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Results for “FOLIC ACID ANTAGONISTS”

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At least 775 records · Page 43Linked to original sources
PubMed1996

Methotrexate resistance of mouse dihydrofolate reductase: effect of substitution of phenylalanine-31 by serine or tryptophan.

Steady state and preliminary pre steady state studies of the mouse DHFR indicate that the wild-type enzyme used for our mutagenic studies follows a significantly different in vitro kinetic pathway than previously reported. In particular, turnover does not appear to be governed by H4F release from the E.NADPH complex. The discrepancies in catalysis and binding behavior of the mouse DHFRs may be due to the isomeric nature of the DHFRs studied. The enhanced ability of the two mutations at position 31 to confer resistance to MTX, as expected, decreased the affinity of the enzyme for the inhibitor. A correlation between the increased size of the side chain at position 31 and decreased inhibitor affinity was observed. This findings is consistent with previous mutagenesis studies of mouse DHFR but is at odds with conclusions drawn from an analysis of the role of the position in inhibitor binding to human DHFR. It is generally agreed that a highly efficient enzyme is desired for most cellular metabolic functions; however, because substitution of position 31 with tryptophan impairs catalytic efficiency, it appears that there exists a high physiological tolerance for significantly impaired DHFR. Indeed, mice who have received transplants of bone marrow expressing the Trp-31 mutant or the severely impaired Arg-22 mutant are capable of surviving lethal doses of MTX. Nevertheless, the consequences in vivo of a reduction in the observed in vitro catalytic effectiveness of DHFR remain to be determined. Additional mutagenic studies attempting to select catalytically silent mutations that reduce inhibitor binding may further enhance the therapeutic potential of drug-resistant DHFR genes for improved folate antagonist mediated antitumor activity.

Animals↗
PubMed1984

New potential treatment modalities for disseminated prostatic cancer.

The authors consider treatments that are applicable to disseminated prostatic cancer. Several types of potential developments in systemic therapy for prostatic cancer are considered: new hormonal agents, new cytotoxic agents, modulation of the antitumor efficacy or toxicity or both of standard agents, biologic response modifiers, drug delivery systems, and systems for prediction of response.

Androgen Antagonists↗
PubMed1985

Paradoxical effect of BW 301U, a lipophilic antifolate, on methotrexate-inhibitable deoxyuridine incorporation by human hematopoietic cells.

The ability of methotrexate and BW 301U, a lipophilic folate antagonist, to inhibit tritiated deoxyuridine incorporation into acid-precipitable material by human bone marrow cells was evaluated before and after five sequential daily infusions of BW 301U. After in vivo BW 301U therapy, bone marrow cells from five of the six patients exhibited significantly reduced inhibition by 1 microM methotrexate in vitro, whereas the response to 1 microM BW 301U remained unchanged. Megaloblastic marrow morphology and decreased myeloid progenitor cloning efficiency were also observed following five daily BW 301U infusions of 21 and 71 mg/sq m, respectively. A similar reduction in the ability of methotrexate to inhibit tritiated deoxyuridine incorporation was also seen in HL-60 cells, a human acute promyelocytic leukemia cell line, after incubation in vitro with cytostatic concentrations of BW 301U for 3 days. Concomitant changes in the response to BW 301U did not occur. While it is premature to infer clinical significance from this preliminary observation of BW 301U-induced asymmetry in the response to subsequent antifolates, our results augment a growing body of evidence which suggests that lipophilic folate antagonists might be effective in the treatment of methotrexate-resistant neoplasms.

Antineoplastic Agents↗
PubMed1993

Proliferation, migration and invasion of human glioma cells exposed to antifolate drugs.

