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PubMed1978

Preparation of 125iodine-labelled methotrexate and its use in a magnetisable particle solid-phase radioimmunoassay.

Two techniques for the iodination of methotrexate are describes, involving covalent linkage to the drug of 125I-labelled N-succinimidyl-3-(4-hydroxyphenyl)propionate (Bolton and Hunter reagent), or to 125I-labelled histamine. A rapid highly specific radioimmunoassay for methotrexate was developed, employing a specific antiserum covalently linked to magnetisable particles, and 125I-labelled methotrexate as tracer. Incubation times for the assays were 60 and 10 min for the Bolton and Hunter reagent-linked methotrexate and 125I-labelled histamine-linked methotrexate respectively. Separation of bound from free antigen was achieved by a rapid magnetic separation system. Results obtained for serum samples correlated closely with those using an enzymatic (dihydrofolate reductase) competitive protein binding assay for methotrexate. A major advantage of the assay is its potential for processing large numbers of samples rapidly, making it highly suitable for routine clinical use.

Animals↗
PubMed1993

2,4-diamino-7-hydroxy-pteridines in biological fluids of patients on high-dose methotrexate.

Concentrations of 2,4-diamino-7-hydroxy-pteridines in plasma and cerebrospinal fluid (CSF) are reported for the 0.5-8 g/m2 dose range of methotrexate in children with acute lymphoblastic leukemia or non-Hodgkin's lymphoma. This experiment has revealed that: (1) there is a wide inter-individual but relatively narrow intra-individual variability of the maximal concentrations of 2,4-diamino-7-hydroxy-pteridines in plasma during consecutive methotrexate cycles; (2) the increase in the level of the metabolites in plasma was related to increments of the methotrexate dose, but not above 5 g/m2: this can be explained by a saturable conversion of methotrexate to 2,4-diamino-7-hydroxy-pteridines; (3) significant correlations were found between simultaneous values of 2,4-diamino-7-hydroxy-pteridines in plasma and CSF; (4) the formation of 2,4-diamino-7-hydroxy-pteridines did not depend on the ages of patients receiving the same dose of methotrexate. The presence of these compounds in plasma and CSF in significant amounts creates the potential for a number of competitive interactions with pteridine-dependent metabolism which may open up new possibilities for understanding the metabolic side-effects of methotrexate therapy.

Adolescent↗
PubMed1993

Methotrexate and misoprostol for early abortion.

Methotrexate is cytotoxic to trophoblast and, in low doses, has minimal side effects. It is used to treat both gestational trophoblastic neoplasia and ectopic pregnancy. The cytotoxic effects of methotrexate on intrauterine trophoblast should be equivalent. To test this hypothesis, ten pregnant women, < 8 weeks' gestation were treated with methotrexate 50 mg/m2 intramuscularly followed 3 days later by misoprostol, a prostaglandin E1 analogue. The first 4 patients received misoprostol 600 micrograms orally; none aborted soon after the misoprostol. Two patients aborted 25 and 26 days after the methotrexate injection and two elected a suction abortion after 14 days (one by choice and one because the pregnancy was still viable). The last 6 patients received misoprostol 800 micrograms vaginally and aborted within 3-8 hours. One patient had an incomplete abortion requiring a suction curettage 34 days after the misoprostol. Vaginal bleeding for these 6 patients lasted an average of 29 +/- 11 days (range, 12-42 days). No methotrexate side effects were observed. Vaginal misoprostol (800 micrograms) was significantly more effective (p = 0.005) than oral misoprostol (600 micrograms) in effecting abortion after intramuscular methotrexate.

Abortion, Induced↗
PubMed1994

Methotrexate and misoprostol for abortion at 57-63 days gestation.

