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PubMed1985

The effects of cyclophosphamide, ketoconazole, aclacinomycin-A, methotrexate, and scheduled methotrexate-5-fluorouracil combination chemotherapy on the transplantable R-3327 prostatic adenocarcinoma in the F1 hybrid male rat.

Male F1 hybrid rats bearing the R-3327 transplantable prostatic adenocarcinoma demonstrating similar growth patterns within the original sample of animals were carefully separated into control and treatment groups. This assured treatment of tumors with similar cell kinetics within each group. In the first study, two separate drug protocols were investigated by intraperitoneal injection, namely cyclophosphamide (100 mg/kg) once every 4 weeks for 8 weeks and scheduled methotrexate (7.5 mg/kg) followed in 90 minutes by 5-fluorouracil (50 mg/kg) once each week for 8 weeks. Excellent suppression of tumor growth was obtained with each treatment protocol. Both were significant at the 0.01 level. In the second study, methotrexate (100 mg/kg) intraperitoneally once each week for 6 weeks, aclacinomycin-A intraperitoneally once each week for 4 weeks, and ketoconazole (60 mg/kg) via gavage 5 times a week for 6 weeks were administered to the animals in each respective group. Aclacinomycin-A and ketoconazole showed significant suppression of tumor growth at the 0.01 and 0.05 levels, respectively. Methotrexate suppressed tumor growth, but did not reach levels of significance over the duration of the study (0.2 less than P less than 0.3).

Aclarubicin↗

PubMed1986

Methotrexate infusions in poor prognosis acute lymphoblastic leukemia in children: I. The Norwegian methotrexate study in acute lymphoblastic leukemia in childhood, August 1975-December 1980.

One hundred fifty-three children with ALL were diagnosed in Norway in the period August 1975-December 1980. One hundred thirty-two of them received 3 infusions of methotrexate as consolidation therapy combined with methotrexate intrathecally as CNS prophylaxis. Eleven (44%) of the total 25 methotrexate cases with WBC above 50 X 10(9)/L were in CCR after 4 1/2-10 years. Two more cases had discontinued therapy, while in second remission. The event-free survival of all diagnosed 32 children in Norway with WBC above 50 X 10(9)/L was 37%. Seven infants below the age of 1 year are included in the 32 cases.

Adolescent↗

PubMed1987

A randomized study comparing high-dose methotrexate with moderate-dose methotrexate as components of adjuvant chemotherapy in childhood nonmetastatic osteosarcoma: a report from the Childrens Cancer Study Group.

Methotrexate (MTX) has demonstrated significant activity against relapsed and metastatic osteosarcoma. However, there is little published data to indicate the appropriate dose for MTX when given as a component of a multidrug regimen for the treatment of osteosarcoma. Therefore, the investigators at the Childrens Cancer Study Group undertook a randomized clinical trial that compared Adriamycin and vincristine given with either high-dose methotrexate or moderate-dose methotrexate as postoperation chemotherapy in the treatment of childhood osteosarcoma. We report here the results for 166 patients with completely resected nonmetastatic disease of an extremity. The two therapies demonstrated equivalent disease-free survival (DFS). Further, no therapy prejudices survival after relapse. Approximately 38% of patients remain disease free 4 years after diagnosis. Two relapses occurred in patients free of disease at least 36 months after initiation of treatment. Some factors found by other investigators to be prognostic of poorer DFS, namely, male sex, primary tumor in the humerus or femur, and larger primary tumors, demonstrated similar though not statistically significant trends. The presence of spontaneous necrosis in the tumor sample from the definitive surgery was associated with poor prognosis for DFS. We postulate that this feature represents rapidly growing tumors with increased potential for metastases.

Adolescent↗

PubMed1987

The role of methionine in methotrexate-sensitive and methotrexate-resistant mouse leukemia L1210 cells.

A mouse L1210 leukemia cell line was made 25-fold resistant to methotrexate (MTX) and had altered methionine transport and metabolism. L1210 cells resistant to methotrexate also had a 50-fold decrease in the exogenous methionine requirement for optimal cell growth compared to the parent cells. This change in methionine requirement was associated with differences in methionine metabolism between MTX-sensitive and MTX-resistant cell lines. Analysis of amino acid transport systems revealed different Kt and Vmax properties of methionine and nonmetbolizable amino acid analogues. There was a greater than twofold decrease in the initial sodium-dependent uptake of methionine in the resistant cells. Amino acid competition experiments revealed altered substrate specificities in the resistant cells. The cellular alterations occurring upon resistance may result from methotrexate-membrane interactions, and have been previously observed in cisplatinum-resistant cells. Thus modulation of methionine metabolism may provide the biochemical basis for MTX and cisplatinum collateral resistance.

