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A Mechanism of Resistance to 6-Mercaptopurine: Metabo Lism of Hypoxanthine and 6-Mercaptopurine by Sensitive and Resistant Neoplasms*

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A Mechanism of Resistance to 6-Mercaptopurine: Metabo Lism of Hypoxanthine and 6-Mercaptopurine by Sensitive and Resistant Neoplasms* A Mechanism of Resistance to 6-Mercaptopurine: Metabo lism of Hypoxanthine and 6-Mercaptopurine by Sensitive and Resistant Neoplasms* R. W. BROCKMAN WITHTHETECHNICALASSISTANCEOFMARGUERITES.SIMPSON,JOANM. DAVIS,ANDPATRICIASTUTTS (Kettering-Meyer Laboratory,^ Southern Research Institute, Birmingham, Alabama) SUMMARY Leukemia L1210 ascites tumor cells sensitive to inhibition by 6-mercaptopurine were observed to metabolize hypoxanthine-8-C14 and 6-mercaptopurine-S36 to ribo- nucleotide derivatives in vivo. Hypoxanthine-8-CH extensively labeled adenylic and guanylic acids of L1210 nucleic acids. Soluble enzyme preparations from L1210 ascites cells catalyzed the reactions of adenine, guanine, 8-azaguanine, hypoxanthine, and 6- mercaptopurine with 5-phosphoribosyl-l-pyrophosphate (PRPP) to yield 5'-ribo- nucleotide derivatives. Lines of L1210 resistant to 6-mercaptopurine failed to form significant amounts of inosinic acid or 6-mercaptopurine ribonucleotide in vivo.The nucleic acids of the drug- resistant leukemic cells exposed in vivo to hypoxanthine-8-C14 were not extensively la beled. Soluble enzyme preparations from the L1210 ascites cells resistant to purine antagonists did catalyze the reaction of adenine with PRPP to yield adenylic acid but did not yield significant amounts of the 5'-ribonucleotides of guanine, 8-azaguanine, hypoxanthine, or 6-mercaptopurine. These findings support the interrelated hypotheses that (a) the metabolism of 6- mercaptopurine to a ribonucleotide derivative constitutes a lethal synthesis and that (b) an effective mechanism of resistance to 6-mercaptopurine in L1210 mouse leukemia is a decrease in the enzymic capacity of the drug-resistant leukemic cells to form 6-mercap topurine ribonucleotide. Neoplasms sensitive to inhibition by 8-azagua- revealed a significant decrease in the capacity nine were observed to metabolize guanine and 8- of the 8-azaguanine-resistant neoplasms to form azaguanine to the corresponding ribonucleotide ribonucleotide derivatives of guanine, 8-azagua- derivatives in vivo; resistance to 8-azaguanine was nine, hypoxanthine and 6-mercaptopurine (14). Re- found to be accompanied by decreased capacity suits of studies with bacteria that are sensitive to form 8-azaguanine ribonucleotides (8, 13). A or resistant to 8-azaguanine and 6-mercaptopurine study of the capacity of enzyme preparations from support the hypothesis that resistance to these 8-azaguanine-sensitive and -resistant neoplasms purine analogs is a consequence of the decreased to catalyze the reaction of purines and purine capacity of the resistant cells to synthesize the analogs with 5-phosphoribosyl-l-pyrophosphate fraudulent ribonucleotide derivatives (11, 12, 14). * This study was supported by the Cancer Chemotherapy Thej present •. report . extends / \ these. •investigations . • , ., National Service Center, National Cancer Institute, under OD drug-resistance to (a) an investigation of the National Institutes of Health Contract Number SA-43-ph- m mm metabolism of hypoxanthine and 6-mercap- 1741, and by grants from the Charles F. Kettering Foundation topurine in leukemia L1210 ascites tumor cells and the Alfred P. Sloan Foundation. and in 6-mercaptopurine, 6-thioguanine, and 8- t Affiliated with the Sloan-Kettering Institute for Cancer azaguanine-resistant lines of L1210;1 (b) & study Research, New York. 1Lines of Dr. L. W. Law, National Cancer Institute. Received for publication December 18, 1959. L1210/MP = 6-mercaptopurine-resistant; L1210/TG = 6- 643 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1960 American Association for Cancer Research. 