Inhibition of Dihydrofolic Reductase by Aminopterin and Amethopterin.

Osborn, Mary; Freeman, Monroe E.; Huennekens, F.M.

doi:10.3181/00379727-97-23764

Cited by 187 publications

(46 citation statements)

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“…In vitro studies revealed that MTX effect could be enhanced by methionine, perhaps by blocking THFA regeneration from 5-methyl THFA. Such an effect would be additive to the MTX ability to block THFA production from PGA and DHFA by binding dihydrofolate reductase (34)(35)(36)(37). Homocysteine appeared to correct MTX effect in vitro, perhaps by releasing intracellular stores of 5-methyl THFA for THFA regeneration, thus by-passing the blocked DHFA.…”

Section: Methodsmentioning

confidence: 99%

Defective DNA synthesis in human megaloblastic bone marrow: effects of homocysteine and methionine

Waxman¹,

Metz²,

Herbert³

1969

J. Clin. Invest.

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A B S T R A C T In Bin deficiency, inadequate DNA synthesis seems due in large measure to a block of tetrahydrofolic acid (THFA) regeneration from 5-methyl THFA (via homocysteine transmethylation).In support of the above, homocysteine appears to facilitate and methionine to reduce de novo DNA synthesis. This was measured by the ability of deoxyuridine to suppress thymidine-8H uptake into DNA in human bone marrow cultures. The homocysteine effect in B,2-deficient marrow supports the possibility that there is in man an additional Bin-independent pathway for regeneration of THFA by methylation of homocysteine to form methionine.Among possible explanations for the methionine effect is end-product inhibition of the homocysteine transmethylase reaction, resulting in further accumulation of 5-methyl THFA. Homocysteine transmethylation may play an important role in the regulation of THFA availability and de novo DNA synthesis.In vitro and in vivo evidence suggests that methionine may be useful to potentiate and homocysteine to reduce methotrexate action.

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Section: Methodsmentioning

confidence: 99%

Defective DNA synthesis in human megaloblastic bone marrow: effects of homocysteine and methionine

Waxman¹,

Metz²,

Herbert³

1969

J. Clin. Invest.

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“…Partial displacement of radioactivity by one agent did not preclude subsequent additional displacement of radioactivity with either the same or another agent; for example (Subject M.O., Table I and Figure 3), 30 mg of unlabeled pteroylglutamate displaced 5.8% of retained 7 radioactivity 22 days after the initial dose and a further 7 Retained dose was calculated by subtracting the cumulative urinary excretion of radioactivity from the initial dose; if excretion of small amounts of radioactivity took place by additional routes (e.g., the bile), the actual retained dose would be less and, thus, values for percentage of displacement greater than indicated. * Duration of the displacement effect was taken as the period from the administration of the flushing dose to the time when the rate of urinary excretion of radioactivity returned to the base-line level (a period of usually slightly over 24 hours; see Figure 3).…”

Section: Resultsmentioning

confidence: 99%

Methotrexate Displacement in Man*

Johns¹,

Hollingsworth²,

Cashmore³

et al. 1964

J. Clin. Invest.

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In a number of mammalian species, including man, the 4-amino analogs of pteroylglutamate persist in liver and kidney for many months after administration (1-4). In the rat (3) and mouse (4), the binding site appears to be the enzyme dihydrofolate reductase [also termed folate reductase (5) and tetrahydrofolate dehydrogenase.1] Studies with partially purified dihydrofolate reductase obtained from several sources (6-8) have shown the affinity of this enzyme for the 4-amino analogs to be extremely high.Recent work with tritium-labeled pteroylglutamate in vivo has shown that, in man, the labeled compound can be displaced from cells several days after its administration, both by unlabeled pteroylglutamate (9, 10) and by other compounds that possess an affinity for the enzyme dihydrofolate reductase (11). If, as animal experiments suggest, the 4-amino analogs bind to the same enzyme, a similar procedure should also bring about the displacement of these compounds. The studies reported here show that, in man, tritiated methotrexate (amethopterin; 4-amino-AN10-methylpteroylglutamic acid) can be readily displaced

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“…For example, methotrexate is utilized because of its ability to inhibit dihydrofolate reductase, an enzyme that converts dihydrofolate to tetrahydrofolate, before it is converted to the folate cofactor methylene tetrahydrofolate. 119 Therefore, folic acid targeting (such as in PAMAM dendritic polymers conjugated with methotrexate) has been used to increase the concentration of free methotrexate in sensitive tumor cells. This approach allows reduction of methotrexate toxicity and improvement of methotrexate efficacy relative to the nontargeted construct.…”

Section: Exploiting Unique Cell Characteristics At the Tumor Level Fomentioning

confidence: 99%

Nanomedicine for drug targeting: strategies beyond the enhanced permeability and retention effect

Nehoff

Parayath

Domanovitch

et al. 2014

IJN

107

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The growing research interest in nanomedicine for the treatment of cancer and inflammatory-related pathologies is yielding encouraging results. Unfortunately, enthusiasm is tempered by the limited specificity of the enhanced permeability and retention effect. Factors such as lack of cellular specificity, low vascular density, and early release of active agents prior to reaching their target contribute to the limitations of the enhanced permeability and retention effect. However, improved nanomedicine designs are creating opportunities to overcome these problems. In this review, we present examples of the advances made in this field and endeavor to highlight the potential of these emerging technologies to improve targeting of nanomedicine to specific pathological cells and tissues.

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Inhibition of Dihydrofolic Reductase by Aminopterin and Amethopterin.

Cited by 187 publications

References 0 publications

Defective DNA synthesis in human megaloblastic bone marrow: effects of homocysteine and methionine

Defective DNA synthesis in human megaloblastic bone marrow: effects of homocysteine and methionine

Methotrexate Displacement in Man*

Nanomedicine for drug targeting: strategies beyond the enhanced permeability and retention effect

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