combination of methotrexate, antithymocyte globulin, and prednisone significantly decreased the incidence of acute graft-versus-host disease and should be used to prevent this disorder in patients receiving allogeneic marrow transplants [5].
• Methotrexate appears effective in maintaining remission in pediatric Crohn's disease, when thiopurines have failed [6].
• Twenty-six patients had one or more of the risk factors and 25 (96%) of these (median cumulative dose methotrexate 1500 mg) developed liver fibrosis [7].
• Compared with the general population, methotrexate-treated RA patients have an increased incidence of melanoma, non-Hodgkin's lymphoma, and lung cancer [8].

Psychiatry related information on methotrexate

• Although its efficacy is widely attributed to a decrease in nucleotide biosynthesis (1), methotrexate is known to increase homocysteine (2), a compound associated with an elevated risk of heart disease, Alzheimer's disease (3), and neural tube defects (4) [9].
• The mean (+/- 1 SD) cumulative methotrexate dose was 66 +/- 41 mg/sq m in the C x T group and 173 +/- 64 mg/sq m in the 12 mg/sq m/dose group (p less than 0.005) [10].
• During maintenance therapy with intraventricular methotrexate, progressive dementia developed in a child with meningeal leukemia [11].
• Response time ranged from 3 to 9 weeks (mean, 5 weeks) after implementation of methotrexate therapy [12].
• Reasons for biopsy included hepatitis C (10 cases), abnormal liver enzyme levels (2 cases), methotrexate use (1 case), and alcohol abuse (1 case) [13].

High impact information on methotrexate

• Results of the B-13 and B-19 studies demonstrated that systemic chemotherapy (either with methotrexate and sequentially administered fluorouracil followed by leucovorin, or with cyclophosphamide plus methotrexate and fluorouracil) increased overall disease-free survival in women 49 years of age or younger, as well as in those 50 years old or older [14].
• The most obvious improvements in the care of patients with bladder cancer over the past 20 years are bacille Calmette-Guérin immunotherapy for superficial bladder cancer and cisplatin and methotrexate-based combination chemotherapy for advanced disease [15].
• Leukemia cells that had acquired an additional chromosome containing a wild-type TPMT or GGH allele had significantly lower accumulation of thioguanine nucleotides or methotrexate polyglutamates, respectively [16].
• To elucidate the genomics of cellular responses to cancer treatment, we analyzed the expression of over 9,600 human genes in acute lymphoblastic leukemia cells before and after in vivo treatment with methotrexate and mercaptopurine given alone or in combination [17].
• CONCLUSIONS: In patients with persistently active rheumatoid arthritis despite methotrexate therapy, repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage [18].

Chemical compound and disease context of methotrexate

• Ondansetron compared with dexamethasone and metoclopramide as antiemetics in the chemotherapy of breast cancer with cyclophosphamide, methotrexate, and fluorouracil [19].
• A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors [20].
• To evaluate postgrafting prophylaxis for graft versus host disease, we studied these patients in a sequential, prospective, randomized trial that compared the effect of a combination of methotrexate and cyclosporine (n = 43) with that of cyclosporine alone (n = 50) [21].
• Determination of methotrexate concentration in plasma thus identified patients at high risk of toxicity, a group that may benefit from supplemental leucovorin rescue [22].
• METHODS: We stratified and randomly assigned 182 children with newly diagnosed acute lymphoblastic leukemia to postremission regimens that included high-dose methotrexate and teniposide plus cytarabine [23].
• Concurrent administration of memantine during the period of methotrexate exposure was protective, decreasing the incidence of methotrexate-induced spatial memory deficits from 56% to 20% (P < 0.05) [24].