Methotrexate and misoprostol have been shown in preliminary studies to be effective for abortion at < or = 56 days gestation with minimal side effects. RU-486 is used in combination with prostaglandin for abortion < or = 49 days gestation in France but < or = 63 days gestation in England. This pilot study was performed to evaluate if methotrexate and misoprsotol may also be effective up to 63 days gestation. Ten pregnant women between 57-63 days gestation were treated with methotrexate 50 mg/m2 intramuscularly followed 3 days later by misoprostol 800 micrograms vaginally. Abortion occurred in 6 women; abortion occurred in one of the women after a repeat dose of misoprostol 24 hours after the first dose. The remaining 4 women all had a surgical abortion. In the successfully treated women, vaginal bleeding lasted 14 +/- 4 (mean +/- standard deviation) days and serum beta-hCG was < or = 25 IU/L by 32 +/- 5 days after the methotrexate injection. No methotrexate side effects occurred. Methotrexate and misoprostol do not appear to be as effective for medical abortion between 57 and 63 days gestation as compared to < or = 56 days gestation.

Abortion, Induced↗
PubMed1987

Alteration of methotrexate toxicity in rats by manipulation of dietary components.

Administration of a chemically defined, elemental diet to rats given 20 mg/kg of methotrexate intraperitoneally has consistently resulted in a 100% mortality from severe enteritis within 156 h. This study examined the importance of specific dietary components in the etiology of this enhanced toxicity. Rats were given their respective diets for 7 days, whereupon methotrexate (20 mg/kg) was given intraperitoneally, and percent of survivors was recorded. Varying the concentration of carbohydrate as polysaccharide (0%, 50%, 100%) (n = 30) had no effect on survival. An increase in the percent of protein as polypeptide (0%, 25%, 50%, 75%, 100%) (n = 50) in the elemental diet resulted in a progressively significant increase in percent survival. Addition of either fat or bulk to this elemental diet had no effect on survivorship. Serum and bile methotrexate levels of rats fed an elemental liquid diet (whether or not all of the protein was provided as polypeptide) were significantly increased from 12 to 72 h (p less than 0.03) compared with rats fed a regular Chow diet. When the protein content of the elemental liquid diet was provided as 100% polypeptide, serum and bile methotrexate levels were significantly lower at 48 h compared with the elemental diet group given 100% of protein as amino acid. Administration of methotrexate to rats fed an elemental liquid diet in which all of the protein is provided as amino acids is extremely toxic to the gastrointestinal tract, probably as a result of delayed clearance of the drug from the systemic circulation and from bile. This toxicity is alleviated by the provision of protein as polypeptide in the elemental diet. No toxicity to the drug is seen at this dose in rats fed a regular Chow diet. If these results are applicable to humans, the use of elemental liquid diets as the only source of enteral nutrition would appear contraindicated in patients receiving methotrexate.

Amino Acids↗
PubMed1988

Photoaffinity analogues of methotrexate as folate antagonist binding probes.

A photoaffinity analogue of methotrexate, APA-[125I]ASA-Lys, specifically binds to dihydrofolate reductase and covalently modifies the enzyme following irradiation. An excess of methotrexate blocks incorporation of the photoprobe. Following cyanogen bromide digestion of the radiolabeled enzyme and high-pressure liquid chromatographic separation of the generated peptides, a majority of the label was centered around residues 63-65 (Lys-Asn-Arg), part of the inhibitor binding domain. This photoprobe is also transported into murine L1210 cells in a temperature-dependent, sulfhydryl reagent inhibitable manner with a Vmax similar to that for methotrexate. Ultraviolet irradiation at 4 degrees C of a cell suspension that had been incubated with the radiolabeled photoprobe resulted in the covalent modification of a 46-48 Kd protein. This can be demonstrated when the plasma membranes from the labeled cells are analyzed via sodium dodecylsulfate-polyacrylamide gel electrophoresis and autoradiography. Labeling of this protein occurs half-maximally at a reagent concentration that correlates with the Kt for transport of the iodinated compound. Protection against labeling of this protein by increasing amounts of methotrexate parallels the concentration dependence of inhibition of photoprobe uptake by methotrexate. In addition, no labeling occurs when a cell line that has a defective methotrexate transport system is similarly treated. Evidence that, in the absence of irradiation and at 37 degrees C, the iodinated probe is actually internalized is demonstrated by the labeling of two soluble proteins (Mr = 38 Kd and 21 Kd) derived from the cell homogenate supernatant.

