Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 6/2008

Open Access 01-11-2008 | Original Article

Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo

Authors: Robert Mauritz, Godefridus J. Peters, Ietje Kathmann, Habte Teshale, Paul Noordhuis, Elizabeth M. Comijn, Herbert M. Pinedo, Gerrit Jansen

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2008

Login to get access

Abstract

Murine L1210 leukaemia cells expressing either the reduced folate carrier (RFC) or the membrane folate receptor (MFR) were studied in vitro and in vivo to assess the dynamics of membrane transport of two categories antifolates; folate-based inhibitors of dihydrofolate reductase (methotrexate, edatrexate, aminopterin, PT523, and PT644) and thymidylate synthase (TS) [CB3717, raltitrexed, plevitrexed (BGC9331), pemetrexed and GW1843]. The potency of in situ inhibition of TS was used as an endpoint to analyze the in vitro dynamics of RFC/MFR-membrane transport of these antifolates. Both for L1210-RFC and L1210-MFR cells, the potency of in situ TS inhibition was closely correlated with increasing affinities of these transporters for the antifolates (r = 0.64, P < 0.05 and r = −0.65, P < 0.05, respectively). Within the group of antifolates for which MFR had a low binding affinity, those that had the ability to become polyglutamylated, were more potent inhibitors of TS in situ activity than non-polyglutamatable antifolates. In vivo activity of methotrexate, edatrexate, raltitrexed and pemetrexed was assessed in L1210-RFC and L1210-MFR bearing mice that were fed either a standard or a folate-deficient chow. Dietary folate depletion significantly reduced the MTD for methotrexate (sevenfold), edatrexate (sevenfold), raltitrexed (50-fold) and pemetrexed (150-fold). Based on increased life spans, antitumor effects of methotrexate and edatrexate were markedly better in L1210-RFC bearing mice on the folate-deficient chow (ILS: 455 and 544%, respectively) than on standard chow (ILS: 213 and 263%, respectively). No therapeutic effects of methotrexate and edatrexate were observed for L1210-MFR bearing mice on either chow condition, which may be consistent with the low binding affinity for MFR. Irrespective of the folate diet status, pemetrexed and raltitrexed were inactive against both L1210-RFC and L1210-MFR bearing mice, which may be due to high circulating plasma thymidine levels. Collectively, this study underscores that modulation of dietary folate status can provide a basis within which the therapeutic effect of antifolates may be further improved.
Literature
1.
Aherne GW, Brown S (1999) The role of uracil misincorporation in thymineless death. In: Jackman AL (ed) Antifolate drugs in cancer therapy. Humana Press, Totowa, pp 409–421
2.
Anderson RG, Kamen BA, Rothberg KG, Lacey SW (1992) Potocytosis: sequestration and transport of small molecules by caveolae. Science 255:410–411PubMedCrossRef
3.
Assaraf YG (2006) The role of multidrug resistance efflux transporters in antifolate resistance and folate homeostasis. Drug Resist Updat 9:227–246PubMedCrossRef
4.
5.
Belkov VM, Krynetski EY, Schuetz JD, Yanishevski Y, Masson E, Mathew S, Raimondi S, Pui CH, Relling MV, Evans WE (1999) Reduced folate carrier expression in acute lymphoblastic leukemia: a mechanism for ploidy but not lineage differences in methotrexate accumulation. Blood 93:1643–1650PubMed
6.
7.
Braakhuis BJ, Jansen G, Noordhuis P, Kegel A, Peters GJ (1993) Importance of pharmacodynamics in the in vitro antiproliferative activity of the antifolates methotrexate and 10-ethyl-10-deazaaminopterin against human head and neck squamous cell carcinoma. Biochem Pharmacol 46:2155–2161PubMedCrossRef
8.
Chu E, Callender MA, Farrell MP, Schmitz JC (2003) Thymidylate synthase inhibitors as anticancer agents: from bench to bedside. Cancer Chemother Pharmacol 52(Suppl 1):S80–S89PubMedCrossRef