Animals↗

PubMed2005

Rat reduced-folate carrier-1 is localized basolaterally in MDCK kidney epithelial cells and contributes to the secretory transport of methotrexate and fluoresceinated methotrexate.

The reduced-folate carrier (Rfc-1), previously also called methotrexate carrier-1 (MTX-1), was recently identified as accounting for approximately 30% of the methotrexate (Mtx) uptake into rat kidney slices. The localization of the carrier and its contribution to secretory or reabsorptive flux of the drug was therefore evaluated in polarized epithelial layers of Madin Darby canine kidney (MDCK) cells. Confocal laser scanning microscopy revealed that the HA-epitope-tagged protein was sorted to the basolateral side. In flux assays, the basolateral-to-apical transport of fluoresceinated methotrexate (FMTX) was two-fold higher than in the apical-to-basolateral direction across rat Rfc-1 transfected, but not mock-transfected, monolayers. The same observation was made for unlabeled Mtx. This secretory transport of FMTX was inhibited by an excess of 1 mM Mtx and was saturable and temperature-dependent. No differences in directional flux were observed for the pure fluorescein label. Removal of sodium resulted in a marked decrease of directional FMTX flux. The pH profile of the active transport component showed a trough around 6.5 and a maximum at acidic pH, as reported for uptake into Rfc-1-expressing cells. Thus, rat Rfc-1 is sorted to the basolateral side in polarized MDCK epithelial cells and mediates the secretion of Mtx, probably in co-operation with efflux proteins, such as multidrug resistance associated proteins, which are also expressed in these cells.

Animals↗

PubMed1988

Radiation, methotrexate, and white matter necrosis: laboratory evidence for neural radioprotection with preirradiation methotrexate.

To investigate the interactions between methotrexate (MTX) and irradiation of the central nervous system, adult rats were infused with MTX via the lateral cerebral ventricle either before, during, or following single fraction irradiation to the cervical spine. Single doses ranging from 1600 cGy to 3200 cGy were administered and the dose-response curve for forelimb paralysis was compared with that seen in irradiated animals which did not receive MTX. There was no effect on the dose-response curve when MTX was administered simultaneously with or following irradiation compared to radiation alone. When MTX was given prior to irradiation, however, the entire dose-response curve shifted in the direction of radioprotection by approximately 225 cGy. Histopathologic examinations were consistent with this observation, with animals pretreated with methotrexate demonstrating significantly less white matter necrosis than observed in untreated controls. Protection of normal CNS tissue from radionecrosis, and from the associated paralysis, may be achieved with preradiation methotrexate.

Animals↗

PubMed1999

Highly sensitive high-performance liquid chromatographic assay for methotrexate in the presence and absence of anti-methotrexate antibody fragments in rat and mouse plasma.

Recently, Balthasar and Fung have proposed that anti-methotrexate antibody fragments may be employed to enhance the selectivity of intraperitoneal methotrexate (MTX) therapy. This current work presents a sensitive high-performance liquid chromatographic method for measuring plasma concentrations of total (i.e., bound and unbound) MTX and free (unbound) MTX in rat and mouse plasma, in the presence or absence of therapeutic anti-MTX antibody fragments. The assay involves pre-column derivatization of MTX by sodium hydrosulfite to 2,4-diamino-6-methylpteridine. The limit of quantitation for MTX by this assay was 1.25 ng in rat plasma, mouse plasma and mouse plasma ultrafiltrate, which corresponds to a concentration of 25 ng/ml for a 50 microl sample. The limit of quantitation was found to be 2.5 ng in rat plasma ultrafiltrate (i.e., 50 ng/ml in 50 microl rat plasma ultrafiltrate). The method was shown to be quite accurate, as the mean assayed concentration of quality control samples was within 10% of theoretical values. We have applied the method to the investigation of MTX pharmacokinetics in mice and rats, following the administration of MTX alone or following simultaneous administration of MTX and anti-MTX Fab fragments. The method has been shown to be suitable for the assay of total and free methotrexate in the plasma of these species and will enable the testing of pharmacokinetic hypotheses regarding the influence of anti-MTX Fab fragments on the disposition of MTX.

Animals↗

PubMed1998

A randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced transitional cell carcinoma: results and a report on prognostic factors in a Medical Research Council study. MRC Advanced Bladder Cancer Working Party.

