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Stereochemical Characteristics of the Folate-Antifolate Transport Mechanism in L1210 Leukemia Cells1

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Stereochemical Characteristics of the Folate-Antifolate Transport Mechanism in L1210 Leukemia Cells1 [CANCER RESEARCH 34, 371-377, February 1974] Stereochemical Characteristics of the Folate-Antifolate Transport Mechanism in L1210 Leukemia Cells1 Francis M. Sirotnak and Ruth C. Donsbach Memorial Sloan-Kellering Cancer Center, New York. New York 10021 SUMMARY versus normal cells. This apparently occurs because of the larger potential for concentrative uptake of drug by the The rate of influx, extent of concentrative uptake, and the tumor cells after the serum concentration has fallen to a rate of efflux (loss) by active transport in L1210 leukemia low level. Although the significance of these findings to anti cells has been compared for the pteridine antifolates, amino- folate treatment of human leukemia remains to be deter pterin and methotrexate, eight related quinazoline analogs, mined, the potential for therapeutic exploitation of this and two pyrimidine derivatives. The data reveal a difference physiological site seems obvious. in the Stereochemical specificity for influx and efflux. Influx The manner by which antifolates penetrate tumor cells is preferential in the order pteridine, quinazoline, and py has been of interest to a number of workers (3, 5, 6-11, 15- rimidine. Influx of aminopterin is more rapid than that of 17, 20, 21, 23, 27, 28). There is extensive evidence (6-9, 16, methotrexate. L-Glutamylquinazolines were taken up faster 17, 20, 21, 23, 27, 28) in vitro indicating that uptake in than L-aspartylquinazolines, but influx of a D-glutamyl- L1210 cells occurs by active transport. In most other tumor quinazoline was slower than the corresponding D-aspartyl cells, uptake has been shown (3, 5, 17) to at least resemble derivative. Influx of the quinazolines was faster when there an active transport process. was a methyl- or chloro- substitution at position 5. Influx of The characteristics of uptake in L1210 cells demonstrated the pyrimidines was also faster when a methyl group was at in vitro closely approximate that seen in the animal (24, 25). position 6. Michaelis constants (Km) for influx of the various analogs varied from 1.42 x 10~6Mto over 10"4 M. Individ In another aspect of these studies, the Stereochemical re quirements of the transport mechanism in L1210 cells were ual Vmax values were essentially the same (1.87 to 2.22 examined. Measurements were made of the rate of influx nmoles/min/g dry weight). The relationship between the and extent of concentrative uptake, as well as the rate of values for initial velocity of influx (v), the Km and Vmaxob efflux (loss) of a variety of folate analogs. The results of pre tained with each analog are in agreement with that predicted liminary studies comparing aminopterin, methotrexate, and by the Michaelis-Menten equation and is consistent with the methasquin have been reported from our laboratory (23). notion that differences in rates of influx are attributable to Comparisons between methotrexate and methasquin (20) differences in the affinity of the carrier for the system. Ef and methotrexate and a pteroate analog (16) have also been flux is preferential in the order pteridine, pyrimidine, and made elsewhere. A more extensive kinetic analysis involving quinazoline. Efflux of aminopterin and methotrexate occurs a number of individual Stereochemical differences among at the same rate. Both aspartyl- and glutamylquinazolines analogs is presented here. efflux at about the same rate, but the D-aspartyl and D- glutamyl forms efflux more rapidly than the corresponding L forms. A methyl, and particularly a chloro, substitution MATERIALS AND METHODS at position 5 of the quinazoline reduces the rate of efflux. The extent of concentrative uptake observed for each analog The maintenance and transplantation of the ascitic L1210 directly reflects the relative magnitude at which the influx line (V) in vivo has been described (14). Methotrexate and and efflux processes operate and may be the physiological aminopterin were supplied by Lederle Laboratories, Pearl parameter most relevant to therapeutic efficacy. River, N. Y. The quinazoline and pyrimidine analogs were provided by Parke Davis and Co., Detroit, Mich. Amino pterin and methotrexate were purified by chromatography INTRODUCTION (22). The final purity of all drug samples was evaluated bioautographically (4). The dihydrofolate reducíasecon Recent findings (24, 25) from this laboratory attribute the tent of the LI 210 cells was determined by titration inhibition selective activity of methotrexate during therapy of the with methotrexate or methasquin (30). L1210 leukemia to a greater persistence of drug in tumor Enzyme Assay for Antifolate. The content of drug in cell- free extracts was determined by titration (30) with a par ' This work supported in part by Grant CA-08748 from the National tially purified (29) dihydrofolate reducíasefrom a high- Cancer Institute and Grant BC-108 from the American Cancer Society. level recombinant strain of Diplococcus pneumoniae (26). Received June 20, 1973; accepted