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Results for “Methotrexate”

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At least 253 records · Page 14Linked to original sources

PubMed1998

Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group phase III trial.

PURPOSE: To determine whether early intensification with 12 courses of intravenous methotrexate and intravenous mercaptopurine (IVMTX/IVMP) is superior to 12 courses of repetitive, low-dose oral MTX with I.V. MP (LDMTX/IVMP) for prevention of relapse in children with lower-risk B-lineage acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Seven hundred nine patients were entered onto the study. Vincristine, prednisone, and asparaginase were used for remission induction. Patients were randomized to receive intensification with either IVMTX 1,000 mg/m2 plus IVMP 1,000 mg/m2 (regimen A) or LDMTX 30 mg/m2 every 6 hours for six doses with IVMP 1,000 mg/m2 (regimen B). Twelve courses were administered at 2-week intervals. Triple intrathecal therapy (TIT) was used for CNS prophylaxis. Continuation therapy included standard oral MP, weekly MTX, and TIT every 12 weeks for 2 years. RESULTS: Six hundred ninety-nine (99%) patients achieved remission. Three hundred forty-nine were assigned to regimen A and 350 to regimen B. The estimated 4-year continuous complete remission (CCR) rate for patients treated with regimen A is 80.3% (SE = 2.9%) and with regimen B is 75.9% (SE = 3.1%). By log-rank analysis, regimen A demonstrated superior CCR (P = .013). Transient neutropenia/thrombocytopenia, bacterial sepsis, neurotoxicity, stomatitis, and hospitalizations were more frequent among patients treated on regimen A. CONCLUSION: Intensification with IVMTX/IVMP is more effective than LDMTX/IVMP for prevention of relapse in children with B-precursor ALL at lower risk for relapse.

Administration, Oral↗

PubMed2003

The induction of apoptosis by methotrexate in activated lymphocytes as indicated by fluorescence hyperpolarization: a possible model for predicting methotrexate therapy for rheumatoid arthritis patients.

The objectives of this study were to test the in vitro response of healthy non-activated, activated, and rheumatoid arthritis (RA) lymphocytes to methotrexate (MTX), and design an in vitro model for predicting the efficiency of MTX treatment for RA patients. Considering the RA profile of clonal-expanded CD4(+) T cells, phytohemagglutinin-activated mononuclear cells taken from healthy donors were incubated with different concentrations of MTX. The MTX-immunosuppressive effect was tested by fluorescence intensity measurements, including PI assay and annexin V assay. For simple detection, we used the Individual Cell Scanner (IC-S), which enables the measurement of early events in individual cells. Healthy mononuclear cells (MNC), and MNC derived from RA patients, were tested by the IC-S while utilizing fluorescence polarization (FP) measurements of fluorescein diacetate (FDA) as an established marker of activation or suppression. In healthy activated MNC, we found that MTX, through its early incubation period, interferes with the activation signal obtained by PHA and exerts an apoptotic signal, which is noted by increases in the FP. Comparing our model to six long-standing RA patients and five newly-diagnosed patients revealed significant differences in the FP measurements, including fluorescence depolarization as an early established measurement of lymphocyte activation, and hyperpolarization as a measurement of an early immunosuppressive effect. We conclude that MTX, an effective therapy for RA patients, could easily be tested by fluorescence polarization measurements of FDA before (or during) clinical use in order to predict its efficiency on a specific RA patient. Moreover, the FP measurements can be used for the diagnosis, and making timing and dosage decisions.

Adult↗

PubMed1995

Interruption of long-term methotrexate treatment in psoriasis. Evaluation of clinical course and laboratory parameters after discontinuation and reintroduction of weekly oral methotrexate.