Transitional cell carcinomas may arise at any site within the urinary tract and are a source of considerable morbidity and mortality. In particular, patients with metastatic disease have a poor prognosis, with less than 5% alive at 5 years. A multicentre randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced or metastatic transitional cell carcinoma was conducted in the UK. From April 1991 to June 1995, 214 patients were entered by 16 centres, 108 randomized to CMV and 106 to MV. A total of 204 patients have died. The hazard ratio (relative risk of dying) was 0.68 (95% CI 0.51-0.90, P-value = 0.0065) in favour of CMV. This translates to an absolute improvement in 1-year survival of 13%, 16% in MV and 29% in CMV. The median survival for CMV and MV was 7 months and 4.5 months respectively. Two hundred and eight patients objectively progressed or died. The hazard ratio was 0.55 (95% CI 0.41-0.73, P-value = 0.0001) in favour of CMV. Two hundred and nine patients symptomatically progressed or died. The hazard ratio was 0.48 (95% CI 0.36-0.64, P-value = 0.0001) in favour of CMV. The most important pretreatment factors influencing overall survival were WHO performance status and extent of disease. These two factors were used to derive a prognostic index which could be used to categorize patients into three prognostic groups. We conclude that the addition of cisplatin to methotrexate and vinblastine should be considered in patients with transitional cell carcinoma, taking into account the increased toxicity.

Aged↗

PubMed1999

Serosal complications of single-agent low-dose methotrexate used in gestational trophoblastic diseases: first reported case of methotrexate-induced peritonitis.

Methotrexate (MTX) is a folate antagonist widely used both as an anticancer drug and as an immunosupressant. Administration of an 8-day methotrexate and folinic acid regime may be associated with pleuritic chest pain and pneumonitis. We have reviewed the toxicity seen in 168 consecutive patients treated with low-dose MTX for persistent trophoblastic disease. Twenty-five per cent of patients developed serosal symptoms, pleurisy was the commonest complaint. The majority of patients had mild to moderate symptoms which were controlled with simple analgesia and did not necessitate a change in treatment; 11.9% had severe symptoms which necessitated a change in treatment. One patient developed a pericardial effusion and a second patient developed severe reversible peritoneal irritation. The possible aetiology and pathophysiology of methotrexate-induced serosal toxicity is discussed.

Adult↗

PubMedDate not supplied

Drug survival and reasons for discontinuation of intramuscular methotrexate: a study of 212 consecutive patients switching from oral methotrexate.

OBJECTIVES: To assess the drug survival and reasons for discontinuation of intramuscular methotrexate (imMTX) in rheumatological patients who had switched to imMTX from oral methotrexate (oMTX). METHODS: Data from 212 consecutive patients who switched from oMTX to imMTX therapy at our outpatient clinic between April 1997 and January 2004 were collected retrospectively through survey of case records. Data included reason for discontinuation of oMTX, disease activity parameters, duration of imMTX therapy, and, in patients who withdrew, the reason for discontinuation of imMTX. RESULTS: The main reasons for switching from oMTX to imMTX were lack of efficacy (66%) and adverse events (28%). After 6 months, 114 patients (54%) were still receiving imMTX therapy, and their median serum C-reactive protein (CRP) and the percentage of patients who had received glucocorticoids during the previous 6 weeks had decreased (p<0.001). The median survival of imMTX therapy was 7.5 months (interquartile range 3-17). Twenty per cent of the patients received imMTX for more than 24 months. Of the 212 patients, 41% and 9% stopped imMTX therapy because of lack of efficacy and adverse events, respectively. Of the patients who had stopped oMTX because of adverse events, 22% also withdrew from imMTX because of adverse events. CONCLUSION: Half of the patients benefited from switching from oral to intramuscular methotrexate for at least 6 months, but only a minority adhered to the treatment for years. Lack of efficacy was the most frequent reason for discontinuation, while adverse events were rare.

Administration, Oral↗

PubMed1989

Graft-versus-host disease prevention by methotrexate combined with cyclosporin compared to methotrexate alone in patients given marrow grafts for severe aplastic anaemia: long-term follow-up of a controlled trial.

Forty-six patients with aplastic anaemia (median age 23 years) were given cyclophosphamide followed by infusion of marrow from an HLA-identical family member. To evaluate postgrafting prophylaxis for graft-versus-host disease (GVHD), the patients were entered into a randomized prospective trial comparing a combination of methotrexate and cyclosporin (n = 22) to methotrexate alone (n = 24). Methotrexate/cyclosporin significantly reduced the incidence and severity of acute GVHD and improved early survival. This report updates the results of the randomized trial with followup ranging from 3 to more than 6 years. The methotrexate/cyclosporin regimen did not interfere with sustained engraftment, and there were no significant differences in the incidence of early or late graft rejection among the two treatment groups (10% v 4%). The incidence of chronic GVHD was higher among methotrexate/cyclosporin-treated patients (58% v 36%; P = 0.18). Two patients in each treatment group still require treatment for chronic GVHD, while treatment is no longer needed in the other patients. Projected 4-year survival is 73% in patients given methotrexate/cyclosporin compared to 58% in patients given methotrexate alone (P = 0.16). Having achieved a reduction in the incidence of acute GVHD and associated early mortality without impairing engraftment, it is clear that future progress in marrow grafting for aplastic anaemia must come in the area of chronic GVHD.

