Inhibition of Furine Nucleotide Metabolism by 6-Methylthiopurine Ribonucleoside and Structurally Related Compounds1

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[CANCER RESEARCH 33, 2867 2871, November 1973] Inhibition of Furine Nucleotide Metabolism by 6-Methylthiopurine Ribonucleoside and Structurally Related Compounds1

Geraldine D. Shantz,2 Camilla M. Smith, Lydia J. Fontanelle, Herbert K. F. Lau/ and J. Frank Henderson5

University of Alberta Cancer Research Unit (McEachern Laboratory) and Department of Biochemistry. Edmonton T6G 2E1, Alberta, Canada

SUMMARY lich ascites tumor cells has been studied. In addition, biochemical effects of a number of other methylthiopurine 6-Methylthiopurine ribonucleoside was found to inhibit derivatives and analogs are also reported. nucleotide formation from hypoxanthine and aminoimida- zole carboxamide in Ehrlich ascites tumor cells in vitro and to inhibit inosinate dehydrogenase activity in intact cells. MATERIALS AND METHODS These effects are produced at higher drug concentrations 6MeMPR-3H (2564 mCi/mmole) was purchased from than required to inhibit purine biosynthesis de novo. New England Nuclear Corp. (Dorval, Quebec, Canada), 4-Methylthio-7-|8-D-ribofuranosyl pyrrolo[2,3-i/]pyrimi- AIC-2-14C (24.2 mCi/mmole) was from Calbiochem (Los dine also inhibited nucleotide formation and inosinate Angeles, Calif.), and 6MeMPR was from Sigma Chemical dehydrogenase activity, and several other methylthio purine Co. (St. Louis, Mo.). Fischer's medium, RPMI Medium ribonucleoside analogs or derivatives also inhibited one or 1620, and fetal calf serum were obtained from Grand Island another of these processes. Biological Co. (Berkeley, Calif.). Sources of most other materials used have been reported previously (6). INTRODUCTION The following compounds were provided by the Drug Evaluation Branch, Drug Research and Development, Na Before a specific biochemical effect of a drug can be tional Cancer Institute: 9-ethyl-6-(methylthio)purine (NSC identified as its mechanism of growth inhibition, as many 14576), 6-methylthio-9-phenyl purine (NSC 26294), 6- areas of metabolism as possible should be studied in order methylthio-9-(tetrahydro-2-pyranyl)purine (NSC 33184), 2- to detect drug effects which might previously have gone amino-9-benzyl-6-(methylthio)purine (NSC 42380), 6- unrecognized. Thus the best known and most thoroughly methylthio-9-(tetrahydro-2-furyl)purine (NSC 44579), 9-(2- studied biochemical effect of 6MeMPR6 ribonucleoside is hydroxyethyl)-6-(methylthio)purine (NSC 55464), 6-meth- inhibition of PP-ribose-P amidotransferase (EC 2.4.2.14) ylthio-9-(tetrahydro-2-thienyl)purine (NSC 56937), 6-meth- (10, 14, 21), the 1st enzyme of the pathway of purine ylthio-9-^-D-xylofuranosyl purine (NSC 95103), 4-meth- biosynthesis de novo. Although evidence has been presented ylthio-l-0-n-ribofuranosyl imidazol[4,5-c]pyridine (NSC that supports the view that inhibition of this pathway is the 95965), 4-methylthio-7-/3-D-ribofuranosyl pyrrolo[2,3-pyrimidine (NSC 105826), 6-methylthio-9-(6-[3,5-dihy- few studies of possible effects of 6MeMPR on other droxy-2-hydroxymethyl]dioxane)purine (NSC 111702), pathways of purine metabolism have been conducted. The 5-bromo-4-(methylthio)-7-j8-i)-ribofuranosyl pyrrolo[2,3- report of Hill (13) that 6MeMPR inhibits the incorporation Â¿Ipyrimidine (NSC 113942), 4-methylthio-7-/3-r>-ribo- of radioactive adenine, guanine, and hypoxanthine into furanosyl pyrrolo[2,3-d]pyrimidine-5-carbonitrile (NSC nucleotides and nucleic acids in Adenocarcinoma 755 cells, 116098), 6-methylthio-7-|8-[)-ribofuranosyl purine (NSC however, suggests the need for further studies of the 122326), 7-methylthio-3-/8-D-ribofuranosyl pyrazolo[4,3- biochemical effects of this purine antimetabolite. In this i/]pyrimidine (NSC 124166), and 6-methylthio-9-(2-amino- paper the possibility that 6MeMPR affects the reactions of 2-deoxy-0-D-ribofuranosyl)punne (NSC 131605). purine ribonucleotide synthesis and interconversion in Ehr- Methods for the propagation and incubation of Ehrlich ' This work was supported by the National Cancer Institute of Canada. ascites tumor cells have been reported (6). Human leukemia "Present address: Department of Microbiology, Hershey Medical RPMI 6410 cells (obtained from Associated Biomedic Center, Hershey, Pa. 'Present address: Department of Pharmacology, Idaho State Univer Systems, Buffalo, N. Y.) were grown in RPMI Medium sity, Pocatello, Idaho. 1620 containing 10% fetal calf serum, 100 Â¿jgstreptomycin 4 Present address: Department of Biochemistry, State University of per ml, and 100 units penicillin per ml. New York, Buffalo, N. Y. Procedures for separation and measurement of radioac "To whom requests for reprints should be addressed. "The abbreviations used are: 6MeMPR, 6-methylthiopurine ribonu tivity in purine bases, ribonucleosides, and ribonucleotides cleoside: PP-ribose-P, phosphoribosyl pyrophosphate; A 1C, aminoimida- following incubation of cells with radioactive purines have zole carboxamide. RPMI, Roswell Park Memorial Institute. been described (6, 22). Results presented are measurements Received March 5, 1973; accepted July 27, 1973. of the amounts of radioactivity in each metabolite, ex-

