Identification and characterization of a mutation in the dihydrofolate reductase gene from the methotrexate-resistant Chinese hamster ovary cell line Pro-3 MtxRIII.

Dicker, Adam P.; Volkenandt, Matthias; Schweitzer, Barry; Banerjee, D.; Bertino, Joseph R.

doi:10.1016/s0021-9258(19)39074-x

Cited by 45 publications

(12 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In general, acquirement of MTX resistance is known to be related to the following: 1) decreased MTX transport attributed by the absence or defects of RFC; 15,16 2) loss of MTX polyglutamation activity through decreased FPGS expression; 17,18 3) increased levels of DHFR resulting from gene amplification 15,19,20 or DHFR mutation resulting in reduced affinity for MTX. [21][22][23] In this study, we employed LDH intercalatively encapsulated with MTX (MTX-LDH nanohybrid) to overcome MTX resistance and to enhance drug efficacy in DHFR-overexpressing human osteosarcoma (HOS) cells (Scheme 1). The mechanism of action as to whether the hybrid system could bypass the drug resistance and enhance the anticancer activity has been systematically investigated.…”

Section: Introductionmentioning

confidence: 99%

Anticancer drug encapsulated in inorganic lattice can overcome drug resistance

Choi

et al. 2010

J. Mater. Chem.

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

Anticancer drug encapsulated in inorganic lattice can overcome drug resistance

Choi

et al. 2010

J. Mater. Chem.

View full text Add to dashboard Cite

“…However, the ineffectiveness of MTX has been often reported for patients with certain cancers, due to the multidrug resistance as well documented (Gottesman, 2020). In general, the MTX resistance is partly related with a reduced MTX transfer because of defects of RFC (Frei 3rd et al, 1984;Jansen et al, 1998); and/or decreased activity of MTX polyglutamation because of reduced FPGS expression (Cowan & Jolivet, 1984;Roy, Egan, Sirlin, & Sirotnak, 1997); and/or enhanced levels of DHFR because of the gene amplification (Alt, Kellems, Bertino, & Schimke, 1978;Frei 3rd et al, 1984;Schimke, 1984) or DHFR mutation giving rise to the reduced affinity for MTX (Dicker, Volkenandt, Schweitzer, Banerjee, & Bertino, 1990;Srimatkandada, Schweitzer, Moroson, Dube, & Bertino, 1989;Yu & Melera, 1993). As can be seen in Figure 3, how the intact MTX or the MTX-LDH nanohybrid could influence on the suppression of tumor cell growth were studied in MTX sensitive HOS cells and MTX resistant HOS cells, respectively, on the basis of MTT assay.…”

Section: Bypassing Drug Resistancementioning

confidence: 99%

Recent progress in layered double hydroxides as a cancer theranostic nanoplatform

Choi

2020

WIREs Nanomed Nanobiotechnol

View full text Add to dashboard Cite

Layered double hydroxide (LDH) has been a big challenge in exploring new hybrid materials by intercalating inorganic, organic, or bio molecules into their lamellar lattice, those which often showed dual functions from each other or new mutative properties. Recently, nano‐bio convergence technology becomes one of the most extensively studied research fields in the view point of developing advanced drugs and diagnostic agents to fight against disease and eventually to improve the lives of human beings. Therefore, LDH as one of the nanomaterials have been intensively investigated not only as biocompatible drug delivery vehicle for cancer chemotherapy but also as diagnostic and imaging agents. In the present review, we have attempted to summarize theranostic functions of drug‐LDH hybrid nanoparticles including their synthetic methods, physico‐chemical and biological properties, and their unique mechanism overcoming drug resistance, and targeting properties based on in vitro and finally in vivo results. This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > in vivo Nanodiagnostics and Imaging

show abstract

“…Inhibition constants K of compounds [5][6][7][8][9][10][11] against wild-type human DHFR and the Leu22-Phe mutant were determined as previously described for the binding of MTX to site-directed Phe31-Ser and Phe34-Ser mutants of human DFHR. 22 The results are summarized in Tables 1 and 2, which also include reference data for MTX, AMT, 5,8-dideazaAMT (3), PTX, and TMQ.…”