The effects of interval treatment were evaluated in 10 psoriatic patients on long-term treatment with low-dose oral methotrexate (MTX). In all patients, the dosage of MTX had already been tapered off as much as possible. After interruption of MTX treatment, the clinical course and changes in laboratory parameters were evaluated. The mean MTX-free period was 17 weeks, and the mean reduction in cumulative MTX dose was 76 mg (p = 0.05). However, only 3 patients preferred interval treatment to a continuous schedule. During the first 3 weeks of discontinuation, a significant decrease in the serum transaminases was observed, indicating a direct toxic influence of MTX on the liver parenchym. We conclude that interruption of long-term MTX treatment leads to a substantial reduction of the cumulative MTX dose and reduces the hepatotoxic load of MTX. It is necessary to motivate patients on long-term MTX treatment for regular treatment interruptions to establish a further reduction in their cumulative MTX dose.

Administration, Oral↗

PubMedDate not supplied

Lymphatic delivery and pharmacokinetics of methotrexate after intramuscular injection of differently charged liposome-entrapped methotrexate to rats.

The lymph node targeting ability and pharmacokinetics of methotrexate (MTX) after intramuscular (i.m.) injection of differently charged liposome-entrapped [3H]MTX to rats were evaluated using [3H]MTX as a tracer. Neutral liposomes were prepared with a mixture of phosphatidylcholine, cholesterol and alpha-tocopherol (8:4:0.1, molar ratio). Positively and negatively charged liposomes were also prepared by incorporation of stearylamine (8:4:0.1, molar ratio) and dicetylphosphate (8:4:0.1:1, molar ratio) into neutral liposomes respectively. The encapsulation efficiency (as expressed in terms of radioactivity) in liposomes was increased as alpha-tocopherol was incorporated into the lipid bilayer. The disappearance of [3H]MTX from the i.m. injection site was rapid and essentially complete after 30 min. On the other hand, the disappearance of radioactivity of liposome-entrapped [3H]MTX was much slower when compared to free drug. The area under the drug concentration-time curve (AUC) of liposome-entrapped [3H]MTX in lymph nodes was significantly increased when compared to free [3H]MTX. It suggested that liposomes injected by the i.m. route entered into the lymphatics and only drug released from liposomes diffused directly into the systematic circulation. The liposome-entrapped [3H]MTX by i.m. route was markedly localized in the lymph nodes. The concentration of MTX-equivalents in regional lymph node after i.m. injection of liposome-entrapped [3H]MTX was > 100-350 fold higher when compared to the plasma concentration. These values are more than 10-20 fold higher compared to the i.m. injection of free [3H]MTX. The positively charged liposomes were more localized in lymph nodes compared to neutral and negatively charged ones. While liposomes injected by i.v. route were localized in liver, spleen and lung compared to free [3H]MTX, it was evident that i.m. administration of liposomes resulted in enhanced localization of MTX in the lymphatic system but decreased deposition in kidney, liver and other non-targeting tissues compared to free [3H]MTX. The targeting ability and carrier properties of liposome-entrapped anticancer drugs with varying surface charge, lipid compositions and route of administration are of significant importance to alter biodistribution in chemotherapy.

Animals↗

PubMed1984

Early transient accumulation of methotrexate in the cerebrospinal fluid of rabbits after treatment with methotrexate and roentgen rays.

Concomitant application of intrathecal methotrexate (MTX) and cranial irradiation has been described as being able to cause brain abnormalities in patients with leukemia. In the investigation presented, rabbits were treated once weekly for 6 weeks with intraventricular MTX and irradiation. Cerebrospinal fluid (CSF) sampled at various time points after each treatment contained for the samples obtained 4 hours after treatment increasing amounts of MTX. This indicated a retardation in MTX clearance from the CSF. Such a retardation might contribute to the generation of brain abnormalities, although no data have as yet been obtained to prove this suggestion.

Animals↗

PubMed1978

Direct administration of methotrexate into the central nervous system of primates. Part 1: Distribution and degradation of methotrexate in nervous and systemic tissue after intraventricular injection.