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Table 2 pressed in nmoles/g, wet weight of cells, rather than the Effect ofbMeMPR on inosinate dehydrogenase activity total amount of each metabolite. Average values from Ehrlich ascites tumor cells were incubated as described in Table I with 50 MM hypoxanthine-14C, 50 uu adenine-"C, or 50 /Ã•M samples in 2 experiments are reported. AIC-"C.

Radioactive metabolites (nmoles/g) RESULTS Xanthosine Furine Ribonucleotide Synthesis. Table 1 shows the monophos effects of a range of concentrations of 6MeMPR on phate nucleotide synthesis from radioactive adenine, guanine, GMP + Inosine hypoxanthine, and AIC in Ehrlich ascites tumor cells 6MeMPR GDP + Xantho- + hypo- Hypo- Precursor (MM) GTP sine xanthine xanthine incubated in Fischer's medium buffered with phosphate. It t may be seen that 6MeMPR inhibited nucleotide formation HypoxanthineAdenineAIC02050100100002050[0002050100350356338282176113110997.969.819718514656.324.122.017.211.875.666.161.250.014517017625717.324.375.9123264267294352 from hypoxanthine-I4C by 37% at 1000 MMand from AIC by 32% at 100 MM.Little or no effect of 6MeMPR was observed when radioactive adenine and guanine were used as precursors. Inosinate Dehydrogenase. Measurements of radioactivity in individual metabolites suggested that 6MeMPR also inhibits one of the reactions of purine ribonucleotide interconversion, inosinate dehydrogenase (EC 1.2.1.14). Data for radioactivity in products of this reaction (Xantho- sine monophosphate + GMP + GDP + GTP and xanthosine) and products of IMP catabolism (hypoxanthine plus inosine or inosine only when hypoxanthine is used as pre cursor) are presented in Table 2. It may be seen that 6MeMPR inhibited the conversion of radioactive hypox 250 anthine, adenine, and AIC to Xanthosine monophosphate _ + GMP + GDP + GTP and to xanthosine, while causing o E an increase in the formation of hypoxanthine plus inosine or e inosine alone; concentrations of radioactive IMP were within the normal range (10 to 50 nmoles/g) under all of these conditions. The potency of 6MeMPR on inosinate I 150 dehydrogenase was greater than on total nucleotide syn Q- l/l thesis from hypoxanthine but varied with the precursor O I and medium used. No other effects of 6MeMPR on purine Q_ ribonucleotide synthesis, interconversion, and catabolism were noted. 6MeM PR-phosphate Concentration. The concentrations ee. 0. 50 of 6MeMPR required to inhibit inosinate dehydrogenase and nucleotide synthesis from hypoxanthine were higher than those required to inhibit purine biosynthesis de novo in 50 100 Table 1 Effect ofoMeMPR on purine ribonucleotide synthesis Ã³MeMPR (/Â¿M) Ehrlich ascites tumor cells, 2% by volume, were incubated with various Chart 1. 6MeMPR-phosphate synthesis. Ehrlich ascites tumor cells concentrations of 6 MeMPR for 20 min at 37Â°with shaking in 0.1 ml of were incubated as described in Table l in Krebs-Ringer medium containing Fischer's medium containing 25 m.\i phosphate and an air atmosphere. 25 mMphosphate (D), Fischer's medium containing 25 mMphosphate (A), Hypoxanthine-"C (50 MM).final concentration; adenine-"C (50 ^M); or Fischer's medium containing 15 mM sodium bicarbonate (O). After 20 guanine-"C (50 /IM): or AIC-"C (50 MM)were then added and in min, 6MeMPR-3H was added and the incubation was continued for 30 cubation continued for 60 min. min. Each figure represents the mean of separate analyses of 4 flasks in 2 Total nucleotides (nmoles/g) at 6MeMPR experiments. concentration (/Â¿M)below cells (1, 3, 7, 10, 12, 17, 18), and experiments were Precursor 20 50 100 1000 conducted to measure the intracellular concentrations of Hypoxanthine 6MeMPR-phosphate (the presumed active drug metabolite) AdenineGuanineAIC1758218119041370175921592099109817672137199610861622201519679371104in cells incubated with a range of initial extracellular concentrations of 6MeMPR. These data are shown in Chart 1. It is apparent that nucleotide formation from 6MeMPR