Adolescent↗

PubMed1995

Differential effects of methotrexate and liposomally conjugated methotrexate in rat adjuvant-induced arthritis.

In this study we evaluated the comparative efficacy of free and liposomally conjugated methotrexate on both disease induction and suppression of acute inflammation in rat adjuvant-induced arthritis. Rats were given either empty liposomes (E-LIPO), free methotrexate (MTX) or the liposomally conjugated methotrexate (MTX-LIPO) at a dose of 100 micrograms/day for 7 consecutive days by the intravenous route. When MTX treatment was initiated on the day of arthritis induction the drug suppressed but did not abolish the development of joint inflammation. Free MTX had no significant anti-inflammatory effect upon an established arthritis when dosing was commenced on day 11 post-adjuvant induction. Conversely, MTX-LIPO did not affect the progression of the arthritis when dosing was started on day 0, but exerted a significant anti-inflammatory effect on an established arthritis. MTX-LIPO treatment was significantly less haematotoxic than free MTX.

Animals↗

PubMed1991

A prospective randomised trial of cyclosporin and methotrexate versus cyclosporin, methotrexate and prednisolone for prevention of graft-versus-host disease after HLA-identical sibling marrow transplantation for haematological malignancy.

A prospective randomised trial was performed in patients given HLA-identical sibling bone marrow transplants for haematological malignancy comparing the combination of cyclosporin and methotrexate (CM) (n = 20) with the combination of cyclosporin, methotrexate and prednisolone (CMP) (n = 21) as prophylaxis for graft-versus-host disease (GVHD). There was no significant differences between the two arms for the incidence of acute GVHD grades I-IV, acute GVHD grades II-IV, chronic GVHD, interstitial pneumonitis, relapse, survival and disease-free survival. The actuarial incidence of acute GVHD grades II-IV in the CMP group was 10% and in the CM group 15% (ns). The incidence of leukaemic relapse in good risk patients was 42% in the CMP group and 40% in the CM group (ns), although the majority of these relapses were cytogenetic relapses only in patients with chronic myeloid leukaemia. The incidence of acute GVHD grades II-IV in both arms of the current trial was significantly lower than in our previous trial comparing cyclosporin and methotrexate as single agents. Leukaemic relapse is now the principal cause of treatment failure in this patient population. We conclude that prednisolone should not be included as part of the prophylactic GVHD regime and that further improvement in therapeutic outcome is dependent upon better control of the underlying malignancy.

Actuarial Analysis↗

PubMed1977

Purification and properties of dihydrofolate reductase from methotrexate-sensitive and methotrexate-resistant Chinese hamster ovary cells.

We have previously described methotrexate-resistant Chinese hamster ovary cells which appear to contain normal levls of a structurally altered dihydrofolate reductase (EC 1.5.1.3) (Flintoff, W.F., Davidson, S.V., and Siminovitch, L. (1976) Somatic Cell Genet.2,245-261). By selecting for increased resistance form these class I cells, class III resistant cells were isolated which appeared to possess an increased activity of the altered enzyme. In the report, we describe the purification and several properties of the reductase from wild-type cells, two independently selected class I cells, and class III resistant cell. The reductases from wild-type and resistant cells had similar specific activities using folate and dihydrofolate as substrates, and similar molecular weights as determined by sodium dodecyl sulfate gel electrophoresis. The mutant enzymes, however, were about six- to eight-fold more resistant to inhibition by methotrexate than the wild-type enzyme, suggesting a decreased affinity of the mutant reductases to methotrexate-binding. Small differences between various enzymes were also seen in other physicochemical properties such as pH optima and Km values for folate, and in their heat stabilities, which suggest that different structural alterations may lead to the same mutant phenotype. As expected from earlier studies with crude extracts, class III cells did produce a higher (about 10-fold) yield of the reductase than the class I or wild-type cells.

Cell Line↗

PubMed1991

Methotrexate, vinblastine, adriamycin and cisplatin versus methotrexate and cisplatin in advanced urothelial cancer. A randomized study.

