Journal Article•
A study of the distribution of methotrexate in human tissues and tumors.
01 May 1970-Cancer Research (American Association for Cancer Research)-Vol. 30, Iss: 5, pp 1344-1348
TL;DR: Mtx is readily detectable in varying concentrations in many tissues and tumors assayed, regardless of the mode of administration, and tissue that is within an area of arterial infusion has a higher Mtx concentration than tissue obtained from outside the area of infusion.
Abstract: Summary Methotrexate (Mtx) is readily detectable in varying concentrations in many tissues and tumors assayed, regardless of the mode of administration. In general, tissue that is within an area of arterial infusion has a higher Mtx concentration than tissue obtained from outside the area of infusion. Higher and sustained Mtx tissue levels were achieved by prolonged and continuous administration of the drug as opposed to single dose administration. The higher dose resulted in higher but not directly proportional levels of Mtx in tissue. When Mtx is administered as a single injection either i.v. or by regional intraarterial administration at the same dosage, the intraarterial route results in higher tissue concentration of the drug. These results do not answer all questions pertaining to the distribution of Mtx in human tissues and tumors and are merely presented as preliminary data. Further studies in this area are currently in progress.
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TL;DR: The review summarizes the pharmacologic findings and illustrates how they are currently being applied to the treatment of malignant disease.
Abstract: Methotrexate is now used widely for the treatment of acute leukemia, non-Hodgkin's lymphoma, osteogenic sarcoma, choriocarcinoma, breast carcinoma, pulmonary and epidermoid carcinoma, and intrathecal chemotherapy. It is also useful in bone marrow transplantation, severe psoriasis, rheumatoid arthritis, dermatomyositis, Wegener's granulomatosis and sarcoidosis. The recent dramatic intensification of methotrexate therapy can be attributed in part to advances in our understanding of the clinical pharmacology of the folate antagonists, as well as to the combination of positive results and their effective dissemination to medical oncologists. The review summarizes the pharmacologic findings and illustrates how they are currently being applied to the treatment of malignant disease.
534 citations
TL;DR: It is important that all patients receiving methotrexate be educated concerning this potential adverse reaction and instructed to contact their physicians should significant new pulmonary symptoms develop while undergoing therapy, and if metotrexate pneumonitis is suspected, methotRexate should be discontinued.
Abstract: Pneumonitis is a serious and unpredictable side-effect of treatment with methotrexate (MTX) that may become life-threatening. The clinical and histological features of nine cases of MTX pneumonitis are reported and the literature reviewed. The typical clinical symptoms include progressive shortness of breath and cough, often associated with fever. Hypoxaemia and tachypnoea are always present and crackles are frequently audible. Chest radiography reveals a diffuse interstitial or mixed interstitial and alveolar infiltrate, with a predilection for the lower lung fields. Pulmonary function tests show a restrictive pattern with diminished diffusion capacity. Lung biopsy reveals cellular interstitial infiltrates, granulomas or a diffuse alveolar damage pattern accompanied by perivascular inflammation. These clinical and pathological findings are not specific to MTX pneumonitis and can be seen with other drug-induced lung toxicities. It is important that all patients receiving methotrexate be educated concerning this potential adverse reaction and instructed to contact their physicians should significant new pulmonary symptoms develop while undergoing therapy. If methotrexate pneumonitis is suspected, methotrexate should be discontinued, supportive measures instituted and careful examination for different causes of respiratory distress conducted.
330 citations
TL;DR: The relationship between the use of various drugs and pulmonary disease is being recognized with greater frequency and the means whereby drugs can cause pulmonary disease vary widely.
Abstract: The relationship between the use of various drugs and pulmonary disease is being recognized with greater frequency. The means whereby drugs can cause pulmonary disease vary widely and are ...
244 citations
191 citations
TL;DR: Methotrexate was approved by the food and drug administration for the treatment of severe and disabling psoriasis in 1971 and for RA only in 1988 and pulmonary toxicity was first observed during treatment of childhood leukaemia in 1969 and later in malignancies, Psoriasis and polymyositis.