The present study describes the effects of 2 folate antagonists, methotrexate (MTX) and the lipophilic antifolate trimetrexate (TMX) on 2 permanent human glioma cell lines (GaMg and D-54Mg) grown as monolayers and as multicellular tumor spheroids. In addition, the effects of drug exposure on tumor cell invasion was studied using a three-dimensional organ co-culture system. In monolayer cultures, TMX was a more potent inhibitor of cell growth than MTX, especially towards the GaMg cell line. The 2 drugs, however, showed similar cytotoxicity as assessed by the plating efficiency assay. Reduced ability of directional migration of cells on a plastic surface was seen by either antifolate usually at concentrations to 10-fold higher than those exerting a cytotoxic effect in the plating efficiency assay. TMX was somewhat more potent than MTX as an inhibitor of spheroid growth. When tumor spheroids were exposed to MTX or TMX at concentrations that caused 65 to 70% inhibition of cell migration, there was a latent period of 4 to 5 days before inhibition of spheroid growth ensued. Invasion was investigated in a co-culture system, where tumor spheroids were confronted with fetal rat brain cell aggregates. Neither drug reduced tumor cell invasion, although histological examination revealed toxic effects both in GaMg and in D-54Mg spheroids. We conclude that spheroids from human glioma cells were less sensitive to the antifolates than monolayers. For both drugs a latency period was observed before inhibition of spheroid growth. The spheroids retained their ability to invade normal brain tissue when exposed to levels of folate antagonists inhibiting spheroid growth.

Animals↗
PubMed2004

Homocysteine: exploring its potential as a pharmacodynamic biomarker of antifolate chemotherapy.

For decades it has been well known that elevated levels of homocysteine are harmful to humans on the basis of clinical observations derived from classical model diseases, such as inherited metabolic disorders. This group of diseases includes classical homocystinuria and several other inherited diseases affecting the so-called 'transsulfuration pathways'. Homocysteine lies in a metabolic checkpoint that interconnects one-carbon-transferring reactions with metabolism of sulfur-containing amino acids, since every molecule of 5-methyltetrahydrofolate derived either from plasma or generated from other folate species must be demethylated to liberate the reduced tetrahydrofolate. This unidirectional mechanism operates in every cell and has no alternative in eukaryotic cells. Antifolates are a group of anticancer agents targeting various metabolic steps within folate metabolism. They exert an indirect influence on the rate of appearance/disappearance of homocysteine from cellular and plasma compartments. Recently, it has been postulated that homocysteine may be a marker of the 'pharmacodynamic effect' of methotrexate, but studies attesting to this role are only now emerging. Here, we explore the genetic disease of folate and homocysteine metabolism and discuss the links between these model disorders with pharmacology and pharmacogenetics of folate antagonists used in the clinic. We outline possible ways of how homocysteine may be used as a biomarker of antifolate therapy.

Animals↗
PubMed2005

The human multidrug resistance protein MRP5 transports folates and can mediate cellular resistance against antifolates.

Members of the multidrug resistance protein family, notably MRP1-4/ABCC1-4, and the breast cancer resistance protein BCRP/ABCG2 have been recognized as cellular exporters for the folate antagonist methotrexate (MTX). Here we show that MRP5/ABCC5 is also an antifolate and folate exporter based on the following evidence: (a) Using membrane vesicles from HEK293 cells, we show that MRP5 transports both MTX (KM = 1.3 mmol/L and VMAX = 780 pmol per mg protein per minute) and folic acid (KM = 1.0 mmol/L and VMAX = 875 pmol per mg protein per minute). MRP5 also transports MTX-glu2 (KM = 0.7 mmol/L and VMAX = 450 pmol per mg protein per minute) but not MTX-glu3. (b) Both accumulation of total [3H]MTX and of MTX polyglutamates were significantly reduced in MRP5 overexpressing cells. (c) Cell growth inhibition studies with MRP5 transfected HEK293 cells showed that MRP5 conferred high-level resistance (>160-fold) against the antifolates MTX, GW1843, and ZD1694 (raltitrexed) in short-term (4 hours) incubations with high drug concentrations; this resistance was proportional to the MRP5 level. (d) MRP5-mediated resistance (8.5- and 2.1-fold) was also found in standard long-term incubations (72 hours) at low concentrations of ZD1694 and GW1843. These results show the potential of MRP5 to mediate transport of (anti)folates and contribute to resistance against antifolate drugs.

Biological Transport↗