Studies Concerned with Overcoming Resistance to Methotrexate: A Comparison of the Effects of Methotrexate and 2,4-Diamino-5-(3′,4′-Dichlorophenyl)-6-Methylpyrimidine (BW50197) on the Colony Forming Ability of L5178Y Cells

Hill, Bridget T.; Goldie, James H.; Price, L A

doi:10.1038/bjc.1973.146

Cited by 23 publications

(4 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar results have been obtained by studying the effect of methodichlorophen (2,4-diamino-j- ( 3 ',q'-dichlorophenyl)d-methylpyrimidine) on the colony forming ability of Ls178Y cells, i.e. the methotrexate resistance did not greatly alter the sensitivity to the diaminopyrimidine (Hill et al, 1973) ; cross resistance would have been expected if the two agents shared the same transport system. Direct transport studies with these two diaminopyrimidines indicated competition for uptake with folinic acid but not with methotrexate (B. T. Hill, personal communication).…”

Section: Discussionsupporting

confidence: 74%

The Effect of Trimethoprim on Cellular Transport of Methotrexate and its Cytotoxicity to Human Lymphoblastoid Cells in Vitro

Niethammer

Jackson

1976

Br J Haematol

View full text Add to dashboard Cite

A study has been made of the effects of the antifolate drug trimethoprim (2,4-diamino-5-(3'4',5'-trimethoxybenzyl)pyrimidine) on the cellular transport of natural folates and of methotrexate in a human lymphoblastoid cell line grown in culture. The results indicated that cellular uptake of 5-methyltetrahydrofolate, folic acid and methotrexate could be inhibited by trimethoprim; the inhibition, for methotrexate at least, was competitive, but it was in every case rather weak. Calculations showed that under conditions used during therapy with methotrexate, trimethoprim could be employed as an antibacterial agent without the cellular uptake of methotrexate being impaired by more than 1%. The cytotoxic effect of trimethoprim against the cell line used was 2000 times less, on a molar basis, than that of methotrexate. However, the degree of growth inhibition caused by the two agents in combination was greater than the sum of the individual toxicities. Again, this effect was not large at clinically useful concentrations of trimethoprim.

show abstract

Section: Discussionsupporting

confidence: 74%

The Effect of Trimethoprim on Cellular Transport of Methotrexate and its Cytotoxicity to Human Lymphoblastoid Cells in Vitro

Niethammer

Jackson

1976

Br J Haematol

View full text Add to dashboard Cite

show abstract

“…Hill et al [8] demonstrated the toxicity of DDMP in a MTX-resistant L5178Y cell line. Rosowsky et al [17] showed that a MTX transportresistant cell line was still sensitive to MTX esters as well as lipophilic antifolates such as DDMP.…”

Section: Discussionmentioning

confidence: 99%

“…drug uptake, and DHFR activity indicate a correlation between drug sensitivity and levels of bound drug [1][2][3][4]. However, resistance to MTX is also related to the amount of DHFR and its inhibition, in cells where MTX transport is unchanged [5][6][7] studies suggested that lipid-soluble antifolates may be useful in overcoming resistance to MTX due to inabil ity of cells to take up MTX [8,9]. New antifolate compounds, particularly the lipid-soluble analogs, are being extensively studied for use against MTXresistant cells because of their different pharmacologi cal and physicochemical properties relative to MTX [10][11][12][13].…”

mentioning

confidence: 99%

Inhibition of Dihydrofolate Reductase and Cell Growth by Antifolates in a Methotrexate-Resistant Cell Line

Hamrell¹

1984

Oncology

View full text Add to dashboard Cite

The structural features and lipid solubility of four different classes of antifolate compounds were compared for their inhibition of dihydrofolate reductase (DHFR) and growth in a normal and methotrexate (MTX)-resistant 3T6 mouse cell line. All of the compounds have been shown previously to have antifolate activity. The resistant cell line has a 7-fold increase in DHFR activity with normal transport, but an altered affinity for MTX. All the antifolates were equally effective in inhibiting DHFR and growth in the parent cell line. Inhibition of partially purified DHFR from the resistant cells increased with changes in lipid solubility and structure of the compounds, compared to the parent DHFR. These data demonstrate that the resistant cells may be more sensitive to the structurally dissimilar antifolates than to MTX and lend importance to further development of this type of antifolate. These results suggest that these compunds may be useful in circumventing antifolate resistance due to alterations in target enzyme concentration and drug-enzyme affinity, as well as drug transport.