Abstract: Methotrexate (MTX) was described as a drug in 1946' and first used in the treatment of human disease (childhood leukaemia) in 1948.2 Successful MTX treatment for rheumatoid arthritis (RA) and psoriasis was reported in 1951,3 although the interest in this drug at that time was probably overshadowed by the impressive results of cortico-steroid treatment until approximately 1980. MTX was approved by the food and drug administration (FDA) for the treatment of severe and disabling psoriasis in 1971 and for RA only in 1988.4 MTX-related pulmonary toxicity was first observed during treatment of childhood leukaemia in 19695 and later in malignancies, psoriasis6 7 and polymyositis.7 I Though it was postulated that pulmonary toxicity would appear only with a weekly dose higher than 20 mg,7 this did not prove to be true when in 1983 pneumonitis was also reported during low-dose MTX treatment for RA9 10
136 citations
References
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TL;DR: The occurrence of what the author interpreted as an "acceleration phenomenon" in the leukemic process as seen in the marrow and viscera of children with acute leukemia treated by the injection of folic acid conjugates1 and pteroyltriglutamic acid (teropterin) — and an experience gained from studies on folic .
Abstract: IT IS the purpose of this paper to record the results of clinical and hematologic studies on 5 children with acute leukemia treated by the intramuscular injection of a synthetic compound, 4-aminopteroylglutamic acid (aminopterin). This substance is an antagonist to folic acid regarding the growth of Streptococcus faecalis R. The occurrence of what he interpreted as an "acceleration phenomenon" in the leukemic process as seen in the marrow and viscera of children with acute leukemia treated by the injection of folic acid conjugates1 — pteroyltriglutamic acid (teropterin) and pteroyldiglutamic acid (diopterin) — and an experience gained from studies on folic . . .
1,543 citations
TL;DR: Unequivocal clinical improvement and radiological evidence of regression of pulmonary metastases was observed in all 3 cases and extreme variations in pattern of clinical behavior of this type of tumor necessitate more observations before any definitive therapeutic implications may be drawn from these studies.
Abstract: Summary1) Two patients with choriocarcinoma and one with chorioadenoma destruens with proven progressive metastases were treated with methotrexate, a folic acid antagonist, according to intensive regimen of repeated courses of dosages producing substantial but reversible toxicity. Initially high urinary gonadotropin present in all 3 cases approached normal levels following this regimen and such low levels were sustained following cessation of treatment. 2) Unequivocal clinical improvement and radiological evidence of regression of pulmonary metastases was observed in all 3 cases. Nevertheless, extreme variations in pattern of clinical behavior of this type of tumor necessitate more observations before any definitive therapeutic implications may be drawn from these studies.
425 citations
"A study of the distribution of meth..." refers background in this paper
...(2), Mtx1 has proven to be of increasing value in cancer chemotherapy....
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TL;DR: Experiments are described which demonstrate that the agent which binds amethopterin and related 4-amino derivatives of folic Acid is the enzyme folic acid reductase and that this binding is specific and exceedingly tight.
401 citations
Journal Article•
TL;DR: The quantitative determination of folic acid by the measurement of diazotizable amine following complete reduction of the substrate by the enzyme has been demonstrated and is free from interference by the presence of growth factors such as folic Acid, folinic acid or thymine.
Abstract: A precise, specific assay for the 4-amino analogues of folic acid in urine, serum and tissues has been described. The method is based on the stoichiometric inhibition of the enzyme folic acid reductase by these drugs. A titration of drug with enzyme is measured by a colorimetric determination (Bratton-Marshall reaction) of the diazotizable p -aminobenzoylglutamate
derived from the enzymic product, tetrahydrofolate. This method is specific for the unaltered form of these drugs and is free from interference by the presence of growth factors such as folic acid, folinic acid or thymine. The quantitative determination of folic acid by the measurement of diazotizable amine following complete reduction of the substrate by the enzyme has also been demonstrated.
56 citations
"A study of the distribution of meth..." refers methods in this paper
...Serum and urine specimens were assayed using the modified Werkheiser (9, 10) microbiochemical method or a liquid scintillation counting technique....
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