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Results for “Folic Acid Antagonists”

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At least 19 recordsLinked to original sources
PubMed1977

Mutagenic studies of folic acid antagonists.

Compounds that compete with folic acid (folic acid antagonists [FAAs]) become limited in their usefulness in the treatment of leukemia, malaria, and bacterial infections by the rapid development of resistance. Assays of the plasma levels of certain of these FAAs led to the observation, in about 25% of the determinations, that a higher density of growth of Streptococcus faecium var. durans (ATCC 8043) was obtained at an FAA concentration just below the completely inhibitory level than at one-half this concentration. This and other considerations suggested that FAAs may act not only as selective agents for resistant organisms but also as mutagens. Seven FAAs including amethopterin, pyrimethamine, trimethoprim, chlorguanide triazine, an experimental quinazoline, WR-158,122, and two experimental triazines, WR-99,210 and WR-38,839, were tested for mutagenicity in the Salmonella reversion assay developed by Ames et al. (1975). All were found to be negative for strains TA1535, TA1537, TA1538, TA98, and TA100, both with and without microsomal activation. These compounds were then tested as mutagens for three traits in the folic acid-requiring S. faecium. FAAs were shown to cause mutations to folic acid independence, rifampin resistance, and FAA resistance. It is postulated that the FAAs induce mutations by causing thymine deprivation in the folic acid-requiring host.

Culture Media↗
PubMed1978

Effects of the teratogenic folic acid antagonist, 9-methyl pteroylglutamic acid on uronic acid levels in fetal rat limbs.

Experimental pregnant rats were placed on a transitory folic acid-deficient regimen, i.e. dietary restriction of folic acid plus the teratogen and folic acid antagonist, 9-methyl pteroylglutamic acid; a regimen resulting in multiple congenital skeletal malformations. Controls received a folic acid-supplemented regimen. Accumulation of a primary component of the extracellular matrix, glycosaminoglycans (GAG), was quantitatively evaluated by measuring uronic acid concentrations in fetal limbs. On days 16 and 18 of gestation, fetal limbs were removed, pooled from each litter, and prepared for uronic acid, protein, and DNA quantitation. The treatment results in (1) a decreased rate of protein and DNA accumulation prior to day 16 of gestation, the rate not being affected from day 16 to day 18 of gestation; (2) a trend toward an increased rate of uronic acid accumulation prior to day 16 of gestation, and (3) a decreased rate of uronic acid accumulation from day 16 to day 18 of gestation. Furthermore, our observations confirm our earlier suggestion that there is a decreased rate of accumulation of some nonprotein component(s) in fetal limbs obtained from folic acid-deficient mothers from day 16 to day 18 of gestation.

Animals↗
PubMed1978

Recognition in adult patients of malformations induced by folic-acid antagonists.

Three patients are reported, two of whom had mothers who revealed ingestion of abortifacient drugs during pregnancy. All patients resemble one another and those described earlier with malformations that were probably either aminopterin- or methotrexate-induced. It is likely that Patients I and II have abnormalities associated with the teratogenic action of these folic-acid antagonists. The etiology of Patient III's defects remains uncertain.

Abnormalities, Drug-Induced↗
PubMed1979

[Histochemical demonstration of tetrahydrofolate dehydrogenase in human bone marrow: apparent enzymatic induction after administration of folic acid antagonists].

Folate antagonists interfere to a varying extent with the histochemical demonstration of tetrahydrofolate dehydrogenase. Some aspects of this interaction are investigated in normal hemopoietic cells of patients following antitumor treatment with methotrexate. In this situation the histochemically detectable activity of tetrahydrofolate dehydrogenase exceeds the control levels (apparent enzymatic induction). A protection of the enzyme-metabolite complex from degradation and diffusion might be effective for the changes in reaction intensity.

Bone Marrow↗
PubMed1977

In vitro screening of biochemical activity of folic acid antagonists in skin.

Dihydrofolate reductase (DHFR) inhibitors, which differ from the classical folate antagonists in physicochemical and pharmacologic parameters such as lipid solubility and mechanisms of cellular transport, were screened for DHFR inhibitory activity and biologic activity in newborn rat skin. The most effective drugs from this screen were tested for their effects on de novo DNA synthesis in psoriatic epidermis in vitro. Of the 24 compounds studied, methotrexate (MTX) was the most potent inhibitor of rat skin DHFR (I50=8.6 X 10(-9) M). Methotrexate-dimethylester, methasquin-diethylester, DDEP (2,4-diamino-5-(3',4'-dichlorophenyl)-6-ethylprimidine), and Baker's triazine antifolate (NSC 139105), while less effective than MTX as DHFR inhibitors, were more effective than MTX as inhibitors of de novo DNA synthesis in rat skin in vitro. Baker's antifolate was the only compound tested which was considerably more effective than MTX as an inhibitor of de novo DNA synthesis in psoriatic epidermis in vitro.

Animals↗
PubMed1979

Folate antagonism following teratogenic exposure to diphenylhydantoin.