9.
Cocconi G, Cunningham D, Van Cutsem E, Francois E, Gustavsson B, Van Hazel G, Kerr D, Possinger K, Hietschold SM (1998) Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group. J Clin Oncol 16:2943–2952PubMed
10.
Cole PD, Drachtman RA, Smith AK, Cate S, Larson RA, Hawkins DS, Holcenberg J, Kelly K, Kamen BA (2005) Phase II trial of oral aminopterin for adults and children with refractory acute leukemia. Clin Cancer Res 11:8089–8096PubMedCrossRef
11.
Cole PD, Zebala JA, Alcaraz MJ, Smith AK, Tan J, Kamen BA (2006) Pharmacodynamic properties of methotrexate and Aminotrexate during weekly therapy. Cancer Chemother Pharmacol 57:826–834PubMedCrossRef
12.
Corona G, Giannini F, Fabris M, Toffoli G, Boiocchi M (1998) Role of folate receptor and reduced folate carrier in the transport of 5-methyltetrahydrofolic acid in human ovarian carcinoma cells. Int J Cancer 75:125–133PubMedCrossRef
13.
Duch DS, Banks S, Dev IK, Dickerson SH, Ferone R, Heath LS, Humphreys J, Knick V, Pendergast W, Singer S (1993) Biochemical and cellular pharmacology of 1843U89, a novel benzoquinazoline inhibitor of thymidylate synthase. Cancer Res 53:810–818PubMed
14.
Elnakat H, Ratnam M (2004) Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Adv Drug Deliv Rev 56:1067–1084PubMedCrossRef
15.
Gibbs DD, Theti DS, Wood N, Green M, Raynaud F, Valenti M, Forster MD, Mitchell F, Bavetsias V, Henderson E, Jackman AL (2005) BGC 945, a novel tumor-selective thymidylate synthase inhibitor targeted to alpha-folate receptor-overexpressing tumors. Cancer Res 65:11721–11728PubMedCrossRef
16.
Hazarika M, White RM Jr, Booth BP, Wang YC, Ham DY, Liang CY, Rahman A, Gobburu JV, Li N, Sridhara R, Morse DE, Lostritto R, Garvey P, Johnson JR, Pazdur R (2005) Pemetrexed in malignant pleural mesothelioma. Clin Cancer Res 11:982–992PubMed
17.
Henderson GB, Zevely EM (1984) Transport routes utilized by L1210 cells for the influx and efflux of methotrexate. J Biol Chem 259:1526–1531PubMed
18.
Hooijberg JH, Broxterman HJ, Kool M, Assaraf YG, Peters GJ, Noordhuis P, Scheper RJ, Borst P, Pinedo HM, Jansen G (1999) Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res 59:2532–2535PubMed
19.
Jackman AL, Calvert AH (1995) Folate-based thymidylate synthase inhibitors as anticancer drugs. Ann Oncol 6:871–881PubMed
20.
Jackman AL, Judson IR (1996) The new generation of thymidylate synthase inhibitors in clinical study. Expert Opin Investig New Drugs 5:719–736CrossRef
21.
Jackman AL, Kimbell R, Aherne GW, Brunton L, Jansen G, Stephens TC, Smith MN, Wardleworth JM, Boyle FT (1997) Cellular pharmacology and in vivo activity of a new anticancer agent, ZD9331—a water-soluble, nonpolyglutamatable, quinazoline-based inhibitor of thymidylate synthase. Clin Cancer Res 3:911–921PubMed
22.
Jackman AL, Taylor GA, Calvert AH, Harrap KR (1984) Modulation of anti-metabolite effects. Effects of thymidine on the efficacy of the quinazoline-based thymidylate synthetase inhibitor, CB3717. Biochem Pharmacol 33:3269–3275PubMedCrossRef
23.
Jackman AL, Taylor GA, Gibson W, Kimbell R, Brown M, Calvert AH, Judson IR, Hughes LR (1991) ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study. Cancer Res 51:5579–5586PubMed
24.
Jackman AL, Theti DS, Gibbs DD (2004) Antifolates targeted specifically to the folate receptor. Adv Drug Deliv Rev 56:1111–1125PubMedCrossRef
25.
Jansen G (1999) Receptor- and carrier-mediated transport systems for folates and antifolates—exploitation for folate-based chemotherapy and immunotherapy. In: Jackman AL (ed) Antifolate drugs in cancer therapy. Humana Press, Totowa, pp 293–321
26.
Jansen G, Kathmann I, Rademaker BC, Braakhuis BJ, Westerhof GR, Rijksen G, Schornagel JH (1989) Expression of a folate binding protein in L1210 cells grown in low folate medium. Cancer Res 49:1959–1963PubMed
27.
