Increased Level of Dihydrofolic Reductase in Leucocytes of Patients Treated with Amethopterin

Bertino, Joseph R.; Donohue, D. R.; Gabrio, Beverly Wescott; Silber, Robert; Alenty, A.; Meyer, Michael; Huennekens, F.M.

doi:10.1038/193140a0

Cited by 76 publications

(29 citation statements)

References 4 publications

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“…Thus, the net effect of this chain of events would be to overcome the original amethopterin block, and the resulting increased level of reductase would then persist during the life span of each cell. The properties of such an induced enzyme should be similar in all respects to those of the original enzyme (19), as the present study shows is the case. A somewhat analogous mechanism has been postulated to explain the inhibition of histidine synthesis that occurs when bacteria are treated with the histidine analogue thiazolealanine (39).…”

Section: Discussionmentioning

confidence: 54%

“…In a previous study (19), an increased level of dihydrofolic reductase after amethopterin was noted in the leukocytes from patients with leukemia. The present investigation extends these observations and includes the effect of amethopterin treatment on the level of dihydrofolic reductase in leukocytes and erythrocytes of nonleukemic patients.…”

mentioning

confidence: 99%

“…Since the observation that dihydrofolic reductase is powerfully inhibited by the folic acid antagonists aminopterin 1 and amethopterin 2 (6)(7)(8)(9)(10), the development of resistance to these agents has been studied in bacteria (11)(12)(13)(14), cultured cells (15, 16), L-1210 leukemic mice (17), and human leukemia (1,18,19). In each of these instances, exposure of the system to the folic acid antagonists resulted in an increased level of dihydrofolic reductase, suggesting that these events were associated with resistance.…”

mentioning

confidence: 99%

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The “Induction” of Dihydrofolic Reductase Activity in Leukocytes and Erythrocytes of Patients Treated With Amethopterin*

Bertino

Donohue²,

Simmons³

et al. 1963

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 54%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The “Induction” of Dihydrofolic Reductase Activity in Leukocytes and Erythrocytes of Patients Treated With Amethopterin*

Bertino

Donohue²,

Simmons³

et al. 1963

J. Clin. Invest.

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“…17 Blood smears were stained with Wright's stain, and leukocyte counts were performed in duplicate. Hemoglobin was measured by its absorbancy at 410 my (millimolar extinction coefficient = 120).…”

mentioning

confidence: 99%

Studies on Normal and Leukemic Leukocytes. Iv. Tetrahydrofolate-Dependent Enzyme Systems and Dihydrofolic Reductase*

Bertino¹,

Silber²,

Freeman³

et al. 1963

J. Clin. Invest.

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“…Such a hypothesis is supported by studies of Bertino et al (1962Bertino et al ( , 1963 indicating that both leukaemic and non-leukaemic leukocytes and erythrocytes develop high levels of dihydrofolic reductase after treatment with MTX.…”

Section: Methodsmentioning

confidence: 83%

The Variability of Individual Tolerance to Methotrexate in Cancer Patients

Hansen¹,

Selawry²,

Holland³

et al. 1971

Br J Cancer

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Individual tolerance to single or widely spaced doses of methotrexate was explored in 49 patients with advanced cancer with normal serum creatinine and/or blood urea nitrogen. Methotrexate was given as an intravenous infusion over 1 hour at initial doses of 80-120 mg./m 2 body surface area. The doses were increased by 50% increments every 2 weeks until moderate toxicity occurred, arbitrarily defined as leukopenia <5000/mm. 3 , and/or thrombocytopenia <100,000/mm. 3 , and/or the appearance of oral mucous or intestinal toxicity. The individual dose required to produce initial evidence of toxicity varied by a factor of 18 between 50 and 900 mg./m 2 . Starting doses above 80 mg./m 2 were potentially hazardous. Dose limiting toxicity consisted of leukopenia with or without stomatitis in 81% of the patients, and stomatitis without leukopenia, in 19%. Thrombocytopenia was seen in 19% of the patients, but was never a dose limiting factor alone. Leukopenia always preceded thrombocytopenia. The nadir for haematologic toxicity varied considerably between day 5-15 and 9-14 for leukocytes and platelets, respectively, while oral ulcerations, when they occurred, consistently began between days 3-6 after drug administration. Other toxic manifestations included dermatologic changes in 8 patients, hepatic dysfunction in 7, conjunctivitis in 7, nausea and vomiting in 6, alopecia in 4, and diarrhea in 3 patients. The only factor which predicted toxicity was the patient's age. Drug tolerance was independent of previous chemotherapy or radiotherapy, weight loss, serum albumin or pretreatment serum folic acid levels.

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Increased Level of Dihydrofolic Reductase in Leucocytes of Patients Treated with Amethopterin

Cited by 76 publications

References 4 publications

The “Induction” of Dihydrofolic Reductase Activity in Leukocytes and Erythrocytes of Patients Treated With Amethopterin*

The “Induction” of Dihydrofolic Reductase Activity in Leukocytes and Erythrocytes of Patients Treated With Amethopterin*

Studies on Normal and Leukemic Leukocytes. Iv. Tetrahydrofolate-Dependent Enzyme Systems and Dihydrofolic Reductase*

The Variability of Individual Tolerance to Methotrexate in Cancer Patients

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