Biological context of methotrexate

• To correlate the pharmacokinetics and toxicity of methotrexate, we measured the drug's clearance from plasma after 395 high-dose, six-hour infusions given to 78 patients [22].
• The kinetics and distribution of methotrexate in intraventricular and intrathecal cerebrospinal-fluid spaces were studied in patients with meningeal leukemia and meningeal carcinomatosis after drug administration by intravenous infusion, indwelling intraventricular subcutaneous reservoir (Ommaya), or standard lumbar puncture [25].
• Satellite DNA in large marker chromosomes of methotrexate-resistant mouse cells [26].
• Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. double-blind, placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and The Cooperative Children's Study Group [27].
• Transfection of the human alpha 5 and beta 1 cDNAs into transformed Chinese hamster ovary (CHO) cells followed by methotrexate-induced amplification yielded clonal cell lines overexpression this fibronectin receptor [28].

Anatomical context of methotrexate

• A similar organization is found in independently isolated methotrexate-resistant cell lines, in the parental sensitive cell line and in several inbred mouse strains, indicating that this organization represents that of the natural gene [29].
• Among patients with increased risk, radiation offered greater protection to the central nervous system than methotrexate (P = 0.03); there was no difference in the rate of hematologic relapse [30].
• RESULTS: Recipients of cord blood were younger than recipients of bone marrow (median age, 5 years vs. 8 years; P<0.001), weighed less (median weight, 17 kg vs. 26 kg; P<0.001), and were less likely to have received methotrexate for prophylaxis against GVHD (28 percent vs. 65 percent, P<0.001) [31].
• Letter: Methotrexate in cerebrospinal fluid [32].
• These variables, as well as the grip strength and erythrocyte sedimentation rate, showed significant (P less than 0.01) improvement at 24 weeks in the population crossed over to methotrexate [33].

Associations of methotrexate with other chemical compounds

• Cyclosporine and methotrexate for severe rheumatoid arthritis [34].
• In a proportional-hazards model, the time-dependent systemic exposure to methotrexate, but not to teniposide or cytarabine, was significantly related to the risk of early relapse in children with B-lineage leukemia [23].
• In patients with rheumatoid arthritis, combination therapy with methotrexate, sulfasalazine, and hydroxychloroquine is more effective than either methotrexate alone or a combination of sulfasalazine, and hydroxychloroquine [1].
• We have used two complementary two-dimensional gel electrophoretic methods to localize replication inititation sites and to determine replication fork direction in the amplified 240 kb dihydrofolate reductase domain of the methotrexate-resistant CHO cell line CHOC 400 [35].
• Enhanced 5-fluorouracil nucleotide formation after methotrexate administration: explanation for drug synergism [36].
• The substitution of sirolimus for methotrexate as GVHD prophylaxis is associated with rapid engraftment, a low incidence of acute GVHD, minimal transplant-related toxicity, and excellent survival [37].

Gene context of methotrexate

• The associated increase in DHFR expression resulted in increased resistance to methotrexate but had no effect on other classes of anticancer agents [38].
• CONCLUSIONS: These results indicate that MRP4 confers resistance to short-term methotrexate and continuous PMEA treatment [39].
• Tumors with overexpression of cyclin D1 may be relatively refractory to methotrexate treatment [38].
• We have constructed a cDNA library from a murine cell line expressing high levels of a dihydrofolate reductase (tetrahydrofolate dehydrogenase; 5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.3) that displays an abnormally low affinity for methotrexate [40].
• DHFR/MSH3 amplification in methotrexate-resistant cells alters the hMutSalpha/hMutSbeta ratio and reduces the efficiency of base-base mismatch repair [41].

Analytical, diagnostic and therapeutic context of methotrexate

• Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children [30].
• We conclude that the combination of methotrexate and cyclosporine is superior to cyclosporine alone in the prevention of acute graft versus host disease after marrow transplantation for leukemia, and that this therapy may have a beneficial effect on long-term survival [21].
• CONCLUSIONS: In patients with Crohn's disease who enter remission after treatment with methotrexate, a low dose of methotrexate maintains remission [42].
• Treatment of massive intrathecal methotrexate overdose by ventriculolumbar perfusion [43].
• One product of the in vitro synthesis was dihydrofolate reductase (DHFR), as confirmed by methotrexate-substituted Sepharose affinity chromatography followed by SDS-polyacrylamide slab gel electrophoresis and autoradiography of the proteins labeled with 35S-methionine [44].

References