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Multiple Membrane Transport Systems for the Uptake of Folate-Based Thymidylate Synthase Inhibitors'

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Multiple Membrane Transport Systems for the Uptake of Folate-Based Thymidylate Synthase Inhibitors' (CANCER RESEARCH 50, 7544-7548. December I. I990| Multiple Membrane Transport Systems for the Uptake of Folate-based Thymidylate Synthase Inhibitors' Gerrit Jansen,2 Jan H. Schornagel, G. Robbin Westerhof, Gert Rijksen, David R. Newell, and Ann L. Jackman Department of Internal Medicine, Oncology Unii /G. J., J. H. S.. G. K. W.¡,and Laboratory of Medical Enzymology, Department of Haematology /G. R.J, University Hospital Utrecht, P. O. Box 85500, 3508 CA Utrecht, The Netherlands; and Drug Development Section, Institute of Cancer Research, Sutton, Surrey, United Kingdom ¡D.R. N., A. L. J.J ABSTRACT inhibited MTX uptake by this carrier (5, 15). On the other hand, MTX carrier-defective mutants did not show marked /V10-Propargyl-5,8-dideazafolic acid (CB3717) and 2-desamino-2- methyl-/V"'-propargyl-5,8-dideazafolicacid (ICI-198,583) are potent fol cross-resistance to CB3717 (14-19) suggesting that other trans port route(s) may be utilized. In this study we have investigated ate-based inhibitors of thymidylate synthase. We studied the membrane the membrane transport characteristics of ['H]ICI-198,583 and transport and the growth-inhibitory effects of the two thymidylate syn thase inhibitors on human CCRF-CEM leukemia cells with different CB3717 in human CCRF-CEM leukemia cells and variants transport properties for folie acid, reduced folates, and methotrexate with different folate transport properties. These variants include (MTX). Membrane transport of |'H|ICI-198,583 can proceed via the CEM cells which either lack (20, 21) or overexpress (22) the high affinity/low capacity reduced folate carrier as supported by findings reduced folate/MTX carrier system present in control CCRF- that (a) uptake of |'H]ICI-198,583 was significantly impaired in CEM CEM cells (23-25). In addition, CEM cells were used that do cells which have a transport defect for MTX, (A) variants of CEM cells not have the reduced folate carrier but express a membrane- which overproduce the reduced folate carrier system showed a concomi tant increase in the uptake of |'H|ICI-198,583 as for |'H|MTX, (c) MTX associated FBP (21, 25). The results suggest that membrane inhibited transport of |'II|I( 1 l'),S,58i, and (</) uptake of |'II|- transport of the two folate-based TS inhibitors can proceed via ICI-198,583 was inhibited after treatment of CEM cells with an \- the reduced folate carrier system, but a preferred route of uptake hydroxysuccinimide ester of MTX, which is a potent inhibitor of MTX can be a FBP. transport. However, a membrane-associated folate-binding protein (I Ifl'I offers another route for entry of CB3717 and ICI-198,583. CEM-FBP cells MATERIALS AND METHODS that have an elevated amount of FBP and do not have a functional reduced folate carrier were 640- and 61-fold more sensitive to CB3717 and ICI- Materials. RPMI 1640, with and without folie acid, and (non)dialyzed sera were obtained from Gibco, Grand Island, NY. Folie 198,583, respectively, compared to control CEM cells expressing the acid, aminopterin, r>t.-5-formyltetrahydrofolate, r>i.-5-methyltetrahy- reduced folate/MTX carrier. This high sensitivity was related to a high drofolate, and jY-hydroxysuccinimide were purchased from Sigma affinity of the FBP for CB3717 and ICI-198,583 (Ka 2-3 nM), which is Chemical Co., St. Louis, MO. Unlabeled methotrexate was a gift from only 3-fold lower than for folie acid (A,, 1 IIM) but significantly higher Pharmachemie, Haarlem, The Netherlands. 10-Ethyl-10-deazaaminop- than for MTX (A,, 100 nM). Furthermore, after incubation of CEM-FBP cells for 24 h at 10 nM ('HjICI-198,583, the high affinity binding of the terin was a gift from Ciba Geigy, Basel, Switzerland. CB3717 and ICI- FBP for ICI-198,583 allowed a 600-fold concentrative uptake of |-'H]- 198,583 were provided by ICI-Pharmaceuticals Division, Alderley Park, Macclesfield, Cheshire, United Kingdom. ['HjFolic acid (0.5 Ci/mmol) ICI-198,583 and its conversion to polyglutamate forms. was purchased from Amersham, United Kingdom, and ['HJMTX (10- These results indicate that multiple folate transport systems may be 20 Ci/mmol) was from Moravek Biochemicals, Brea, CA. Radiolabels involved in the uptake of folate-based thymidylate synthase inhibitors. were purified prior to use as described previously (21, 23, 26). ['HjICl- 198,583 (25.6 Ci/mmol) was prepared as the diethyl ester as a custom INTRODUCTION synthesis by Amersham, United Kingdom, and provided in solution at a radiochemical concentration of 1 mCi/ml in ethanohwater (50:50, v/ TS1 (EC 2.1.1.45), one of the key enzymes in folate metabo v). The stock solution was stored at -20°C prior to use. The diethyl lism, is a recognized target of cytotoxic antifolates (1-4). Two ester of [5H]ICI-198,583 was hydrolyzed as required as follows. To 2 of these folate-based TS inhibitors, the quinazoline folate ana ml of the ethanolic solution of ['HJIC1-198,583 was added 0.08 ml of logues CB3717 and ICI-198,583, have activity in the preclinical l M NaOH following which the solution was allowed to stand in the (CB3717, ICI-198,583) and clinical (CB3717) settings (5-14). dark at room temperature for 4 h. Acetic acid (0.16 ml, 1 M) was then added and the solution was concentrated by blowing with nitrogen at A question still unanswered is whether membrane transport 30-40°C.The concentrated solution of ['HjICI-198,583 was then pu of these compounds proceeds via mechanisms similar to those rified by high performance liquid chromatography. The stationary operative for folate analogues that are inhibitors of DHFR (e.g., phase was a 15 x 0.46-cm Spherisorb C6 column and the ['H]IC1- MTX). A putative role for the high affinity/low capacity re 198,583 was eluted with a linear gradient from 5:95 CH,CN:0.1 M duced folate carrier, which is shared by MTX, has been sup sodium acetate, pH 5, to 15:85 CH_,CN:0. l M sodium acetate, pH 5, ported by observations that CB3717 (and related compounds) over 20 min starting the injection of |'H]ICI-198,583 onto the column. The fractions containing |'H]ICI-198,583 were pooled and reanalyzed Received 1/30/90; accepted 9/5/90. using a separate column, containing the same stationary phase, and the The costs of publication of this article were defrayed in part by the payment above solvent system. The radiochemical purity of |'H]ICI-198,583 of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate (his fact. prepared in this manner was >99.5% and the UV and H-nuclear ' This study was supported by the Dutch Cancer Society (Grant UUKC 89- magnetic resonance spectra were consistent with the structure proposed. 06) and grants from the Cancer Research Campaign and the Medical Research NHS-MTX was synthesized as described previously (21, 23, 27). Council (o D. R. N. and A. L. J. 2To whom requests for reprints should be addressed. Cell Cultures. Human leukemic CCRF-CEM cells and MTX trans 1The abbreviations used are: TS, thymidylate synthase: MTX. mctholrexale; port-defective CEM/MTX cells (20, 21) were grown as a suspension CB3717, A"°-propargyl-5,8-dideazafolic acid: ICI-198,583,2-desamino-2-melhyl- A"°-propargyl-5.8-dideazafolic acid; 10-EdAM, 10-ethyl-IO-deazaaminopterin; culture in RPMI 1640 (with folie acid) supplemented with either 10% horse serum or fetal calf serum, 2 HIMglutamine, penicillin (100 units/ NHS-MT.X, /V-hydroxysuccinimide ester of MTX; HBSS, 4-<2-hydroxyelhyl)-l- ml), and streptomycin (100 fig/ml) at 37"C in a 5% CO2 humidified pipcrazincelhanesulfonic acid buffered saline solution; FBP. folate binding pro tein; DHFR, dihydrofolate reducíase. atmosphere. In addition, CEM/MTX cells were maintained in the 7544 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1990 American Association for Cancer Research. MEMBRANE TRANSPORT OF FOLATE-BASED TS INHIBITORS continuous presence of 1 UM MTX. Prior to growth inhibition or The clear supernatant was applied to a DE52 minicolumn to separate transport studies CEM/MTX cells were maintained for at least 4 monoglutamate from polyglutamate forms of ['HJICI-198,583 accord transfer generations in the absence of MTX. CEM-7A cells, a subline ing to methods described by McGuire et al. (32). The column was of CCRF-CEM with a 30-fold overproduction of the reduced folate/ washed with 35 ml 10 mM Tris-HCl (pH 7.5), 125 mM NaCl, and 2.5 MTX carrier (22) were grown in folate-free RPMI 1640 supplemented mM dithiothreitol. Polyglutamates were eluted with 3 ml 0.1 N HC1. with 10% dialyzed fetal calf serum, 2 mM glutamine, and antibiotics as described above, and 0.25 nM 5-formyltetrahydrofolate as the sole folate source. CEM-FBP cells, a subline of CEM/MTX (21), were grown in RESULTS folate-free RPMI 1640, 10% dialyzed horse serum, glutamine, and antibiotics as described above and 0.5-1.0 nM of either folie acid or 5- Growth Inhibition Studies. Table 1 shows the growth-inhibi formyltetrahydrofolate as the sole folate source. tory effects of MTX, CB3717, and ICI-198,583 on CEM cells Growth Inhibition Assay. Cells in the logarithmic phase of growth and three different sublines. CCRF-CEM cells were 41-fold were plated at an initial density of 7.5 x 104/ml into the individual more sensitive to ICI-198,583 than for CB3717. CEM/MTX wells of a 24-well tissue culture plate.
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