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dc.contributor.authorTheti, DS
dc.contributor.authorJackman, AL
dc.identifier.citationCLINICAL CANCER RESEARCH, 2004, 10 pp. 1080 - 1089
dc.description.abstractPurpose: Raltitrexed, pemetrexed, lometrexol, and ZD9331 are antifolate drugs transported into cells via the ubiquitously expressed reduced-folate carrier. They display also high affinity for the alpha-folate receptor (alpha-FR), a low capacity folate transporter that is highly overexpressed in some epithelial tumors. The role of alpha-FR in the activity of the antifolates has been evaluated in two alpha-FR-overexpressing cell lines grown in a physiological concentration of folate (20 nM R,S-Leucovorin). Experimental Design and Results: A431-FBP cells (transfected with the alpha-FR) were 3-5-fold more sensitive to the antifolates than A431 cells. KB cells (constitutive alpha-FR overexpression) were less sensitive to the drugs when coexposed to 1 muM folic acid to competitively inhibit binding to the alpha-FR. Raltitrexed, pemetrexed, and lometrexol are polyglutamated in cells leading to drug retention, e.g., the raltitrexed 4- and 24-h IC(50)s in A431 cells were similar to0.6 and 0.008 muM, respectively, compared with 0.003 muM for 72-h continuous exposure. A431-FBP cells were similar to3-fold more sensitive to raltitrexed and pemetrexed at all exposure times. ZD9331 is not polyglutamated, and the 4- and 24-h IC50S in A431 cells were >100 and similar to100 muM, respectively, reducing to 2 and 0.1 muM, respectively, in A431-FBP cells. The ZD9331 4-and 24-h IC(50)s in KB cells were 20 and I muM, respectively, and reversible by coaddition of 1 muM folic acid. An in situ thymidylate synthase assay demonstrated continued thymidylate synthase inhibition after ZD9331-treated A431-FBP and KB, but not A431, cells were placed in drug-free medium for 16 h. A model is proposed in which the antifolates accumulate in the alpha-FR/endosomal apparatus, leading to slow release into the cytoplasm. In particular, this leads to cellular retention of the nonpolyglutamatable ZD9331. Conclusions: Antifolate drugs, particularly ZD9331, have the potential for increased efficacy in tumors that highly overexpress the alpha-FR.
dc.format.extent1080 - 1089
dc.titleThe role of alpha-folate receptor-mediated transport in the antitumor activity of antifolate drugs
dc.typeJournal Article
rioxxterms.typeJournal Article/Review
pubs.notesaffiliation: Jackman, AL (Reprint Author), Inst Canc Res, Haddow Labs, Med Sect, 15 Cotswold Rd, Sutton SM2 5NG, Surrey, England. Inst Canc Res, Haddow Labs, Med Sect, Sutton SM2 5NG, Surrey, England. Inst Canc Res, Haddow Labs, Canc Res UK, Ctr Canc Therapeut, Sutton SM2 5NG, Surrey, England. keywords-plus: THYMIDYLATE SYNTHASE INHIBITOR; L1210 LEUKEMIA-CELLS; MALIGNANT PLEURAL MESOTHELIOMA; HUMAN KB-CELLS; PHASE-I TRIAL; BINDING-PROTEIN; HIGH-AFFINITY; OVARIAN-CARCINOMA; SOLID TUMORS; CARRIER research-areas: Oncology web-of-science-categories: Oncology author-email: [email protected] number-of-cited-references: 60 times-cited: 52 usage-count-last-180-days: 1 usage-count-since-2013: 4 journal-iso: Clin. Cancer Res. doc-delivery-number: 774MF unique-id: ISI:000188982700034 oa: gold_or_bronze da: 2018-09-11
pubs.notesNot known
pubs.embargo.termsNot known
dc.contributor.icrauthorJackman, Ann

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