November 7, 1973. The details of the routine tube assay have already been FEBRUARY 1974 371 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1974 American Association for Cancer Research. Francis M. Sirotnak and Ruth C. Donsbach described (23). All but 2 of the antifolates (see legend of the total uptake at 37°)provides a measure of drug rapidly Table 1) titrate the microbial enzyme to about 80% inhibi adsorbed on the cell surface. This is essentially a tempera tion. Both D-deazaaminopterin and D-quinaspar titrate the ture-independent process (9, 23). In agreement with the enzyme only to about 60% inhibition. However, in our ex known lipophobic character of the folate analogs, the rate perience a good level of reliability in assays for both com of passive diffusion occurring within the concentration range pounds can still be obtained by using additional sample (2.2 n\i or less) used during these studies would be ex replicates. The range for the amount of drug detectable in pected to be negligible (2, 18). This was confirmed (6) for this assay varies between 0.05 and 0.5 ng. methotrexate by an estimation made at 37°at an external Antifolate Uptake by I 1210 Cells. The harvesting of cells concentration (100 ßM)wellin excess of that necessary to has been described (23, 27). Usually 2 x IO7cells in 1 ml saturate the carrier mechanism. Similar measurements of (A6oo = 3.0) of suspending medium (pH 7.5) were incu the diffusion at 37°of methotrexate were also made in the bated with drug. The uptake of drug at 37°corrected for current study at an external concentration of 500 ¿IM.The drug associating with cells at 0°was used as a measure of rate of diffusion at 0.45 JÕM(theconcentration used in the uptake by active transport. Uptake at 0°(about 1 to 2% of rate determinations shown in Table 1) calculated from Table 1 The uptake of folate antagonists by LI210 leukemia cells Substituents of influx' ring acid (nmole/min/ Compound"AminopterinMethotrexateD-Deaza-aminopterinDeazaaminopterin5-Methyldeaza-aminopterin5-Chlorodeazaami-nopterinD-QuinasparQuinasparMethasquinChlorasquinNSCstructure"2,4-Diami-nopteridine2,4-Diaminop-teridine2.4-Diamino-quinazoline2,4-Diamino-quinazoline2,4-Diamino-quanazoline2,4-Diamino-quinazoline2.4-Diamirio-quinazoline2,4-Diamino-quinazoline2,4-Diamino-quinazoline2,4-Diamino-quinazoline2,4-Diamino-pyrimidine2,4-Diamino-pyrimidineAmino5 6 10moietyL-GlutamylCH, g drywt)0.7100.2300.0410.2080.2370.3500.1750.0470.0680.0760.00330.0047Km"(X10"M)1.424.9557.206.655.952.777.6538.3027.2023.50>100>100 L-GlutamylD-GlutamylL-GlutamylCH3 L-GlutamylCl i.-GlutamylD-AspartylL-AspartylCH3 L-AspartylCl L-Aspartyl* 110180NSC L-Aspartyl• 110191Basic CHj L-AspartylRate " Aminopterin, /V-|p-|((2,4-diamino-6-pteridinyl)methyl]amino|benzoyl|-L-glutamate; methotrexate. A'-(p-|((2,4-diamino- 6-pteridinyl)methyl]methylamino|benzoyl|-L-glutamate; D-deazaaminopterin, Ar-|p-|[(2,4-diamino-6-quinazolinyl)methyl]- amino|benzoyl|-i)-glutamate, hemihydrate; deazaaminopterin, N-\p |[(2,4-diamino-6-quinazolinyl)methyl]amino|benzoyl](- L- glutamate: 5-methyldeazaaminopterin, W-|/>-|[(2,4-diamino-5-methyl-6-quinazolinyl)methyl]amino|benzoyl|-L-glutamate, diso- dium, tetrahydrate; 5-chlorodeazaaminopterin, Ar-(/j-|[(2,4-diamino-5-chloro-6-quinazolinyl)methyl]amino|benzoyl|-L-glutamate, hemihydrate; D-quinaspar, /V-(p-{[(2,4-diamino-6-quinazolinyl)methyl]amino|benzoyl|-D-aspartate, disodium, heptahydrate; quinaspar, /V-|/7-|[(2,4-diamino-6-quinazolinyl)methyl]amino|benzoyl|-L-aspartate; methasquin, /V-(/>-|((2,4-diamino-5-methyl- 6-quinazolinyl)methyl]amino|genzoyl|-L-aspartate. disodium, pentahydrate; chlorasquin, /V-|p-|[(2,4-diamino-5-chloro-6-quina- zolinyl)methyl]amino|benzoyl|-L-aspartate, dihydrate; NSC 110180, Ar-(p-|(/)-(2,4-diamino-5-pyrimidinyl)benzoyl]amino|ben- zoyl|-L-aspartate; NSC 110191,/V-jp-|[p-(2,4-diamino-6-methyl-5-pyrimidinyl)benzoyl]amino|benzoyl|-L-aspartate. "p-Aminobenzoyl moiety attached at position 9 of the pteridinyl ring and benzylaminobenzoyl attached at position 5 of the pyrimidines. ' The initial rate of uptake at 37°corrected for uptake at 0°.Rate = nmoles/min/g dry weight (drug],,«,!,.]= 0.45 M.Values are an average of 4 to 6 replicate experiments, with a standard deviation of less than 30%. Each compound was always compared to methotrexate run as an internal control in the same experiment. " Michaelis constant (molar). Values are an average of 5 to 8 replicate experiments, with a standard deviation of less than 30%. Each compound was always compared to methotrexate run as an internal control in the same experiment. Precautions used in deter mining rates for true initial velocity were the same as described previously (6, 15). ' Not applicable, since this is a 5-arylpyrimidine (see above). 372 CANCER RESEARCH VOL. 34 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1974 American Association for Cancer Research. Antifolate Transport in L/210 Leukemia Cells these data was 0.00075 to 0.001 nmole/min/g dry weight. The initial rate of temperature-dependent influx of the The suspending medium consisted of 107 HIMNaCl, 5.3 various analogs, at a concentration of 0.45 ¿tM,isshown in mM KC1, 26.2 mM NaHCO3, 1.9 mM CaCl2, 1 mM Table 1.
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