Jansen G, Mauritz R, Drori S, Sprecher H, Kathmann I, Bunni M, Priest DG, Noordhuis P, Schornagel JH, Pinedo HM, Peters GJ, Assaraf YG (1998) A structurally altered human reduced folate carrier with increased folic acid transport mediates a novel mechanism of antifolate resistance. J Biol Chem 273:30189–30198PubMedCrossRef
28.
Jansen G, Westerhof GR, Kathmann I, Rademaker BC, Rijksen G, Schornagel JH (1989) Identification of a membrane-associated folate-binding protein in human leukemic CCRF-CEM cells with transport-related methotrexate resistance [published erratum appears in Cancer Res 1995 Sep 15;55(18):4203]. Cancer Res 49:2455–2459
29.
Kamen BA, Capdevila A (1986) Receptor-mediated folate accumulation is regulated by the cellular folate content. Proc Natl Acad Sci USA 83:5983–5987PubMedCrossRef
30.
Keefe DA, Capizzi RL, Rudnick SA (1982) Methotrexate cytotoxicity for L5178Y/Asn-lymphoblasts: relationship of dose and duration of exposure to tumor cell viability. Cancer Res 42:1641–1645PubMed
31.
32.
Mauritz R, Bekkenk MW, Rots MG, Pieters R, Mini E, Van Zantwijk CH, Veerman AJP, Peters GJ, Jansen G (1998) Ex vivo activity of methotrexate versus novel antifolate inhibitors of dihydrofolate reductase and thymidylate synthase against childhood leukemia cells. Clin Cancer Res 4:2399–2410PubMed
33.
McCloskey DE, McGuire JJ, Russell CA, Rowan BG, Bertino JR, Pizzorno G, Mini E (1991) Decreased folylpolyglutamate synthetase activity as a mechanism of methotrexate resistance in CCRF-CEM human leukemia sublines. J Biol Chem 266:6181–6187PubMed
34.
McGuire JJ, Hsieh P, Coward JK, Bertino JR (1980) Enzymatic synthesis of folylpolyglutamates. Characterization of the reaction and its products. J Biol Chem 255:5776–5788PubMed
35.
Mini E, Srimatkandada S, Medina WD, Moroson BA, Carman MD, Bertino JR (1985) Molecular and karyological analysis of methotrexate-resistant and -sensitive human leukemic CCRF-CEM cells. Cancer Res 45:317–324PubMed
36.
Moran RG (1999) Roles of folylpoly-gamma-glutamate synthetase in therapeutics with tetrahydrofolate antimetabolites: an overview. Semin Oncol 26:24–32PubMed
37.
Niyikiza C, Hanauske AR, Rusthoven JJ, Calvert AH, Allen R, Paoletti P, Bunn PA Jr (2002) Pemetrexed safety and dosing strategy. Semin Oncol 29:24–29PubMed
38.
Peters GJ, Jansen G (2001) Folate homeostasis and antiproliferative activity of folates and antifolates. Nutrition 17:737–738PubMedCrossRef
39.
Peters GJ, Vander Wilt CL (1995) Thymidylate synthase as a target in cancer chemotherapy. Biochem Soc Trans 23:884–888PubMed
40.
Peters GJ, Vander Wilt CL, Van Triest B, Codacci-Pisanelli G, Johnston PG, Van Groeningen CJ, Pinedo HM (1995) Thymidylate synthase and drug resistance. Eur J Cancer 31A:1299–1305PubMedCrossRef
41.
Qi H, Ratnam M (2006) Synergistic induction of folate receptor beta by all-trans retinoic acid and histone deacetylase inhibitors in acute myelogenous leukemia cells: mechanism and utility in enhancing selective growth inhibition by antifolates. Cancer Res 66:5875–5882PubMedCrossRef
42.
Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, Sandoval C, Zhao R, Akabas MH, Goldman ID (2006) Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127:917–928PubMedCrossRef
43.
Qiu A, Min SH, Jansen M, Malhotra U, Tsai E, Cabelof DC, Matherly LH, Zhao R, Akabas MH, Goldman ID (2007) Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, and response to dietary folate restriction. Am J Physiol Cell Physiol 293:C1669–C1678PubMedCrossRef
44.
Ratnam M, Marquardt H, Duhring JL, Freisheim JH (1989) Homologous membrane folate binding proteins in human placenta: cloning and sequence of a cDNA. Biochemistry 28:8249–8254PubMedCrossRef
45.
Rhee MS, Galivan J, Tyobeka EM, Sherman ML, Rosowsky A (1993) Effect of a novel antifolate, N alpha-(4-amino-4-deoxypteroyl)-N delta- hemiphthaloyl-l-ornithine (PT523), on growth of H35 rat hepatoma and HEPG2 human hepatoma cells. Adv Exp Med Biol 338:461–464PubMed