Animals↗
PubMed1990

Methotrexate infusion and folinic acid in the primary therapy of nonmetastatic gestational trophoblastic tumors.

Thirty-two patients with nonmetastatic gestational trophoblastic tumors were treated with methotrexate infusion and folinic acid and the results of this therapy were compared to our prior experience with the 8-day methotrexate-folinic acid regimen. Complete remission was achieved in 22 of 32 (68.7%) patients treated with methotrexate infusion and 147 of 163 (90.2%) patients treated with the 8-day regimen (P less than 0.01). One course of chemotherapy induced complete remission in 19 (86.3%) patients treated with methotrexate infusion and 121 (82.2%) patients treated with the 8-day regimen. All 10 patients resistant to methotrexate infusion later achieved remission with other chemotherapy. Following methotrexate infusion, no patient developed myelosuppression, hepatotoxicity, or alopecia. Efforts should continue to identify new chemotherapeutic protocols that maximize remission rates and minimize toxicity and hospitalization.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Rapid escalation of weekly intramuscular methotrexate for nonmetastatic gestational trophoblastic disease: a Gynecologic Oncology Group study.

Patients with postmolar nonmetastatic gestational trophoblastic disease were entered into this Gynecologic Oncology Group study to determine the relationship of efficacy and toxicity to a rapidly escalating dose of weekly intramuscular methotrexate. The treatment was initiated at 40 mg/m2 weekly of intramuscular methotrexate. If no major toxicity was encountered, the weekly dose was escalated 5 mg/m2 at 2-week intervals until a maximum dose of 50 mg/m2 per week was achieved. Complete response was defined as three normal beta-hCG values measured on consecutive weeks. Forty-six of sixty-two (74%) evaluable patients had a complete response to this regimen. Duration of therapy ranged from 3 to 16 weeks with a median of 7 weeks. No major toxicity occurred. Eight patients experienced leukopenia at a median of 3200/microliters (range 2100-3900). Two patients had platelet nadirs of 128,500 and 131,000. Only 50% (8/16) of the nonresponders subsequently responded to second-line 5-day methotrexate every 2 weeks. Fifteen of the sixteen weekly intramuscular methotrexate failures ultimately had complete responses after treatment with subsequent chemotherapy. In this study, second-line therapy results support administration of another agent such as dactinomycin rather than 5-day methotrexate. This higher dose (1.36 relative dose intensity to median complete response) of weekly intramuscular methotrexate therapy (40 mg/m2) is no more effective and of similar toxicity to a lower-dose regimen (30 mg/m2) reported earlier.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1981

Phorbol ester dramatically increases incidence of methotrexate-resistant mouse cells: possible mechanisms and relevance to tumor promotion.

I have tested the hypothesis that at least some of the known tumor promoters may act by facilitating gene amplification. A series of single-step selections for resistance to methotrexate, a specific inhibitor of dihydrofolate reductase (DHFR), was carried out with 3T6 cells in the presence and in the absence of a potent tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Incidence of methotrexate-resistant, colony-forming 3T6 cells is increased up to 100 fold if selection is carried out in the presence of TPA. For a major portion of this new TPA effect to be observed, it is sufficient to add TPA simultaneously with methotrexate. The effect of TPA on the incidence of methotrexate resistance is detectable at less than 20 nM TPA and is maximal at about 200 nM TPA. Phorbol (a nonpromoting analog of TPA), thymidine and dimethylsulfoxide each fail to produce any TPA-like effect in this system. DHFR gene copy numbers per cell in clones resistant to 100, 200 and 300 nM methotrexate are approximately 3, 10 and 16 times higher, respectively, than the DHFR gene copy number in the parental 3T6 cells. These numbers do not depend on the presence or absence of TPA during methotrexate selection.