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Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1973 American Association for Cancer Research. 6-MeMPR was the same in all 3 media used. It was also shown that 6MeMPR-phosphate concentration is virtually constant during the periods of measurement of purine metabolism used in the previous experiments. Other Methylthio Compounds. The effects of other purine derivatives and analogs containing a methylthio group at position 6 or an equivalent position on nucleotide synthesis from hypoxanthine and on inosinate dehydrogenase were tested in attempts to establish structure activity relation ships in this system. Of the 16 such compounds listed under "Materials and Methods," 7 produced more than 10% inhibition of nucleotide formation from hypoxanthine (Table 3), and 8 produced more than 10% inhibition of inosinate dehydrogenase activity (Table 4). 4-MethyUhio-7-j8-D-ribofuranosyl Pyrrolo[2,3-d- pyrimidine. The cytotoxicity of this compound, which inhibited both nucleotide synthesis from hypoxanthine and inosinate dehydrogenase about 55% in the preceding experi HOURS ments, was tested for its cytotoxicity to cultured human Chart 2. Cytotoxicity of 4-methylthio-7-/3-t>-ribofuranosyl pyrrolo[2,3- Â¿jpyrimidine. Human leukemia RPMI 6410 cells were grown in RPMI Table 3 Medium 1620containing 10%fetal calf serum, 100>igstreptomycin per ml, Effects of meihylthio compounds on nucleolide formation from and 100 units penicillin per ml with 0(9), 1.0 (A), IO(B), and 100(O) MM hypoxanthine 4-methylthio-7-/3-D-ribofuranosyl pyrrolo[2,3-i/]pyrimidine. Ehrlich ascitcs tumor cells were incubated as described in Table I, with 100 /IMhypoxanthine-"C and I mvi test compound. leukemia RPMI 6410 cells. Chart 2 shows that a concentra tion of about 100 Â¿Â¿Mwasrequired to achieve 50% inhibition % inhibition of growth. When these cells (80,000 cells per ml) were of nucleotides incubated with 100 Â¿/Mdrugand 20 Â¿iMhypoxanthine-14C,it Compounds tested formed was found that nucleotide formation from hypoxanthine 4-Methylthio-5-carbonitrile-7-/3-n-ribofuranosyl pyr- 67.4 rolo(2,3-rf)pyrimidine was inhibited 46%, and inosinate dehydrogenase activity 4-Methylthio-7-/}-i)-ribofuranosyl pyrrolo[2,3-i/jpyri- 55.2 was inhibited 28%. midine 7-Methylthio-3-Â£f-i>-ribofuranosylpyrazolo[4,3-i/Jpyri- 48.3 midine 6-Methylthio-9-(tetrahydro-2-thienyl)purine 34.5 DISCUSSION 6-Methylthio-9-(6-[3,5-dihydroxy-2-hydroxymethyljdi- 23.6 oxane)purine The inhibition by 6MeMPR of nucleotide formation from 6-Methylthio-9-phenyl purine 12.7 hypoxanthine-14C observed here is in agreement with the 6-Methylthio-9-(2-hydroxyethyl)purine 11.3 results of Hill (13), using Adenocarcinoma 755 cells and 100 /Â¿M6MeMPR. In the latter case, however, nucleotide Table 4 formation from adenine and guanine was also inhibited. Effects of methylthio compounds on inosinate dehydrogenase Henderson and Khoo (10) previously reported a slight (17%) activity inhibition of nucleotide formation from adenine-14C in Ehrlich ascites tumor cells were incubated as described in Table 1, Ehrlich ascites tumor cells incubated with 1 mM 6MeMPR. with 100 Â¿iMhypoxanthine and I mM test compound. Inosinate dehy drogenase activity was calculated to be equal to the sum of radioactivity Henderson and Gadd (9) reported that partially purified in xanthosine monophosphate + GMP + GDP + GTP. adenine phosphoribosyltransferase (EC 2.4.2.7) was not inhibited by 1 mM 6MeMPR, and Hill (13) found that % inhibition hypoxanthine-guanine phosphoribosyltransferase (EC of inosinate dehydrogenase 2.4.2.8) activity in cell extracts was inhibited less than Compounds tested activity 15% by 100 //M 6MeMPR at 10 /Â¿Mguanine or 25 /iM hypoxanthine and 250 ^M PP-ribose-P; however, intact cells 6-Methylthio-9-(6-[3,5-dihydroxy-2-hydroxymethyl]di- 54.2 incubated with this drug contain 100 to 300 MM6MeM PR- oxane)purine 4-Methylthio-7-/3-D-ribofuranosyl pyrrolo[2,3--ribofuranosyl pyr- 25.9 inhibit PP-ribose-P accumulation in Ehrlich ascites tumor rolo[2,3-rf]pyrimidine 6-Methylthio-9-(tetrahydro-2-t'uryl)purine 21.1 cells. 6-Methylthio-9-(tetrahydro-2-pyranyl)purine 20.3 Inhibition of inosinate dehydrogenase activity in intact 6-Methylthio-2-amino-9-benzyl purine 19.2 cells by 6MeMPR has not previously been reported. 6-Methylthio-9-ethyl purine 17.7 6MeM PR-phosphate may act by direct inhibition of this 6-Methylthio-9-(2-amino-2-deoxy-/3-n-ribofuranosyl)pu- 15.4 enzyme as an analog of inosinate or possibly through some indirect effect.