From September 1984 to December 1988, 28 consecutive patients with metastatic urothelial cancer entered a randomized study to compare 4 courses of modified methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) to 4 courses of methotrexate followed by folinic acid rescue and cisplatin (MP). Non-responders or relapsing patients were to be crossed to the other therapy. Hematological toxicity was more frequent (85%), but less severe, in patients treated with M-VAC than in patients treated with MP (21%, with 1 septic death). Complete plus partial remissions were achieved in 10 (71.4%) of 14 patients treated with M-VAC and in 6 (50%) of the 12 evaluable patients treated with MP. The 20% difference lay only on complete remissions, which were 8.3% in the MP versus 28.5% in the M-VAC group. At cross-over, however, only 1 of 5 patients resistant to MP responded to M-VAC, while 3 of 5 patients resistant to M-VAC responded to MP. It seems that M-VAC should be considered as the first-line therapy of choice in metastatic urothelial cancer, while MP, or high-dose methotrexate, could be considered for salvage.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

Adjuvant chemotherapy in operable breast cancer: cyclophosphamide, methotrexate, and fluorouracil versus chlorambucil, methotrexate, and fluorouracil--11-year results of Swiss Group for Clinical Cancer Research trial SAKK 27/82.

PURPOSE: To compare two adjuvant combination chemotherapies, cyclophosphamide, methotrexate, and fluorouracil (CMF) and chlorambucil, methotrexate, and fluorouracil (LMF), for patients who had undergone potentially curative surgery for unilateral breast cancer, in terms of relapse, survival, and toxicity. PATIENTS AND METHODS: Selection criteria was as follows: stage pT1-3a, N+ or N-, M0, less than 72 years of age. Eligible patients were randomized to receive either CMF (cyclophosphamide 100 mg/m2 orally on days 1 to 14, methotrexate 40 mg/m2 intravenously (I.V.) on days 1 and 8, fluorouracil 600 mg/m2 I.V. on days 1 and 8) or LMF (Leukeran [Wellcome A.G., Bern, Switzerland] 5 mg/m2 orally on days 1 to 14 with the some I.V. cytostatic drugs). Follow-up examinations were performed every 3 months during the first 3 years after mastectomy, and every 6 months thereafter. RESULTS: A total of 246 patients were randomized, of whom 232 who were fully eligible and contribute to the analyses presented here. No statistically significant difference in favor of adjuvant CMF over LMF emerges after a median follow-up duration of 11.2 years, for either overall survival (P = .15) or disease-free survival (P = .14). A consistent trend suggestive of a possible relative benefit associated with CMF should be pointed out. However, CMF presents a significantly worse toxicity profile as concerns hematologic parameters as well as alopecia, nausea, and vomiting. CONCLUSION: This prospective trial has not identified a statistically significant difference in disease-free survival or overall survival between the two adjuvant regimens LMF and CMF. Although a trend in favor of CMF has been observed in premenopausal patients, this has to be weighted against its definitely more pronounced toxicity profile.

Adult↗

PubMed1985

The use of protein as a carrier of methotrexate for experimental cancer chemotherapy. I. Preparation of pea seed lectin-methotrexate derivative and the preliminary experiments.

A method of preparation of pea seed lectin-methotrexate derivative by means of hydroxy-succinimide ester of methotrexate was elaborated. Five moles of methotrexate was bound to one lectin mole on the average as verified by analysis. For the distribution study lectin was labeled with 131I. Labeled lectin was administered intravenously to Yoshida sarcoma bearing rats and its distribution in the organism was monitored. After 24 hours the labeled lectin was entrapped predominantly in the reticuloendothelial system but after 48 and 72 hours the accumulation was seen also in thyroid, urinary bladder and tumor (1/4 cases only). The discrepancy in distribution of lectin in the tumor has been discussed.

Animals↗

PubMed1983

[Comparative study of 2 chemotherapy induction protocols. Cisplatinum-methotrexate-bleomycin and oncovin-methotrexate-bleomycin].

A prospective randomized study was conducted in 77 patients with stages III and IV epidermoid carcinomas of the buccal cavity, oropharynx, and pharyngolaryngeal regions to compare effects of two induction chemotherapy regimens: cisplatinum, methotrexate, bleomycin, and oncovin, methotrexate, bleomycin. Tumoral response and complications were analyzed as a function of the regimen, the tumoral site, and the stage. Chemotherapy including cisplatinum provided a tumoral response in 58.8 p.cent of stage III pharyngolaryngeal epitheliomas as against 38.4 p.cent with oncovin, methotrexate, bleomycin, but with a higher frequency of complications.

Antineoplastic Combined Chemotherapy Protocols↗