Levels of methotrexate (MTX) measured by both 3H radioactivity and dihydrofolate reductase assays were determined in cerebrospinal fluid (CSF), plasma, urine, and both neural and non-neural tissues at varying times after a single intraventricular injection into Cynomolgus monkeys (Macaca fascicularis). Clearance of the MTX from CSF was rapid after injection. A relatively constant level of 3HMTX was reached in plasma 2 1/2 hours after injection, and about 30% of the 3HMTX dose was excreted in the urine within 4 hours after injection. Maximum levels in CNS tissues were obtained by 4 hours after injection, and average concentrations of 10(-6) M MTX (moles/kg wet weight) were maintained in CSF for up to 12 hours and in brain for up to 24 hours after injection. Conversion of MTX to non-MTX products was detected in CSF between 4 and 12 hours, and in brain tissue between 12 and 24 hours after injection, and the amount of these products increased with time. Regional distribution studies in the cerebrum showed a U-shaped distribution curve for 3HMTX up to 12 hours after injection, which closely followed the 14C inulin distribution. Thus, the levels in deep cerebral tissue were less than the average level for brain, and this suggests that treatment of CNS tumors by intraventricular injection may have variable results, partly due to complex tissue distribution patterns.

Animals↗

PubMed1998

[Primary chemotherapy of metastatic breast carcinoma with bendamustine hydrochloride, methotrexate and fluorouracil versus cyclophosphamide, methotrexate and fluorouracil].

The combination bendamustine/methotrexate/fluorouracil (BMF) was proven versus cyclophosphomide/methotrexate/fluorouracil (CMF) in a stratified randomized pilot study as primary chemotherapy in 61 patients with metastatic breast cancer. Bendamustine was given in a dose of 240 mg/m2 and cyclophosphamide in a dose of 960 mg/m2 per therapy-cycle. The doses of methotrexate (40 mg/m2 i.v., day 1 and 8) and fluorouracil (500 mg/m2 i.v., day 1 and 8) were identical in both groups. 25 patients in the BMF- and 24 patients in the CMF-group were evaluable. The remission rates were 52% vs. 46%. The median duration of remission was 15.2 months (ranging from 8.1 to 19.7 months) in the BMF-group and 6.2 months (ranging from 1.9 to 11.1 months) in the CMF-group. The aim of this study was to identify the main criterion for further randomized studies. The results of this pilot study indicate, that it is possible to prolong the median duration of remission without changing the antineoplastic activity by replacing cyclophosphamide with bendamustine.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

5-Fluorouracil simultaneously maintains methotrexate antineoplastic activity in human breast cancer and protects against methotrexate cytotoxicity in human bone marrow.

High-dose methotrexate (MTX) cytotoxicity is maintained in MCF-7 breast cancer cells but reduced in Hs824.T human bone marrow by a priming and nontoxic 5-fluorouracil (5-FU) dose. When MCF-7 breast or Hs824.T bone marrow cells are incubated with 10 microM 5-FU and 10 microM MTX for 48 h, the growth rates of breast cancer cells were 97.59 +/- 0.97% and 21.81 +/- 3.33% of the control rate, respectively, and the growth rates of bone marrow cells were 90.61 +/- 3.71% and 29.58 +/- 2.99% of the control rate. The combinations of 5-FU 2 h prior to MTX or MTX 2 h prior to 5-FU followed by a 48 h incubation, respectively, gave growth rates of 20.96 +/- 2.44% and 19.86 +/- 2.56% of the control rate for MCF-7 cells. In bone marrow cells, the combinations of 5-FU 2 h prior to MTX or MTX 2 h prior to 5-FU followed by a 48 h incubation, respectively, gave growth rates of 79.66 +/- 7.41% (protection) and 31.39 +/- 1.77% of the control rate. Similar patterns to bone marrow emerges in platelets. These studies suggest that: a) MTX and 5-FU combination on the growth of human MCF-7 breast cancer cells is independent of sequence; and b) a priming-dose of 5-FU will protect bone marrow from MTX cytotoxicity but not breast cancer cells. Therefore, a priming and non-toxic dose of 5-FU and MTX may have maximum antineoplastic activity while at the same time provide protection to the hematopoietic system.