Section: Enzyme Inhibitionmentioning

confidence: 99%

“…Although a natural Leu22 -Phe mutation in human DHFR remains to be found, such a mutation has been observed in two different Chinese hamster ovary cell lines selected for resistance to the classical antifolate methotrexate (MTX, 1; Chart 1) in two independent laboratories. 5,6 In addition to the Leu22-Phe mutation, a Leu22-Arg mutation has been reported in a murine transformed fibroblast cell line, 3T6-R400. 7 The Leu22-Phe mutant is able to reduce dihydrofolate normally, but the binding of MTX is decreased 100-fold 0022-2623/95/1838-0745$09.00/0 © 1995 American Chemical Society as a result of a sterically unfavorable interaction between the phenyl ring of the MTX and the Phe residue of the enzyme.…”

mentioning

confidence: 99%

“…To enable this prediction to be tested, we synthesized the previously unknown compound iV-[4-[[(2,4-diaminoquinazolin-5-yl)methyl]amino]benzoyl]-Lglutamic acid (5). In addition we prepared a series of 5-substituted 2,4-diaminoquinazolines (6)(7)(8)(9)(10)(11) that lack a (p-aminobenzoyl)glutamate moiety and can thus be viewed as analogues of PTX and another nonclassical antifolate, the quinazoline trimetrexate (TMQ,12). This would enable the effect of moving the side chain from the 6-to the 5-position in nonclassical as well as classical antifolates to be compared and would constitute a rare, if not the first, example of a "designer antifolate" targeted to a site-directed mutant of human DHFR.…”

mentioning

confidence: 99%

See 1 more Smart Citation

2,4-Diamino-5-substituted-quinazolines as Inhibitors of a Human Dihydrofolate Reductase with a Site-Directed Mutation at Position 22 and of the Dihydrofolate Reductases from Pneumocystis carinii and Toxoplasma gondii

Rosowsky¹,

Mota²,

Queener³

et al. 1995

J. Med. Chem.

View full text Add to dashboard Cite

2,4-Diaminoquinazoline antifolates with a lipophilic side chain at the 5-position, and in one case with a classical (p-aminobenzoyl)-L-glutamate side chain, were synthesized as potentially selective inhibitors of a site-directed mutant of human dihydrofolate reductase (DHFR) containing phenylalanine instead of leucine at position 22. This mutant enzyme is approximately 100-fold more resistant than native enzyme to the classical antifolate methotrexate (MTX), yet shows minimal cross resistance to the nonclassical antifolates piritrexim (PTX) and trimetrexate (TMQ). Although they were much less potent than trimetrexate and piritrexim, the lipophilic 5-substituted analogues were all found to bind approximately 10 times better to the mutant DHFR than to the wild-type enzyme. The potency of the analogue with a classical (p-aminobenzoyl)-L-glutamate side chain was similarly diminished in comparison with MTX, but the difference in its binding affinity to the two DHFR species was only 5-fold. Thus, by making subtle structural changes in the antifolate molecule, it may be possible to attack resistance due to mutational alterations in the active site of the target enzyme. Also, to test the hypothesis that DHFR from Pneumocystis carinii and Toxoplasma gondii may have a less sterically restrictive active site than the enzyme from mammalian cells, inhibition assays using several of the lipophilic analogues in the series were carried out against the P. carinii and T. gondii reductases in comparison with the enzyme from rat liver. In contrast to their preferential binding to mutant versus wild-type human DHFR, binding of these analogues to the P. carinii and T. gondii enzymes was weaker than binding to rat enzyme. It thus appears that, if the active site of the DHFR from these parasites is less sterically restrictive than the active site of the mammalian enzyme, this difference cannot be successfully exploited by moving the side chain from the 6-position to the 5-position.

show abstract

Identification and characterization of a mutation in the dihydrofolate reductase gene from the methotrexate-resistant Chinese hamster ovary cell line Pro-3 MtxRIII.

Cited by 45 publications

References 33 publications

Anticancer drug encapsulated in inorganic lattice can overcome drug resistance

Anticancer drug encapsulated in inorganic lattice can overcome drug resistance

Recent progress in layered double hydroxides as a cancer theranostic nanoplatform

2,4-Diamino-5-substituted-quinazolines as Inhibitors of a Human Dihydrofolate Reductase with a Site-Directed Mutation at Position 22 and of the Dihydrofolate Reductases from Pneumocystis carinii and Toxoplasma gondii

Contact Info

Product

Resources

About