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

Bertino, Joseph R.; Donohue, Dennis M.; Simmons, Barbara S.; Gabrio, Beverly Wescott; Silber, Robert; Huennekens, F.M.

doi:10.1172/jci104735

Cited by 90 publications

(29 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In lysates (17,18). We have reported previously (14) that dihydrofolic reductase could not be detected in normal and chronic lymphocytic leukemic leukocytes when these assays were performed with amounts of lysate protein up to 1.5 mg.…”

Section: Resultsmentioning

confidence: 94%

“…The question might be raised as to whether such quantitative enzymatic differences observed between leukemic and normal leukocytes are inherent characteristics of the leukemic cell or whether they are also found in normal cells of comparable type and maturity. The finding of increased activity of tetrahydrofolate-dependent enzymes in lysates prepared from normal bone marrow aspirations 18 suggests that these alterations may not be specific for leukemia. This problem is difficult to resolve, however, until techniques become available for preparing immature normal cells of a uniform type (e.g., inyeloblasts) for comparative purposes.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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

Bertino¹,

Silber²,

Freeman³

et al. 1963

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

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.

Self Cite

View full text Add to dashboard Cite

“…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: 84%

“…In addition it has been suggested by Werkheiser (1963) that differential permeability through cell membranes is responsible for the differential sensitivity of dividing cells in which the concentration of folic acid reductase is comparable. Furthermore, the initial rate of uptake of the drug as well as the capacity of the cells to retain MTX has varied among different patients (Bertino, 1963). Additional factors for the variability of MTX tolerance in humans include drug interaction between MTX and other pharmacologic agents administered at the same time.…”

Section: Methodsmentioning

confidence: 99%

The Variability of Individual Tolerance to Methotrexate in Cancer Patients

Hansen¹,

Selawry²,

Holland³

et al. 1971

Br J Cancer

View full text Add to dashboard Cite

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.

show abstract

“…Overproduction of these "target" enzymes is often observed, which suggests that this may be a common mechanism of resistance (2,6,12,16,20,21,32,48,57). In the best-characterized systems, gene amplification has been demonstrated as the mechanism of overproduction (1,8,60) either in the form of DMs for unstable resistance or in the form of an expanded region, termed a homogeneously staining region (51), for stable resistance within (usually) one of the chromosomes.…”

Section: Discussionmentioning

confidence: 99%

Co-amplification of double minute chromosomes, multiple drug resistance, and cell surface P-glycoprotein in DNA-mediated transformants of mouse cells.

Robertson¹,

Ling²,

Stanners³

1984

Mol. Cell. Biol.

View full text Add to dashboard Cite

A genetic system comprised of mammalian cell mutants which demonstrate concomitant resistance to a number of unrelated drugs has been described previously. The resistance is due to reduced cell membrane permeability and is correlated with the presence of large amounts of a plasma membrane glycoprotein termed P-glycoprotein. This system could represent a model for multiple drug resistance which develops in cancer patients treated with chemotherapeutic drugs. We demonstrate here that the multiple drug resistance phenotype can be transferred to mouse cells with DNA from a drug-resistant mutant and then amplified quantitatively by culture in media containing increasing concentrations of drug. The amount of Pglycoprotein was correlated directly with the degree of drug resistance in the transformants and amplified transformants. In addition, the drug resistance and expression of P-glycoprotein of the transformants were unstable and associated quantitatively with the number of double minute chromosomes. We suggest that the gene for multiple drug resistance and P-glycoprotein is contained in these extrachromosomal particles and is amplified by increases in double minute chromosome number. The potential use of this system for manipulation of mammalian genes in general is discussed.A genetic system of clinical relevance involving mammalian cell mutants resistant to a wide variety of cytocidal drugs has recently emerged (36). This system began with the isolation of a number of CHO cell mutants which were resistant to colchicine (38). These mutants were shown to be resistant to the drug as a result of a membrane permeability barrier, which reduced the cellular uptake of colchicine (38). They were also found to be cross-resistant to a number of structurally diverse and functionally unrelated drugs, some of which are used in chemotherapy of cancer, again, by virtue of reduced uptake of these compounds (10). Further analysis of the membranes of these cells, in conjunction with hybrid cell studies (37) and selection of revertants (35), clearly demonstrated the association of the multiple drug resistance phenotype and the reduced membrane permeability with the presence in the cell membrane of a glycoprotein of 160,000 to 180,000 daltons termed P-glycoprotein (27, 28). P-glycoprotein was undetectable in the membrane of the drug-sensitive parental CHO cells but present in drugresistant mutants in amounts directly correlated with the level of resistance. The overexpression of a 160,000-to 180,000-dalton protein has also been observed in several drug resistance systems where resistance has been selected for drugs other than colchicine (13,22,45), including a human leukemic cell line selected for vinblastine resistance (11). As it appears likely that the development of resistance to chemotherapy of human tumors after repeated treatment with these drugs involves, at least in part, the emergence of such mutants (10, 36, 52), it seems important to carry their genetic analysis further. As a first step in this direction, we * Correspondin...

show abstract

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

Cited by 90 publications

References 28 publications

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

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

The Variability of Individual Tolerance to Methotrexate in Cancer Patients

Co-amplification of double minute chromosomes, multiple drug resistance, and cell surface P-glycoprotein in DNA-mediated transformants of mouse cells.

Contact Info

Product

Resources

About