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Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1973 American Association for Cancer Research. Shantz, Smith, Fontenelle, Lau, and Henderson No other effects of 6MeMPR on purine metabolism these compounds have not been reported. were detected in these studies. However, Schnebli et al. (19) Previous studies have also investigated the effects of have shown that it inhibited adenosine kinase (EC 2.7.1.20), several of the other methylthio compounds studied here on an enzyme for which it is an alternative substrate. hypoxanthine-guanine phosphoribosyltransferase (15), ade Although these inhibitory effects of 6MeMPR on purine nine kinase (4), nucleoside uptake into human erythrocytes metabolism are of interest, it seems unlikely that they (16) and purine biosynthesis de novo (8). Bennett et al. (2) contribute significantly to the growth-inhibitory properties have reported that the carbocylic analog of 6MeMPR did of this drug. Thus purine biosynthesis de novo is markedly not inhibit adenosine kinase, adenosine deaminase, (EC inhibited by 1 to 10 Â¿iM6MeMPR (5, 7) concentrations 3.5.4.4) or inosine phosphorylase (EC 2.4.2.1) and was not which would not affect nucleotide formation from hypoxan- cytotoxic. thine or inosinate dehydrogenase activity. Likewise, it has been shown that 50% inhibition of purine biosynthesis de REFERENCES novo was achieved in vivo by treatment for 4 days with 6MeMPR, 0.75 mg/kg, or by 1 injection of 6MeMPR, 3.8 1. Bennett, L. L., Jr., and Adamson, D. J. Reversal of the Growth mg/kg; the former treatment also produced 50% inhibition Inhibitory Effects of 6-Methylthiopurine Ribonucleoside. Biochem. of growth. Under both of these conditions the intracellular Pharmacol., 19: 2172 2176, 1970. concentration of 6MeM PR-phosphate was 100 to 120 2. Bennett, L. L., Jr., Allan, P. W., and Hill, D. L. Metabolic Studies nmoles/g (T. Sawa and J. F. Henderson, unpublished with Carbocyclic Analogs of Purine Nucleosides. Mol. Pharmacol., 4: results). Chart 1 shows that intracellular concentrations of 208-217, 1968. 120 nmoles/g are achieved at initial extracellular 6MeMRP 3. Bennett, L. L., Jr., Brockman, R. W., Schnebli, H. P., Dixon, G. J., of about 30 //M, a concentration which produces little or no Schabe!, F. M., Dulmage, E. A., Skipper, H. E., Montgomery, J. A., effect on nucleotide formation from adenine or on inosinate and Thomas, H. J. Activity and Mechanism of Action of 6-Methyl dehydrogenase activity in Ehrlich ascites tumor cells. Thus, thiopurine Ribonucleoside in Cancer Cells Resistant to 6-Mercapto- purine. Nature, 205: 1276-1279, 1965. effects which are observed only at 100 pM 6MeMPR (or 4. Caldwell, I. C., and Henderson, J. F. Inhibitors of Adenosine Kinase. higher) are unlikely to be pharmacologically significant. Cancer Chemotherapy Rept., 2 (Part 2): 237-246, 1971. This conclusion is important in that it very much strength 5. Caldwell, I. C., Henderson, J. F., and Paterson, A. R. P. Resistance to ens the view (I, 20) that inhibition of purine biosynthesis de Purine Ribonucleoside Analogs in an Ascites Tumor. Can. J. Bio novo is the pharmacologically most significant biochemical chem., 45: 735-744, 1967. effect of this purine antimetabolite. 