Animals↗

PubMed2000

Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors.

After the transplantation of unmodified marrow from human leukocyte antigen-matched unrelated donors receiving cyclosporine (CSP) and methotrexate (MTX), the incidence of acute graft-versus-host disease (GVHD) is greater than 75%. Tacrolimus is a macrolide compound that, in previous preclinical and clinical studies, was effective in combination with MTX for the prevention of acute GVHD. Between March 1995 and September 1996, 180 patients were randomized in a phase 3, open-label, multicenter study to determine whether tacrolimus combined with a short course of MTX (n = 90), more than CSP and a short course of MTX (n = 90), would reduce the incidence of acute GVHD after marrow transplantation from unrelated donors. There was a significant trend toward decreased severity of acute GVHD across all grades (P =.005). Based on the Kaplan-Meier estimate, the probability of grade II-IV acute GVHD in the tacrolimus group (56%) was significantly lower than in the CSP group (74%; P =.0002). Use of glucocorticoids for the management of GVHD was significantly lower with tacrolimus than with CSP (65% vs 81%, respectively; P =. 019). The number of patients requiring dialysis in the first 100 days was similar (tacrolimus, 9; CSP, 8). Overall and relapse-free survival rates for the tacrolimus and CSP arms at 2 years was 54% versus 50% (P =.46) and 47% versus 42% (P =.58), respectively. The combination of tacrolimus and MTX after unrelated donor marrow transplantation significantly decreased the risk for acute GVHD than did the combination of CSP and MTX, with no significant increase in toxicity, infections, or leukemia relapse.

Acute Disease↗

PubMed2002

Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system.

Human MRP4 (ABCC4, MOAT-B) is a lipophilic anion transporter that is able to confer resistance to nucleotide analogues and methotrexate (MTX). We previously investigated the implications of the ability of MRP4 to confer resistance to nucleotide analogues and determined that the pump is competent in the MgATP-energized transport of cyclic nucleotides and estradiol 17beta-D-glucuronide. Here we examine the potential role of MRP4 in conferring resistance to MTX and related processes by determining the selectivity of the transporter for MTX, MTX polyglutamates, and physiological folates. In so doing, it is shown that MRP4 is active in the transport of MTX as well as the physiological folates folic acid (FA) and N(5)-formyltetrahydrofolic acid (leucovorin). MTX, FA, and leucovorin are subject to high capacity [V(max(MTX)), 0.24 +/- 0.05 nmol/mg/min; V(max (FA)), 0.68 +/- 0.14 nmol/mg/min; V(max(leucovorin)), 1.95 +/- 0.18 nmol/mg/min], low affinity [K(m(MTX)), 0.22 +/- 0.01 mM; K(m(FA)), 0.17 +/- 0.02 mM; K(m (leucovorin)), 0.64 +/- 0.23 mM] transport by MRP4. In addition, as would be expected were MRP4 a component of the MTX efflux system, its capacity to transport this agent is abrogated by the addition of a single glutamyl residue. It is also shown that glutamylation similarly affects the ability of MRP2 to transport MTX. On the basis of these transport properties, it is concluded that the efflux system for MTX includes MRP2 and MRP4, in addition to MRP1 and MRP3, and that MRP4 represents a common efflux system for both MTX and certain nucleotide analogues.

Animals↗

PubMed2002

Combination therapy with methotrexate and hydroxychloroquine for rheumatoid arthritis increases exposure to methotrexate.