Previous studies have reported indirect evidence for the mediation of folate antagonism in the induction of malformations by diphenylhydantion. We have demonstrated that a teratogenic regimen of folate-deficiency and antagonism using 9-methyl PGA in the rat produces significantly decreased rates of oxygen consumption in the maldeveloping embryos. The present study reports similar reductions in oxygen uptake by mouse embryos from mothers treated with teratogenic doses of diphenylhydantoin, and documents a significant depression of the actual folate levels in such embryos. The differences are less significant with lower doses of diphenylhydantoin, and do not occur with a nonteratogenic dose.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

[Experimental study of the myelotoxic effect of tomizine].

In tests conducted on 220 rats with transplantable sarcoma M-1 and intact animals acute toxicity, antineoplastic effect and the action on the blood system of tomizine, a new neoplastic drug of the group of the folic acid antagonists, were studied. Investigation involved a single intraperitoneal injection of the drug in DL50/30 and MTD. The compound is shown to exert an inhibiting action on the development of sarcoma M-1 and lengthens the survival of the tumour-stricken animals, without producing any pronounced myelotoxic effect. The disclosed shifts on the level of the periphedal blood and marrow were short-lived and concerned mainly the erythroid germ cells.

Anemia, Aplastic↗
PubMed1976

Rapid radioimmunoassay for methotrexate in biological fluids.

We report a radioimmunoassay for the cytostatic folic acid antagonist methotrexate. Antiserum was raised in rabbits immunized with a conjugate of methotrexate and methylated bovine serum albumin. The calibration curve of the assay is linear from 1 to 100 ng methotrexate per 100-mul sample, 0.1 ng methotrexate still inhibiting the binding of the tracer by 20%. The coefficient of variation ranged from 4.04% to 11.58%. The reaction of the antiserum proved to be specific for methotrexate, as only insignificant interference could be demonstrated with folic acid, folinic acid (leucovorin), or tetrahydrofolic acid. With the method, results are available about 20 h after blood sampling at a daily capacity of at least 48 samples (i.e., about 15 determinations), depending on the equipment. Concentrations of methotrexate in plasma and erythrocytes were determined in five patients who were on continuous treatment with the drug. In one patient the concentration/time curves were followed in plasma and erythrocytes by frequent determinations for 24 h after a parenteral dose. The results indicate that the procedure is well suited for clinical investigations.

Adult↗
PubMed1979

Effect of liposome-entrapped methotrexate on Ehrlich ascites tumor cells and uptake in primary liver cell tumor.

A therapeutically useful concentration (0,5 mg/ml) of Methotrexate was prepared in negatively charged artificial liposomes (lecithine: cholesterol: dicetylphosphate=5:5:1 molar ratios). Entrapment yield after separation on Sepharose 6B is nearly 100%. In contrast to free Methotrexate the liposome entrapped folic acid antagonist is eliminated only slowly by the kidneys and after intravenous application it is unevenly distributed in the body of mice, the highest concentrations being found in liver and spleen. Daily injections (7.5 mg/kg/day) of entrapped Methotrexate for 5 days into the tail vein of Ehrlich ascites tumor bearing mice reduced both tumor cell count and the production of ascites fluid about fourfold as compared to mice receiving the same dose of Methotrexate in the free form. Six hours after intravenous application of liposome entrapped Methotrexate the tissue concentration in normal liver is ca. 20-fold higher than when the same amount is applied in the free state. On the other hand, only a little uptake of liposome entrapped Methotrexate was detected in the tissue of nitrosamine-induced primary liver tumor when compared to normal liver tissue of rats.

Animals↗
PubMed1978

Role of carbon dioxide in germination of spores of Streptomyces viridochromogenes.

CO2 is required continuously during germination of Streptomyces viridochromogenes spores. Spores incubated in a defined germination medium in the absence of CO2 remain phase bright and do not release spore carbon. In the presence of CO2, the spores initiate germination accompanied by loss of refractility and spore carbon. The CO2 requirement is replaced by oxaloacetate or a mixture of tricarboxylic acid cycle (TCA) intermediates. Labeled CO2 is taken up by germinating spores, and is incorporated into protein and RNA. TCA cycle intermediates and related amino acids contain most of the acid-soluble label following short term exposures of germinating spores to 14CO2. TCA cycle inhibitors repress germination and 14CO2 uptake whereas folic acid antagonists do not. The results indicate that CO2 is incorporated into oxaloacetate which is converted to biosynthetic intermediates required for germination. Operation of the TCA cycle appears to be essential for spore germination. The conclusion is reached that CO2 is required during germination in order to maintain the cycle by an anaplerotic reaction.

Adenosine↗
PubMed1976

Cytokinetics and chemotherapy of psoriasis.

The successful treatment of psoriasis with folic acid antagonists during the past 25 years has led to extensive research in the areas of cytokinetics and chemotherapy. In this paper we shall review selected aspects of these topics relevant to the treatment of psoriasis. The effectiveness of methotrexate treatment of psoriasis can be related to both the hyperproliferative cytokinetics of psoriasis and an increased biochemical sensitivity of psoriatic epidermal cells to this drug. Future research goals in chemotherapy of psoriasis include (a) optimizing drug schedules for available drugs; (b) identifying other susceptible biochemical points of selective drug attack; (c) identifying secondary advantages in order to facilitate selective drug action in psoriasis, such as ultraviolet light therapy in combination with a systemic drug; and (d) developing topically effective chemotherapeutic agents. Approaches to research on topical therapy are reviewed with specific reference to animal testing models for psoriasis and percutaneous penetration of topically applied agents.

Administration, Topical↗