46.
Rhee MS, Galivan J, Wright JE, Rosowsky A (1994) Biochemical studies on PT523, a potent nonpolyglutamatable antifolate, in cultured cells. Mol Pharmacol 45:783–791PubMed
47.
Rijnboutt S, Jansen G, Posthuma G, Hynes JB, Schornagel JH, Strous GJ (1996) Endocytosis of GPI-linked membrane folate receptor-alpha. J Cell Biol 132:35–47PubMedCrossRef
48.
Rodenhuis S, McGuire JJ, Narayanan R, Bertino JR (1986) Development of an assay system for the detection and classification of methotrexate resistance in fresh human leukemic cells. Cancer Res 46:6513–6519PubMed
49.
Rosowsky A (1999) PT523 and other aminopterin analogs with a hemiphthaloyl-l-ornithine side chain: exceptionally tight-binding inhibitors of dihydrofolate reductase which are transported by the reduced folate carrier but cannot form polyglutamates. Curr Med Chem 6:329–352PubMed
50.
Rots MG, Pieters R, Peters GJ, Noordhuis P, Van Zantwijk CH, Henze G, Janka-Schaub GE, Veerman AJ, Jansen G (2000) Methotrexate resistance in relapsed childhood acute lymphoblastic leukaemia. Br J Haematol 109:629–634PubMedCrossRef
51.
Rumberger BG, Barrueco JR, Sirotnak FM (1990) Differing specificities for 4-aminofolate analogues of folylpolyglutamyl synthetase from tumors and proliferative intestinal epithelium of the mouse with significance for selective antitumor action. Cancer Res 50:4639–4643PubMed
52.
Salazar MD, Ratnam M (2007) The folate receptor: what does it promise in tissue-targeted therapeutics? Cancer Metastasis Rev 26:141–152PubMedCrossRef
53.
Scagliotti GV, Kortsik C, Dark GG, Price A, Manegold C, Rosell R, O’Brien M, Peterson PM, Castellano D, Selvaggi G, Novello S, Blatter J, Kayitalire L, Crino L, Paz-Ares L (2005) Pemetrexed combined with oxaliplatin or carboplatin as first-line treatment in advanced non-small cell lung cancer: a multicenter, randomized, phase II trial. Clin Cancer Res 11:690–696PubMedCrossRef
54.
Schmitz JC, Grindey GB, Schultz RM, Priest DG (1994) Impact of dietary folic acid on reduced folates in mouse plasma and tissues. Relationship to dideazatetrahydrofolate sensitivity. Biochem Pharmacol 48:319–325PubMedCrossRef
55.
Schornagel JH, Verweij J, De Mulder PH, Cognetti F, Vermorken JB, Cappelaere P, Armand JP, Wildiers J, De Graeff A, Clavel (1995) Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: a European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group study. J Clin Oncol 13:1649–1655PubMed
56.
Shih C, Chen VJ, Gossett LS, Gates SB, MacKellar WC, Habeck LL, Shackelford KA, Mendelsohn LG, Soose DJ, Patel VF, Andis SL, Bewley JR, Rayl EA, Moroson BA, Beardsley GP, Kohler W, Ratnam M, Schultz RM (1997) LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res 57:1116–1123PubMed
57.
Sirotnak FM, Schmid FA, Samuels LL, DeGraw JI (1987) 10-Ethyl-10-deaza-aminopterin: structural design and biochemical, pharmacologic, and antitumor properties. NCI Monogr 127–131
58.
Smith A, Hum MC, Winick NJ, Kamen BA (1996) A case for the use of aminopterin in treatment of patients with leukemia based on metabolic studies of blasts in vitro. Clin Cancer Res 2:69–73PubMed
59.
Spinella MJ, Brigle KE, Freemantle SJ, Sierra EE, Goldman ID (1996) Comparison of methotrexate polyglutamylation in L1210 leukemia cells when influx is mediated by the reduced folate carrier or the folate receptor. Lack of evidence for influx route-specific effects. Biochem Pharmacol 52:703–712PubMedCrossRef
60.
Spinella MJ, Brigle KE, Sierra EE, Goldman ID (1995) Distinguishing between folate receptor-alpha-mediated transport and reduced folate carrier-mediated transport in L1210 leukemia cells. J Biol Chem 270:7842–7849PubMedCrossRef
61.