Animals↗
PubMed1987

Chronic effects of fractionated renal irradiation on the pharmacokinetics of intravenous methotrexate.

the chronic effects of renal irradiation on the pharmacology of methotrexate was studied in a rat model. Unanesthetized rats received 2 doses of bilateral fractionated kidney irradiation (16.2 Gy or 19.8 Gy in 9 fractions). Alterations in renal function were first seen at 3 months in the 19.8 Gy group and 12 months in the 16.2 Gy groups. Life table analysis showed a shift in the survival curve of about 3 months between the 2 radiation doses. The pharmacokinetics of i.v. methotrexate showed an increase in the area under the plasma curve beginning at 9 months in the 19.8 Gy group and at 15 months in the 16.2 Gy group. The volume of distribution of methotrexate was smaller in the irradiated rats than in unirradiated controls. Multiple linear regression models showed significant correlations between parameters of methotrexate clearance and certain renal function tests. Nevertheless, no set of renal function tests consistently predicted alteration in methotrexate clearance in the 2 radiation groups. Furthermore, time after irradiation remained a highly significant variable indicating that renal irradiation causes time dependent change in methotrexate pharmacokinetics that can not be accounted for by the usual tests of renal function.

Animals↗
PubMed2005

Comparison of multidose and single-dose methotrexate protocols for the treatment of ectopic pregnancy.

OBJECTIVE: The purpose of this study was to compare success rates of 643 patients who had ectopic pregnancy from the same database who were treated with multidose or single-dose methotrexate protocols. STUDY DESIGN: We compared demographics, gestational age, serum human chorionic gonadotropin, progesterone levels, ectopic sac size and volume, overall ectopic mass size and volume, ectopic cardiac activity, history of ectopic pregnancy, number of treatment days, methotrexate doses, and outcome in consecutive patients with ectopic pregnancy who were treated with methotrexate. RESULTS: Success rates were comparable between patients with multidose and single-dose therapy (95% vs 90%, respectively) as were human chorionic gonadotropin and progesterone levels, history of ectopic pregnancy (21.4% vs 21.7%, respectively), number of treatment days, gestational age, ectopic size, ectopic volume, and ectopic mass volume. Patients who received single-dose therapy were significantly heavier (146 vs 159 pounds), had greater ectopic cardiac activity (3.1% vs 10.3%), and received fewer methotrexate doses. CONCLUSION: This study suggests single-dose methotrexate therapy is as effective as multidose methotrexate therapy for the treatment of ectopic pregnancy.

Abortifacient Agents, Nonsteroidal↗
PubMed2006

Effects of methotrexate on calcium flux in rat liver mitochondria, microsomes and plasma membrane vesicles.

The metabolic effects of methotrexate in perfused livers are similar to those exerted by hormones acting through Ca(2+)-dependent mechanisms. The aim of the present study was to determine whether the effects of methotrexate are mediated by a direct action on cellular Ca(2+) fluxes. Methotrexate did not affect the ATP-dependent (45)Ca(2+) uptake by mitochondria, microsomes and inside-out plasma membrane vesicles and Ca(2+) efflux from plasma membrane vesicles. However, methotrexate was able to stimulate (45)Ca(2+) release from preloaded microsomes. The amount of Ca(2+) released by methotrexate was similar to that induced by IP(3). Methotrexate could be acting through the capacitative calcium entry mechanism.

Animals↗
PubMed2004

Results of a randomised phase II study comparing docetaxel with methotrexate in patients with recurrent head and neck cancer.