OBJECTIVE: To examine the bioavailability of methotrexate (MTX) in the presence of hydroxychloroquine (HCQ), and vice versa, to determine a possible pharmacokinetic explanation for the observation that combination treatment of rheumatoid arthritis with MTX and HCQ has been shown, clinically, to be more potent than MTX used alone. METHODS: In a randomized crossover study, 10 healthy subjects received, on each of 5 dosing occasions, MTX alone as tablets or intravenous solution, HCQ alone as a tablet or oral solution, or a coadministered dose of MTX tablets with an HCQ tablet. The area under the concentration-time curve (AUC) was determined for each subject, on each dosing occasion, for each compound. RESULTS: The mean AUC for MTX was increased (p = 0.005) and the maximum MTX concentration (Cmax) decreased (p = 0.025) when MTX was coadministered with HCQ, compared to MTX administered alone. The time to reach Cmax for MTX administration, tmax, was also increased during the coadministration with HCQ (p = 0.072). The AUC of HCQ showed no significant difference (p = 0.957) between any of the dosing occasions. CONCLUSION: These results may explain the increased potency of the MTX-HCQ combination over MTX as a single agent and also the sustained effects of MTX when administered with HCQ. In addition, the reduced Cmax of MTX observed during the coadministration may explain diminution of acute liver adverse effects. Extra vigilance for MTX adverse effects during combination therapy with HCQ is recommended, especially if renal function is known to be decreased.

Administration, Oral↗

PubMed1976

Exchangeable intracellular methotrexate levels in the presence and absence of vincristine at extracellular drug concentrations relevant to those achieved in high-dose methotrexate-folinic acid "rescue" protocols.

Studies were undertaken to (a) assess intracellular methotrexate (MTX) levels at extracellular drug concentrations comparable to those achieved in high-dose MTX-folinic acid rescue protocols and (b) establish whether there is a rationale for the use of vincristine in these regimens. The data indicate that only low levels of exchangeable MTX (intracellular MTX in excess of the tightly bound fraction) accumulated in Ehrlich ascites tumor cells at high extracellular MTX concentration. For instance, the exchangeable steady-state intracellular MTX level was approximately 6.5 muM when the extracellular drug concentration was 85 muM. Over the interval of these experiments, exchangeable intracellular MTX did not exceed approximately 10 muM even when extracellular MTX was raised to 250 muM. These exchangeable intracellular MTX concentrations are comparable to those levels required experimentally to suppress (a) tetrahydrofolate synthesis from dihydrofolate and (b) tetrahydrofolate-dependent purine, pyrimidine, and amino acid synthesis in these cells in vitro. Vincristine (10 muM) augmented net MTX accumulation when the extracellular MTX level was 10, 100, or 250 muM. The limited capacity of cells to accumulate exchangeable intracellular MTX and the apparent role for this intracellular MTX component in achieving the metabolic effects of this agent may account for the necessity for high MTX blood levels in the treatment of some tumors and may be the basis, in part, for the enhanced chemotherapeutic efficacy of high-dose MTX regimens. These studies provide a rationale for the combined use of vincristine and MTX in high-dose MTX protocols. The addition of vincristine may permit the achievement of the level of exchangeable intracellular MTX that is required to critically inhibit tetrahydrofolate synthesis without an increase in the extracellular MTX concentration. This may permit a reduced MTX dose, diminishing the excretory load on the kidney and minimizing nephrotoxicity due to deposition of MTX in the renal tubule and interstitium. While the data indicate that the ratio of the concentration of exchangeable intracellular MTX to the extracellular drug concentration may be very low under steady-state conditions at high extracellular drug levels, further studies are required to establish that these steady-state gradients for MTX represent nonequilibrium conditions.

Animals↗

PubMed2004

The role of subcutaneous administration of methotrexate in children with juvenile idiopathic arthritis who have failed oral methotrexate.