6. Crabtree, G. W., and Henderson, J. F. Rate Limiting Steps in the 4-Methylthio-7-/3-D-ribofuranosyl pyrrolo[2,3-Â¿]pyrimi- Interconversion of Purine Ribonucleotides in Ehrlich Ascites Tumor dine (1 m.M)was a fairly potent inhibitor of both inosinate Cells in Vitro. Cancer Res., 31: 985 991, 1971. dehydrogenase (53.9%) and nucleotide formation from 7. Henderson, J. F. Feedback Inhibition of Purine Biosynthesis in Ascites hypoxanthine (55.2%) in Ehrlich ascites tumor cells and has Tumor Cells by Purine Analogs. Biochem. Pharmacol., 12: 551-556, previously been shown to inhibit purine biosynthesis de novo 1963. 94% (l 1); it did not inhibit adenine phosphoribosyltransfer- 8. Henderson, J. F. Purine Nucleoside Inhibitors of Purine Biosynthesis de Novo. Cancer Chemotherapy Rept., / (Part 2): 375 382, 1968. ase, adenosine kinase, or nucleoside transport (11). In 9. Henderson, J. F., and Gadd, R. E. A. Inhibitors of Adenine cultured human leukemia cells at growth inhibitory concen Phosphoribosyltransferase. Cancer Chemotherapy Rept., / (Part 2): trations it was still a potent inhibitor of nucleotide synthesis 363-373, 1968. from hypoxanthine (46%) but had a weaker effect on 10. Henderson, J. F., and Khoo, M. K. Y. On the Mechanism of Feedback inosinate dehydrogenase activity (28%). Under the latter Inhibition of Purine Biosynthesis de Novo in Ehrlich Ascites Tumor conditions, of course, the leukemia cells synthesize purine Cells in Vitro. J. Biol. Chem., 240: 3104-3109, 1965. nucleotides de novo rather than from hypoxanthine, and 11. Henderson, J. F., Paterson, A. R. P., Caldwell, I. C., Paul, B., Chan, growth inhibition is probably due to inhibition of purine M. C., and Lau, K. F. Inhibitors of Nucleoside and Nucleotide biosynthesis de novo. Metabolism. Cancer Chemotherapy Rept., 3 (Part 2). 71 85, 1972. 12. Henderson, J. F., Rosenbloom, F. M., Kelley, W. N., and Seegmiller, Both nucleoside formation from hypoxanthine and inosi J. E. Variations in Purine Metabolism of Cultured Skin Fibroblasts nate dehydrogenase activity were inhibited by several com from Patients with Gout. J. Clin. Invest., 47: 1511 1516, 1968. pounds structurally related to 6MeMPR, although only the 13. Hill, D. L. Hypoxanthine Phosphoribosyltransferase and Guanine compound just discussed produced greater than 50% inhibi Metabolism in Adenocarcinoma 755 Cells. Biochem. Pharmacol., 19: tion of both processes. The most potent inhibitor of 545-557, 1970. inosinate dehydrogenase activity, 6-methylthio-9-(6-[3,5- 14. Hill, D. L., and Bennett, L. L., Jr. Purification and Properties of dihydroxy-2-hydroxylmethyl]dioxane)purine, has previ 5-Phosphoribosyl Pyrophosphate Amidotransferase from Adenocar ously been shown (at 1 mM)to inhibit purine biosynthesis de cinoma 755 Cells. Biochemistry, 8: 122 130, 1969. novo 20% and adenosine kinase 31% but to have only slight 15. Lau, K. F., and Henderson, J. F. Inhibitors of Hypoxanthine-Guanine Phosphoribosyltransferase. Cancer Chemotherapy Rept., 3 (Part 2); or negligible effects on adenine phosphoribosyltransferase 87-94, 1972. or nucleoside uptake in human erythrocytes (11). 16. Paterson, A. R. P., and Simpson, A. I. Inhibitors of Nucleoside 4-Methylthio-5-carbonitrile-7-0-D-ribofuranosyl pyrrolo- Metabolism. Cancer Res., 27 (Part 2): 353-363, 1967. [2,3-Â£/]pyrimidine and 7-methylthio-3-/3-D-ribofuranosyl 17. Rosenberg, F. M., Henderson, J. F., Caldwell, I. C., Kelley, W. N., pyrazolo[4,3-d]pyrimidine were effective inhibitors of and Seegmiller, J. E. Biochemical Bases of Accelerated Purine nucleotide synthesis from hypoxanthine: other effects of Biosynthesis de Novo in Human Fibroblasts Lacking Hypoxanthine-