show abstract

“…Lipid-soluble antifolates could help overcome MTX resistance caused by cells' inability to absorb the drug (Hill et al 1973;Nichol 1968). Because of their distinct pharmacological and physicochemical properties compared to MTX, new antifolate compounds are being investigated for use against MTX-resistant cells (Burchenal et al 1952;Mishra et al 1973;Ho et al 1972;Nichol et al 1977).…”

Section: Introductionmentioning

confidence: 99%

Prospect into therapeutic potentials of Moringa oleifera phytocompounds against cancer upsurge: de novo synthesis of test compounds, molecular docking, and ADMET studies

et al. 2021

View full text Add to dashboard Cite

Background Cancer chemotherapy is difficult because current medications for the treatment of cancer have been linked to a slew of side effects; as a result, researchers are tasked with developing greener cancer chemotherapies. Moringa oleifera has been reported with several bioactive compounds which confirm its application for various ailments by traditional practitioners. In this study, we aim to prospect the therapeutic potentials of M. oleifera phytocompounds against cancer proliferation as a step towards drug discovery using a computational approach. Target proteins: dihydrofolate reductase (DHFR) and B-Cell Lymphoid-2 (BCL-2), were retrieved from the RCSB PDB web server. Sixteen and five phytocompounds previously reported in M. oleifera leaves (ML) and seeds (MS), respectively, by gas chromatography–mass spectrometry were synthesized and used in the molecular docking study. For accurate prediction of binding sites of the target proteins; standard inhibitors, Methotrexate (MTX) for DHFR, and Venetoclax (VTC) for BCL-2, were docked together with the test compounds. We further predicted the ADMET profile of the potential inhibitors for an insight into their chance of success as candidates in drug discovery. Results Results for the binding affinities, docking poses, and the interactions showed that ML2, ML4-6, ML8-15, and MS1-5 are potential inhibitors of DHFR and BCL-2, respectively. In the ADMET profile, ML2 and ML4 showed the best drug-likeness by non-violation of Lipski Rule of Five. ML4-6, ML8, ML11, ML14-15, and MS1, MS3-5 exhibit high GI absorption; ML2, ML4-6, ML8, MS1, and MS5 are blood–brain barrier permeants. ML2, ML4, ML9, ML13, and MS2 do not interfere with any of the CYP450 isoforms. The toxicity profile showed that all the potential inhibitors are non-carcinogenic and non-hERG I (human ether-a-go-go related gene I) inhibitors. ML4, ML11, and MS4 are hepatotoxic and ML7, ML10, and MS4 are hERG II inhibitors. A plethora of insights on the toxic endpoints and lethal concentration values showed that ML5, ML13, and MS2 are comparatively less lethal than other potential inhibitors. Conclusion This study has demonstrated that M. oleifera phytocompounds are potential inhibitors of the disease proteins involved in cancer proliferation, thus, an invaluable step toward the discovery of cancer chemotherapy with lesser limitations.

show abstract

Studies Concerned with Overcoming Resistance to Methotrexate: A Comparison of the Effects of Methotrexate and 2,4-Diamino-5-(3′,4′-Dichlorophenyl)-6-Methylpyrimidine (BW50197) on the Colony Forming Ability of L5178Y Cells

Cited by 23 publications

References 12 publications

The Effect of Trimethoprim on Cellular Transport of Methotrexate and its Cytotoxicity to Human Lymphoblastoid Cells in Vitro

The Effect of Trimethoprim on Cellular Transport of Methotrexate and its Cytotoxicity to Human Lymphoblastoid Cells in Vitro

Inhibition of Dihydrofolate Reductase and Cell Growth by Antifolates in a Methotrexate-Resistant Cell Line

Prospect into therapeutic potentials of Moringa oleifera phytocompounds against cancer upsurge: de novo synthesis of test compounds, molecular docking, and ADMET studies

Contact Info

Product

Resources

About