OBJECTIVE: To describe the outcome of patients with juvenile idiopathic arthritis (JIA) treated with subcutaneous (Sc) methotrexate (MTX) after failing oral MTX (either because of inefficacy or toxicity) in a clinic population. METHODS: The study cohort was identified from our clinical database, and consisted of 61 children with JIA treated with MTX between 1988-2001. All patients fulfilled International League Against Rheumatism (ILAR) criteria for JIA and had disease duration of >/= 6 months and 3 or more active joints before institution of MTX. All patients had a core set of outcome variables assessed at baseline and at 3 months after achieving both maximum oral and SC MTX. Outcome variables included physician global assessment of disease activity, number of active joints, number of joints with limited range of motion, duration of early morning stiffness, and erythrocyte sedimentation rate (ESR). Improvement was defined as at least 30% improvement from baseline in 3 of 5 variables in the core set, with no more than one of the remaining variables worsening by more than 30%. RESULTS: A total of 61 patients, 43 females and 18 males with JIA were studied. The disease subtypes were systemic 8, polyarticular 25 (12 rheumatoid factor positive), oligoarticular 14, enthesitis related arthritis 5, and unclassified 4. Thirty-one patients were switched to SC MTX, 13 of whom had not improved, and 18 who had improved, but had nausea (11) or insufficient clinical improvement (7). After 3 months of SC MTX treatment, 76% of patients were classified as improved and 23% as not improved. Toxicity on SC MTX was less than on oral MTX. CONCLUSION: Our results suggest that for patients failing oral MTX either because of inefficacy or toxicity, the use of SC MTX has a high likelihood of success with more than 70% of patients achieving clinically significant improvement, without clinically significant toxicity.

Administration, Oral↗

PubMed2004

A comparative study of etanercept plus methotrexate and methotrexate alone in Taiwanese patients with active rheumatoid arthritis: a 12-week, double-blind, randomized, placebo-controlled study.

BACKGROUND AND PURPOSE: Etanercept (Enbrel), a recombinant tumor necrosis factor receptor fusion protein, has been shown to be effective in the treatment of patients with rheumatoid arthritis (RA). The purpose of this study was to compare the efficacy and safety of etanercept in combination with methotrexate (MTX) and MTX alone in Taiwanese patients with active RA. METHODS: In this double-blind study, 58 patients with active RA who were maintained on MTX therapy at a stable dose of 12.5 to 20 mg per week for 4 weeks were randomized to receive either etanercept 25 mg (n = 29) or placebo (n = 29) by subcutaneous injection twice weekly over a period of 12 weeks. The primary endpoint was the reduction of tender and swollen joint counts by 20% (ACR 20), 50% (ACR 50), and 70% (ACR 70) as determined by the American College of Rheumatology criteria at the 12th week. RESULTS: The addition of etanercept to MTX resulted in a greater reduction in the number of tender (7.00 vs 2.45, p = 0.012) and swollen joints (8.55 vs 3.86, p = 0.017), and in serum levels of C-reactive protein (1.26 mg/dL vs 0.45 mg/dL, p = 0.014) compared to MTX alone after 12 weeks of therapy. In addition, the global assessment of disease activity by both physicians and patients, duration of morning stiffness, pain visual analog scale score, and Health Assessment Questionnaire were all improved by etanercept plus MTX therapy. Results for the overall improvement in disease activity assessed by ACR 20 (90% vs 34%), ACR 50 (66% vs 10%) and ACR 70 (24% vs 0%) all favored the etanercept plus MTX group. However, the adverse events were comparable between the 2 treatment groups. CONCLUSION: Etanercept in combination with MTX was well tolerated and provided significantly more clinical benefit than MTX alone in Taiwanese patients with active RA.

Antirheumatic Agents↗

PubMed1992

[Effects of hydration on plasma concentrations of methotrexate in patients with osteosarcoma treated with high doses of methotrexate].

High dose of methotrexate (HDMTX) with leucovorin rescue requires over-hydratation to avoid nephrotoxicity; nevertheless the relationship between hydratation and plasma MTX levels is unknown. We compared the effects of two different types of hydratation (2 lt/m2 vs 1.5 lt/m2) on plasma MTX levels in two groups of patients with osteosarcoma of the extremities and treated with HDMTX (8 g/m2 IV). Samples were obtained at the end of infusion of MTX and 14 and 38 hours after the start of MTX infusion. At the end of infusion of MTX the medium plasma MTX levels proved significantly higher in the group with low hydratation than in the group with high hydratation (585.5 microns/l vs 427.7 microns/l P less than 0.001). The values obtained at 14 and 38 hours, did not show significant differences. No significant differences were seen between the two groups in term of late elimination of MTX and correlated toxicity. These data show that a low hydratation regime allows higher plasma MTX levels at the end of infusion of HDMTX and does not increase the incidence of late elimination of MTX compared to a high hydratation regime.

Adult↗

PubMed1989

Methotrexate clearance and clinical toxicity in osteosarcoma following high-dose methotrexate therapy.

Two patients with osteogenic sarcoma were treated with high-dose methotrexate (MTX) followed by leucovorin 'rescue'. Profiles of MTX clearance from plasma and erythrocytes were obtained. Clearance of the drug from plasma during the first 36 hours appears to be biphasic with the first phase of elimination of the drug being appreciably more rapid than the second phase. The drug had also incorporated into the bone marrow precursor cells and reappeared after a few days in the circulating mature erythrocytes which may later serve as a slow-changing compartment for MTX. Nonspecific binding of the drug to plasma proteins may have been one of the causes of delayed clearance of plasma MTX observed in one of the patients. However, delayed clearance does not appear to correlate with the severity of clinical toxicity which was found to be more pronounced in a patient with a better clearance of the drug. Our results support the more recent concept that enhanced clinical toxicity may not be predictable by monitoring plasma MTX alone.

Adolescent↗

PubMed1985

Prevention of methotrexate cytotoxicity by asparaginase inhibition of methotrexate polyglutamate formation.

Escherichia coli asparaginase (Asnase) pretreatment of Asnase-sensitive L5178Y cells in vitro is thought to antagonize methotrexate (MTX) cytotoxicity through nonspecific inhibition of protein synthesis and MTX uptake. We have reexamined the mechanism of this interaction in view of recent data demonstrating the importance of MTX metabolism to polyglutamate derivatives (MTXPGs) in the cytotoxic effects of the antifolate. After a 3-hr exposure to 0.5 microM MTX, 67% of intracellular drug was in the form of MTXPGs containing a total of 2 to 5 glutamyl residues (MTX-Glu2-5), and cloning efficiency in drug-free medium was only 7% of untreated control. After a 3-hr pretreatment with E. coli Asnase (0.1 unit/ml), [3H]thymidine incorporation dropped by 29%, MTXPG formation during subsequent MTX exposure decreased by more than one-half (MTX-Glu2 unchanged; MTX-Glu3 and 4 decreased to 51.7 and 18.5% of levels achieved in cells not pretreated with Asnase; no MTX-Glu5 formed), and cloning efficiency increased to 71% of untreated control. This effect was not due to decreased MTX uptake into L5178Y cells or to decreased intracellular free L-glutamate or L-glutamine levels. A 3-hr exposure of L5178Y cells to media lacking L-isoleucine, an essential amino acid for cell growth, prior to MTX exposure inhibited [3H]thymidine incorporation by 37%, decreased subsequent MTXPG formation by 62%, and increased subsequent cloning in drug-free medium to control levels. Decreased MTXPG formation was responsible for the prevention of MTX cytotoxicity seen after both pretreatments. Unmetabolized MTX rapidly left L5178Y cells after removal of extracellular MTX. Consequently, lower levels of unbound intracellular drug, a prerequisite of drug activity, were maintained in pretreated than in control cells after passage in drug-free medium. Asnase pretreatment protects L5178Y cells from the cytotoxic effects of MTX, possibly through inhibition of cell growth which nonspecifically decreases MTXPG formation.

Animals↗

PubMed1977

[Serum methotrexate determination by microbiological assay in patients receiving high-dosage methotrexate (author's transl)].

Microbiological assay according to Burchenal (modified by Mehta) is used for the determination of the serum methotrexate (MTX) level. Fifty cycles of high-dose MTX therapy were monitored in 11 patients with osteogenic sarcoma. The results showed close correlation with the clinical course of the therapy. The serum level of MTX was elevated in patients with symptoms of toxicity.

Bone Neoplasms↗