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Guanine Phosphoribosyltransferase. J. Biol. Chem., 243: 1166 1173, Purine Biosynthesis de Novo and of Ehrlich Ascites Tumor Cell 1968. Growth by 6-Methylmercaptopurine Ribonucleoside. Biochem. Phar- 18. Rosenbloom, F. M., Henderson, J. F., Kelley, W. N., and Seegmiller, macol., 21: 1203-1206, 1972. J. E. Accelerated Purine Biosynthesis de novo in Skin Fibroblasts 21. Tay, B. S., Lilley, R. M., Murray, A. W., and Atkinson, M. R. Deficient in Hypoxanthine-Guanine Phosphoribosyltransferase Activ Inhibition of Phosphoribosyl Pyrosophate Amidotransferase from ity. Biochim. Biophys. Acta, 166: 258 260, 1968. Ehrlich Ascites Tumor Cells by Thiopurine Nucleotides. Biochem. 19. Schnebli, H. P., Hill, D. P., and Bennett, L. L., Jr. Purification and Pharmacol., 18: 936 938, 1969. Properties of Adenosine Kinase from Human Tumor Cells of Type 22. Wong, P. C. L., and Henderson, J. F. Purine Ribonucleotide H.Ep. No. 2. J. Biol. Chem., 242: 1997 2004, 1967. Biosynthesis, Interconversion and Catabolism in Mouse Brain in 20. Shantz, G. D., Fontanelle, L. H., and Henderson, J. F. Inhibition of Vitro. Biochem. J., 129: 1085 1094, 1972.

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Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1973 American Association for Cancer Research. Inhibition of Purine Nucleotide Metabolism by 6-Methylthiopurine Ribonucleoside and Structurally Related Compounds

Geraldine D. Shantz, Camilla M. Smith, Lydia J. Fontenelle, et al.

Cancer Res 1973;33:2867-2871.

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