Role of the membrane-associated folate binding protein (folate receptor) in methotrexate transport by human KB cells

Deutsch, John C.; Elwood, Patrick C.; Portillo, R; Macey, Michelle G.; Kolhouse, J F

doi:10.1016/0003-9861(89)90446-3

Cited by 42 publications

(20 citation statements)

References 22 publications

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“…With sufficient expression of FR, even drugs such as MTX, with low affinity for these proteins relative to folic acid, can be delivered into cells at rates comparable to those mediated by RFC (Dixon et al, 1992;Spinella et al, 1995); and growth inhibition can be enhanced (Chung et al, 1993). The human KB nasopharyngeal epidermoid line with high-level expression of FR-a is highly sensitive to MTX, and transport is mediated largely by this process (Deutsch et al, 1989). On the other hand, CCRF-CEM human leukemia cells that lack RFC but have increased FR-a expression have markedly diminished transport of MTX relative to wild-type cells and are highly resistant to the drug ( Van der Veer et al, 1989).…”

Section: Folic Acid Receptor-mediated Transportmentioning

confidence: 99%

Resistance to antifolates

2003

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Section: Folic Acid Receptor-mediated Transportmentioning

confidence: 99%

Resistance to antifolates

2003

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“…8), and, to a lesser extent, antifolates such as methotrexate (9). It differs from the lowaffinity reduced folate carrier found in nearly all cells, which mediates the uptake of reduced folates at higher concentrations (10).…”

Section: Introductionmentioning

confidence: 99%

Multivitamin and Alcohol Intake and Folate Receptor α Expression in Ovarian Cancer

Kelemen¹,

Sellers

Keeney

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Folate receptor A (FRA) expression in epithelial ovarian cancer may be related to folate intake. We examined this association using multivitamin intake, a proxy for folic acid, and assessed whether the relation was modified by alcohol intake, a folate agonist. Cases (n = 148) with suspected epithelial ovarian cancer, of ages z20 years, were seen at Mayo Clinic, Minnesota, between 2000 and 2004; those with tumor specimens (n = 108) were included in analyses. Outpatient controls (n = 148) without cancer and with at least one ovary intact were matched to cases by age (within 5 years) and state of residence. Multivitamin (z4 pills/wk) and weekly alcohol (z5 drinks) intakes were assessed. Tumor specimens were analyzed immunohistochemically for FRA. Multivariable rate ratios (RR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression. In case-control analysis, the RRs of multivitamin intake with absent/weak/ moderate and strong-expressing FRA tumors were 0.30 (95% CI, 0.12-0.70) and 0.47 (95% CI, 0.24-0.91), respectively. For alcohol, the associations were 0.84 (95% CI, 0.24-2.86) and 1.65 (95% CI, 0.69-3.93), respectively. In case-case analysis, the RR associated with developing strong-expressing versus other FRA tumors was 3.13 (95% CI, 1.14-8.65) for multivitamins and 1.58 (95% CI, 0.45-5.60) for alcohol. The data did not support evidence for an interaction between multivitamin and alcohol intake with risk of developing a strong-expressing FRA tumor. The association of multivitamin intake with ovarian cancer may depend on FRA expression level. (Cancer Epidemiol Biomarkers Prev 2005;14(9):2168 -72)

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“…The 40 kd folate binding protein has a high affinity for folic acid but a low affinity for reduced folates. [3][4][5][6][7][8][9][10] The corresponding complementary DNAs (cDNAs) as well as genomic clones have been isolated from various sources, 11-19 but a detailed characterization of the transporter function is still missing.Different cDNAs and genomic clones for the reduced folate carrier, which has a high affinity for the reduced folates 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, and methotrexate, but a low affinity for folate [20][21][22][23][24] have been also isolated from different immortal cell lines 25-31 but the clones were not characterized in detail.The expression and the abundance of the two carriers varied in different tumor and normal cells. From uptake studies it became evident that, first, in some cell systems both transport systems work in tandem 32 whereas two independently operating carrier systems were also described.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Cloning and functional characterization of the bile acid-sensitive methotrexate carrier from rat liver cells

Honscha¹,

Dötsch²,

Thomsen³

et al. 2000

Hepatology

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The antifolates methotrexate and trimetrexate are potent inhibitors of the dihydrofolate reductase, an enzyme that delivers by the metabolism of folate and its reduced forms the C1-groups for the synthesis of nucleotides and amino acids. Methotrexate, which has a comparatively moderate toxicity is one of the most important clinically used chemotherapeutics for the treatment of leukemias, such as acute lymphoblastic leukemia of children. It is also used in breast cancer, squamous tumors of the head and neck, lymphomas, and choriocarcinomas. 1,2 Uptake studies of methotrexate and the natural folic acid derivatives in different tumor and normal cells have shown that at least two different carrier systems mediate the uptake of these compounds. The 40 kd folate binding protein has a high affinity for folic acid but a low affinity for reduced folates. [3][4][5][6][7][8][9][10] The corresponding complementary DNAs (cDNAs) as well as genomic clones have been isolated from various sources, 11-19 but a detailed characterization of the transporter function is still missing.Different cDNAs and genomic clones for the reduced folate carrier, which has a high affinity for the reduced folates 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, and methotrexate, but a low affinity for folate [20][21][22][23][24] have been also isolated from different immortal cell lines 25-31 but the clones were not characterized in detail.The expression and the abundance of the two carriers varied in different tumor and normal cells. From uptake studies it became evident that, first, in some cell systems both transport systems work in tandem 32 whereas two independently operating carrier systems were also described. 33,34 Second, tumor cells differ from normal cells in their transport properties. [35][36][37][38][39] Results from Chello et al. 40 showed, for example, a 30-fold higher affinity for methotrexate in the mouse leukemia cell line L1210 than in freshly isolated murine intestinal cells.Hepatocytes are exceptional with respect to folate transport. In contrast to most other cells, hepatocytes express a separate carrier system for 5-methyltetrahydrofolate, which is different from the reduced folate transporter. 41,42 We recently characterized the uptake of methotrexate into freshly isolated hepatocytes 43 and showed that this chemotherapeutic is taken up by a sodium-dependent active transport system, which is inhibited by the reduced folates, dihydrofolate, and tetrahydrofolate but not by folate itself. Moreover, substrates of two well-known organic anion transport systems in the liver, the Ntcp1 44,45 and the oatp1, 46 like the bile acids taurocholate and cholate as well as xenobiotics such as bromosulfophthalein, the loop diuretic bumetanide, and the mycotoxin ochratoxin A are potent inhibitors of the hepatocellular methotrexate carrier. Because some substrates were Abbreviations: cDNA, complementary DNA; RL-Mtx, rat liver methotrexate transporter; RACE-PCR, rapid amplification of cDNA ends polymerase chain reaction; DMEM, Dulbecco modi...

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Role of the membrane-associated folate binding protein (folate receptor) in methotrexate transport by human KB cells

Cited by 42 publications

References 22 publications

Resistance to antifolates

Resistance to antifolates

Multivitamin and Alcohol Intake and Folate Receptor α Expression in Ovarian Cancer

Cloning and functional characterization of the bile acid-sensitive methotrexate carrier from rat liver cells

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