We report the results of a randomised phase II trial of docetaxel tested as a single agent in patients with recurrent head and neck cancer using methotrexate as a control arm to validate the results. Eligibility criteria included: histologically-confirmed squamous cell carcinoma, measurable disease, adequate haematological, renal and hepatic functions, no prior chemotherapy for recurrent cancer, signed informed consent. 40 mg/m2 methotrexate was given as a short weekly bolus i.v. injection, and 40 mg/m2 docetaxel was administered as a one hour weekly infusion. A total of 57 patients were randomised based on a ratio of 2/1:37 and 20 patients received docetaxel and methotrexate, respectively. Patient characteristics included 49 males and 8 females; the median age was 59 years (range: 43-82 years). Twenty-eight patients had a local-regional relapse and 29 had distant metastasis, the median disease-free interval was 7.9 months (range: 0-165 months). For patients treated with docetaxel, the following grade 3-4 toxicities occurred: neutropenia (12.5%) with febrile neutropenia in one patient (1%), anaemia (19%) mucositis (9%) and ungueal toxicity (9%). In the methotrexate arm, the grade 3-4 toxicities were: anaemia (15%) and mucositis (5%). The response rate was significantly higher in the docetaxel arm with 27% (95% confidence interval (CI): 21.7-32.3%) of objective responses versus 15% (95% CI: 11.2-18.8%) in the methotrexate arm. Overall survival and time to progression were super-imposable between the docetaxel and methotrexate treatments. Docetaxel given as a weekly infusion has a high activity in patients with head and neck cancer. A phase III trial is needed to test if this translates into a survival benefit for docetaxel use.

Adult↗
PubMed2004

Combination benefit of a pyrimidylpiperazine derivative (Y-40138) and methotrexate in arthritic rats.

Anti-tumor necrosis factor-alpha (TNFalpha) antibody in combination with methotrexate dramatically decreases joint destruction in rheumatoid arthritis. The aim of this study was to examine combined treatment with N-[1-(4-([4-(pyrimidin-2-yl)piperazin-1-yl]methyl)phenyl)cyclopropyl] acetamide HCl (Y-40138) and methotrexate in rat adjuvant-induced arthritis. The increase in hindpaw volume and joint destruction was suppressed by single therapeutic administration (days 15-20) of Y-40138 (30 mg/kg, p.o.), but not by prophylactic administration (days 1-9). However, arthritic progression was suppressed by single prophylactic administration of methotrexate (0.3 mg/kg, p.o.), but not by therapeutic administration. Combined administration (days 10-20) of Y-40138 (0.3-1 mg/kg) and methotrexate (0.03 mg/kg) synergistically suppressed the increase in hindpaw volume and joint destruction. We concluded that Y-40138 in combination with methotrexate synergistically suppressed arthritic progression. These data suggest that combined treatment with Y-40138 and methotrexate may increase efficacy of therapy for rheumatoid arthritis.

Acetamides↗
PubMed2006

EGFP fluorescence as an indicator of cancer cells response to methotrexate.

Methotrexate action in viable cells was monitored by registering changes in EGFP (Enhanced Green Fluorescent Protein) fluorescence intensity. Treatment with 1 microM methotrexate for 48 h of human colorectal adenocarcinoma C85 cells, stably transfected to express EGFP, caused 5-fold increase in EGFP fluorescence assayed by flow cytometry with no distinct increase in EGFP protein level. This was correlated with morphological changes, including an increase of cell granularity and cell shape flattening, as well as cell cycle G1 phase arrest revealed by DNA content analysis. Methotrexate removal allowed the morphology of the cells in culture to revert in 10 days to normal. The cells that survived methotrexate exposure were propagated as C85r cell subline and displayed kinetics of methotrexate sensitivity parallel to that of the parental C85 line. As the increase in EGFP fluorescence could also be visualized by fluorescence microscopy, this reporter system may be employed to image methotrexate action in cancer cells in living models.

Adenocarcinoma↗
PubMed1988

Methotrexate-associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis.