Theti DS, Bavetsias V, Skelton LA, Titley J, Gibbs D, Jansen G, Jackman AL (2003) Selective delivery of CB300638, a cyclopenta[g]quinazoline-based thymidylate synthase inhibitor into human tumor cell lines overexpressing the alpha-isoform of the folate receptor. Cancer Res 63:3612–3618PubMed
62.
Van der Wilt CL, Backus HH, Smid K, Comijn L, Veerman G, Wouters D, Voorn DA, Priest DG, Bunni MA, Mitchell F, Jackman AL, Jansen G, Peters GJ (2001) Modulation of both endogenous folates and thymidine enhance the therapeutic efficacy of thymidylate synthase inhibitors. Cancer Res 61:3675–3681PubMed
63.
Walling J (2006) From methotrexate to pemetrexed and beyond. A review of the pharmacodynamic and clinical properties of antifolates. Invest New Drugs 24:37–77PubMedCrossRef
64.
Wang X, Shen F, Freisheim JH, Gentry LE, Ratnam M (1992) Differential stereospecificities and affinities of folate receptor isoforms for folate compounds and antifolates. Biochem Pharmacol 44:1898–1901PubMedCrossRef
65.
Weitman SD, Lark RH, Coney LR, Fort DW, Frasca V, Zurawski VR Jr, Kamen BA (1992) Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Res 52:3396–3401PubMed
66.
Westerhof GR, Jansen G, Van Emmerik N, Kathmann I, Rijksen G, Jackman AL, Schornagel JH (1991) Membrane transport of natural folates and antifolate compounds in murine L1210 leukemia cells: role of carrier- and receptor-mediated transport systems. Cancer Res 51:5507–5513PubMed
67.
Westerhof GR, Rijnboutt S, Schornagel JH, Pinedo HM, Peters GJ, Jansen G (1995) Functional activity of the reduced folate carrier in KB, MA104, and IGROV-I cells expressing folate-binding protein. Cancer Res 55:3795–3802PubMed
68.
Westerhof GR, Schornagel JH, Kathmann I, Jackman AL, Rosowsky A, Forsch RA, Hynes JB, Boyle FT, Peters GJ, Pinedo HM, Jansen G (1995) Carrier- and receptor-mediated transport of folate antagonists targeting folate-dependent enzymes: correlates of molecular-structure and biological activity. Mol Pharmacol 48:459–471PubMed
69.
Yalowich JC, Kalman TI (1985) Rapid determination of thymidylate synthase activity and its inhibition in intact L1210 leukemia cells in vitro. Biochem Pharmacol 34:2319–2324PubMedCrossRef
70.
Zervos PH, Allen RH, Thornton DE, Thiem PA (1997) Functional folate status as a prognostic indicator of toxicity in clinical trials of the multitargeted antifolate LY231514. Eur J Cancer 33(Suppl 18)
71.
Zhao R, Gao F, Hanscom M, Goldman ID (2004) A prominent low-pH methotrexate transport activity in human solid tumors: contribution to the preservation of methotrexate pharmacologic activity in HeLa cells lacking the reduced folate carrier. Clin Cancer Res 10:718–727PubMedCrossRef
Metadata
Title
Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo
Authors
Robert Mauritz
Godefridus J. Peters
Ietje Kathmann
Habte Teshale
Paul Noordhuis
Elizabeth M. Comijn
Herbert M. Pinedo
Gerrit Jansen
Publication date
01-11-2008
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 6/2008
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-008-0683-0

Other articles of this Issue 6/2008

Cancer Chemotherapy and Pharmacology 6/2008 Go to the issue

Clinical Trial Report

A multicenter phase II study of biweekly paclitaxel and S-1 combination chemotherapy for unresectable or recurrent gastric cancer

Original Article

BRCA1 transcriptional activity is enhanced by interactions between its AD1 domain and AhR

Obituary

Professor Lloyd R. Kelland: man of science

Original Article

Non-invasive MRI tumor imaging and synergistic anticancer effect of HSP90 inhibitor and glycolysis inhibitor in RIP1-Tag2 transgenic pancreatic tumor model

Original Article

Salvage treatment with topotecan in patients with irinotecan-refractory small cell lung cancer

Original Article

Interleukin-6 protects against paclitaxel, cisplatin and vincristine-induced neuropathies without impairing chemotherapeutic activity
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits