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Drug-Induced Stimulation of Nitrogen Mustard and Choline Transport and Other Systems in L5178Y Lymphoblasts in Vitro1

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Drug-Induced Stimulation of Nitrogen Mustard and Choline Transport and Other Systems in L5178Y Lymphoblasts in Vitro1 [CANCER RESEARCH 34, 2511-2516, October 1974] Drug-induced Stimulation of Nitrogen Mustard and Choline Transport and Other Systems in L5178Y Lymphoblasts in Vitro1 Gerald J. Goldenberg2 Department of Medicine, University of Manitoba, and The Manitoba Institute of Cell Biology, Winnipeg, Manitoba, Canada, R3K 0 V9 SUMMARY being more active in rapidly dividing cells (8). As an investigation of other factors that might regulate or influence The effect of 5 drugs on the transport of several substrates, transport activity, the effect of several drugs on the transport including the chemotherapeutic agent nitrogen mustard; of choline, HN2-OH, and other substrates by L5178Y cells was choline; two nonmetabolizable amino acids, a-aminoisobutyric undertaken. acid and cycloleucine; the glucose analog, 3-0-methyl-D- glucose; and the heme precursor, 6-aminolevulinic acid; was undertaken in L5178Y murine lymphoblasts in vitro. Trans port of both hydrolyzed nitrogen mustard and choline was MATERIALS AND METHODS stimulated by 50 /iM atropine, morphine, and cocaine and, in Transport studies were performed on suspension cultures of each instance, the results were highly significant (p < 0.001). L5178Y lymphoblasts incubated in vitro at 37°as described Conversely, diazepam and phénobarbital had no effect. A previously (9, 10). Choline-l,2-14C chloride, specific activity, kinetic analysis of choline transport in the presence of 6.2 mCi/mmole; 3-0-methyl-D-glucose-methyl-14C, specific atropine, morphine, and cocaine revealed primarily an increase in Vmax and, to a lesser extent, an increase in Km. activity, 53.5 mCi/mmole; AIB, specific activity, 9.79 a-Aminoisobutyric acid transport was significantly stimu mCi/mmole; 1-aminocyclopentane-l-carboxylic acid-carboxyl- I4C (cycloleucine), specific activity, 8.9 mCi/mmole; and lated (p < 0.01) by cocaine, atropine, and diazepam, but not by morphine or phénobarbital. Transport of the other amino ALA, specific activity, 26.2 mCi/mmole, were obtained from New England Nuclear, Boston Mass. HN2-(2-chloroethyl-l ,2- acid, cycloleucine, was stimulated by all 5 drugs, with a 14C), specific activity, 3.1 mCi/mmole, was obtained from maximal effect being obtained with diazepam. Transport of the sugar 3-O-methyl-D-glucose was also Mallinckrodt Chemical Works, St. Louis, Mo.; the hydrolyzed derivative HN2-OH was prepared by alkaline hydrolysis of the stimulated by all 5 drugs; however, the findings differed from parent compound in 0.1 N NaOH at 60°for 2 hr and was those noted for cycloleucine in that maximal stimulation was observed with cocaine and atropine. Conversely, none of the preferred to HN2, in that transport could be studied without drugs in this study stimulated 6-aminolevulinic acid transport. the complication of alkylation reactions (9,10). The evidence suggests that drug interactions leading to Previous studies of choline and HN2-OH transport by stimulation of transport systems appear to be complex and, L5178Y lymphoblasts and normal and leukemic human from this initial study, no predictable patterns of stimulation lymphoid cells indicated that uptake was linear for at least 60 may yet be formulated. min (10, 14). A time course of AIB, cycloleucine, and 3-O-methyl-D-glucose uptake by L5178Y lymphoblasts was much more rapid approximating linear conditions for 1 min INTRODUCTION thereafter promptly reaching a plateau; a time course of ALA transport was somewhat intermediate in that uptake was linear Active transport of the alkylating agent HN23 on the for approximately 20 min (Chart 1). On the basis of these transport carrier for choline has been described previously in findings, incubation times were set at 60 min for all L5178Y murine lymphoblasts (9) and in normal and leukemic subsequent studies with choline and HN2-OH as substrate, 10 human lymphoid cells (14). Activity of this transport system min for ALA, and 30 sec each for AIB, cycloleucine, and appears to be dependent upon proliferative rate, transport 3-0-methyl-D-glucose, in order to approximate initial uptake velocity conditions. 1This work was supported by a grant from the National Cancer Unless otherwise indicated, as in a few experiments, drug Institute of Canada. and substrate were added simultaneously to the cell cultures. 'Clinical Research Associate of the National Cancer Institute of Uptake, expressed as the cell/medium distribution ratio of Canada. 3The abbreviations used are: HN2, nitrogen mustard; HN2-OH, substrate, was determined simultaneously in the absence and hydrolyzed nitrogen mustard; AIB, a-aminoisobutyric acid; ALA, presence of drug, by methods described previously (9, 10, 14). 6-aminolevulinic acid-5-14C hydrochloride. Incubations were terminated by rapid chilling to 4°and by Received April 11, 1974; accepted June 20, 1974. centrifugation of the cells through a layer of 0.25 M sucrose to OCTOBER 1974 2511 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1974 American Association for Cancer Research. G. J. Goldenberg io proceeded uphill against a concentration gradient; the cell/me dium ratio (mean ±S.D.) for choline transport was 68.5 ±9.3 and that for HN2-OH transport was 42.8 ±5.7(Table 1). The transport of both choline and HN2-OH was stimulated by atropine, morphine, and cocaine and, for each drug, the increment in uptake over that observed in stimultaneous untreated controls was highly significant (p < 0.001). However, diazepam and phénobarbital had no effect on < uè choline or HN2-OH transport. The more pronounced stimula O li" tion of choline transport relative to that of HN2-OH may be related to the fact that choline is the native and preferred S 1.0 transport substrate (9). Each kinetic analysis of choline transport in the presence 0.5 and absence of atropine obeyed simple Michaelis-Menten kinetics. In a summary of 5 experiments, the linear regression •¿â€¢¿â€¢¿ 20 40 60 20 40 60 equation of the control Lineweaver-Burk plot was y = 0.812 lA- + 0.3024 with a correlation coefficient of 0.9421, TIME (MIN) and in that with atropine present, was y = 0.5891 A"+ 0.1955 Chart 1. Time course of the uptake of AIE-' 4C (A), cycloeucine-1 *C (B), 3-O-methyl-D-glucose-14C (O, and ALA-14 C CD), each at a with a correlation coefficient of 0.9352. A t test comparing concentration of 100 MM,by L5178Y lymphoblasts in vitro at 37°(o) the significance of the differences of slopes was statistically and at 4°(•).Uptake is expressed as cell/medium distribution ratio, as significant (p< 0.01). described in the text and previously (9, 10, 14). Similar findings were obtained with morphine and cocaine, and a summary of kinetic parameters for all 3 drugs showed remove extracellular radioactivity. The washed cells were that stimulation was associated primarily with an increase in solubilized in 0.5 N NaOH, and radioactivity was determined Vmax and, to a lesser extent, an elevation of Km (Table 2). In by liquid scintillation spectrometry. Cell size was determined 5 experiments with atropine, the increase in Vmax for choline in a Coulter Model B electronic particle counter calibrated transport was 56% and the difference was highly significant (p with giant ragweed pollen (mean cell diameter, 19.5 jum) and < 0.001); in single experiments with morphine and cocaine as paper mulberry spores (mean cell diameter, 12.5 pm), both of stimulants, the increase in Vmax was 60 and 54%, respectively. which were obtained from Coulter Diagnostics, Inc. (Miami In the presence of atropine, the increase in Km for choline Springs, Fla.). Cell/medium distribution ratios were based on transport was 13%, and this difference was statistically significant (p < 0.05). In single kinetic experiments with the radioactivity calculated per cell volume relative to that of an equivalent volume of extracellular medium. morphine and cocaine, the increase in Km was 36 and 25%, respectively. In kinetic studies of choline transport, the kinetic param The inability of diazepam and phénobarbital to stimulate eters Km and Vmax were derived from linear regression choline and HN2-OH transport suggested that stimulation of equations of Lineweaver-Burk plots in which the slope represents Km/Vmax; the y intercept is l/Vmax, and the x intercept is -l/Km (9,10). -150CONTROLO RESULTS Experiments examining the interplay of the drugs, atropine, 100Ujal3£ morphine, and cocaine, each at a concentration range of 5 to 500 MM,and the transport substrate choline at a concentration of 10 juM>yielded a series of bell-shaped dose-response curves with a maximal stimulatory effect obtained at a drug concentration of 50 /LtM,as illustrated by a typical study with 50_JODCui-•Õ-[il[i[i•Õ- atropine and choline (Chart 2). The interaction of phéno barbital at a dose range of 5 to 500 pM and diazepam at a concentration of 1 to 100 pM was studied with all 6 transport substrates except HN2-OH, and a similar series of bell-shaped dose-response curves were obtained with a maximum appear 5 IO 50 100 500 ing consistently at a drug concentration of 50 nM , whenever ATROPINE stimulation of substrate uptake occurred. Accordingly, in all Chart 2. Dose-response curve of the effect of atropine on transport subsequent experiments, the dose of stimulant drug used was of 10 nM choline chloride-l,2-'4C by L5178Y lymphoblasts. Choline 50 MM. As in previous studies (9, 10), transport of choline-l,2-14C uptake in vitro is expressed as a percentage of the control cell/medium ratio observed in the absence of atropine; data represent the mean ± chloride and HN2-OH-1,2-14C by L5178Y lymphoblasts S.E. of 4 determinations at each atropine concentration. 2512 CANCER RESEARCH VOL.
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