PURPOSE: Beginning in the 1980s, methotrexate has been used successfully to treat rheumatoid arthritis. The magnitude and severity of short- and long-term methotrexate toxicity, however, have not been adequately investigated. Our study was performed to determine the prevalence of hepatotoxicity in patients with rheumatoid arthritis receiving long-term methotrexate therapy. PATIENTS AND METHODS: We conducted a retrospective, computer-assisted review of all Duke University Medical Center patients undergoing liver biopsy for methotrexate monitoring from January 1979 to January 1988. A total of 538 biopsies were performed in 399 patients, 259 of whom had inflammatory arthritis (210 with rheumatoid arthritis, 47 with psoriatic arthritis, and two with seronegative spondyloarthropathy). RESULTS: No evidence of cirrhosis was defined in the cohort with rheumatoid arthritis; however, six patients with rheumatoid arthritis had histologic changes of fibrotic liver disease (prevalence of 2.9 percent in the group with rheumatoid arthritis) while taking methotrexate. Five of the six patients were obese and three had glucose intolerance or overt diabetes mellitus, and one person admitted to alcohol usage. Only one patient with fibrotic liver disease had elevated liver function test results, and no person showed a declining serum albumin level at the time of biopsy. Sixty-one patients with rheumatoid arthritis underwent multiple samplings (44 with two, 13 with three, and four with four biopsies). Fourteen of these patients showed progressive hepatic disease, whereas four patients improved. CONCLUSION: Although the prevalence of methotrexate hepatotoxicity in this large cohort of patients with rheumatoid arthritis was low, a small but definite risk of hepatic fibrosis, not predictable by laboratory screening, still exists.

Aged↗
PubMed1995

Hematologic malignancies and the use of methotrexate in rheumatoid arthritis: a retrospective study.

PURPOSE: To evaluate the relationship between use of methotrexate in rheumatoid arthritis patients and development of hematologic malignancies. PATIENTS AND METHODS: We retrospectively analyzed all patients registered at the Mayo Clinic from 1976 through 1992 with rheumatoid arthritis (n = 16,263) cross-indexed with patients registered during the same period with a hematologic malignancy (n = 21,270). Adult patients were selected who had rheumatoid arthritis, were treated with a disease-modifying antirheumatic drug, and subsequently developed a hematologic malignancy. RESULTS: Thirty-nine patients met the selection criteria. Twelve of them had been given methotrexate. The characteristics of those who received methotrexate, including the type of hematologic malignancy, did not differ from those of patients who received other disease-modifying antirheumatic drugs. CONCLUSIONS: Hematologic malignancies are uncommon in patients with rheumatoid arthritis treated with disease-modifying antirheumatic drugs, including methotrexate. There does not appear to be a relationship between the peak or cumulative dose or the duration of methotrexate therapy and the subsequent development of hematologic malignancy. The histologic types of hematologic malignancy seen in the methotrexate-treated patients did not differ from those of patients treated with other disease-modifying antirheumatic drugs.

Adult↗
PubMed1996

Single-dose methotrexate for the treatment of ectopic pregnancy: Northwestern Memorial Hospital three-year experience.

OBJECTIVE: Our purpose was to evaluate the effectiveness of single-dose intramuscular methotrexate in the treatment of ectopic pregnancies by physicians in the Department of Obstetrics and Gynecology of Northwestern Memorial Hospital and to compare the results with those of previously published studies. STUDY DESIGN: A retrospective chart review was performed of 50 patients with ectopic pregnancies treated with single-dose methotrexate according to the protocol of Stovall et al. from January 1992 to February 1995. RESULTS: The mean pretreatment level of beta-human chorionic gonadotropin was 1896.4 +/- 2399 mlU/ml. Only 32 women (64%) were successfully treated with a single dose of methotrexate. An additional 7 women required a second or third injection. The combined success rate for medical management of ectopic pregnancy with one to three doses of methotrexate was 78% (39 women). Pretreatment beta-human chorionic gonadotropin levels were significantly lower in women who responded to single-dose therapy than in those who required either two or three doses or who had failure of medical management (p = 0.0011). The mean time to resolution of beta-human chorionic gonadotropin was 26.5 +/- 17 days. Higher pretreatment levels correlated with longer resolution time (r = 0.83, p < 0.001). Eleven women (22%) with failure of medical management required surgery. CONCLUSIONS: In our series single-dose methotrexate was only 64% successful. Women with a pretreatment beta-human chorionic gonadotropin level >5000 mlU/ml had a greater probability of requiring either surgical intervention or multiple doses of methotrexate. The potential for emergency surgery remains an important risk.

Adolescent↗