644 Cancer Research Vol. 20, June, 1960 of the in vivo conversion of 6-mercaptopurine-S36 and normal tissues was obtained by eluting the to the ribonucleotide derivative in L5178-Y ascites 6-mercaptopurine-S35 ribonucleotide from the pa cells,1 in Sarcoma 180 ascites cells, and in L4946 per with water and evaporating the eluates on Lymphoma, Sarcoma 180, and Adenocarcinoma planchéisfor counting in gas-flow proportional 755 grown as subcutaneously implanted tumors; counters. The activity of S35was corrected for the and (c) a comparison of the capacity of enzyme radioactive decay which took place over the period preparations from sensitive and resistant L1210 of time required for accomplishing electrophoretic, ascites cells to catalyze the reaction of purines radioautographic, and quantitative analyses. and purine analogs with 5-phosphoribosyl-l-pyro- Soluble enzyme preparations were prepared phosphate. from L1210 ascites tumor cells as described pre viously (8). These preparations were assayed for MATERIALS AND METHODS their capacity to catalyze the reactions of purines Radioactive substrates used in this investiga and purine analogs with 5-phosphoribosyl-l-pyro- tion were the same as those described previously phosphate. (8). The magnesium salt of 5-phosphoribosyl-l- pyrophosphate (PRPP) was obtained from Pabst RESULTS Metabolism of hypoxanthine-8-Clt in vivo : anal Laboratories, Milwaukee, Wisconsin. The in vivo tracer experiments with hypoxan- ysis of alcohol-soluble fraction.—Hypoxanthine is thine-8-C14, 6-mercaptopurine-8-C14, and 6-mer extensively anabolized in vivo by the parent drug- captopurine-S35 were carried out in the manner sensitive L1210 ascites cells to yield nucleotide described in previous experiments (8). The pro derivatives of adenine, guanine and hypoxanthine cedure is briefly outlined here. including AMP, ADP, ATP, DPN, IMP, and Hypoxanthine-8-C14 or 6-mercaptopurine-8-C14 GMP (Table 1). Radioactive nucleoside-5'-di- and was injected intraperitoneally into mice bearing triphosphate derivatives of hypoxanthine and gua sensitive or resistant L1210 ascites cells. The radio nine were not conclusively identified although active substrate (10 /tc/mouse) was given in two they may have been present in small amounts. equally divided doses 1 hour apart. One hour after This result is in marked contrast with the anabo- the second injection the neoplasms and normal lism of hypoxanthine by L1210/MP, L1210/TG, tissues were removed and extracted with hot 80 and L1210/8-Aza (Table 1). These differences are per cent ethanol-water. The extracts were con clearly revealed in a comparison of the radio- centrated and lyophilized for Chromatographie, autogram patterns (Fig. 1). In the drug-resistant electrophoretic, and radioautographic analyses as lines of L1210 the only radioactive ribonucleotide previously described (8). The solid residue remain present in any detectable quantity was adenylic ing after ethanol extraction served as the starting acid, and it was present only in trace amounts. point for the isolation of nucleic acids, which An examination of the results of a similar analysis of the fate of hypoxanthine-8-C14 in non- were analyzed for radioactivity by chemical oxida tion of organic carbon to C14O2 for gas phase neoplastic tissues from animals bearing L1210 counting by a modification of the Bernstein- revealed that significantly more catabolic than Ballentine technic (57). anabolic products were present in soluble extracts The 6-mercaptopurine-S35 was similarly admin from liver and spleen (Table 2). For example, istered at a level of 40 ^c/mouse in two equally allantoin accounted for considerably more than divided doses 1 hour apart. One hour after the half of the total radioactivity found in liver and second injection the neoplasm and normal tissues spleen. A similar result was obtained in analyses were removed for analysis. The concentrated ex of the soluble extracts of liver and spleen from tracts were subjected to high-voltage paper elec- mice bearing drug-resistant L1210 ascites lines. trophoresis (20 volts/cm) in ammonium formate Pronounced predominance of anabolism over ca- buffer (pH 3.5) to isolate 6-mercaptopurine-S35 tabolism in drug-sensitive neoplasms and the in ribonucleotide (see Table 3). The radioactive ribo verse relationship in non-neoplastic tissues could nucleotide was located by exposing the electro- account for the degree of selective toxicity that phoresis strips to x-ray film. Quantitative data certain of the purine analogs have on neoplasms. on the amount of 6-mercaptopurine-S35 ribonucleo Allantoin was the major product of catabolism of hypoxanthine-8-C14 found in extracts of the tide present in sensitive or resistant neoplasms sensitive and resistant lines of L1210. There do thioguanine-resistant; L1210/8-Aza = 8-azaguanine-resistant. not appear to be significant differences in the L1210/TG and L1210/8-Aza are also resistant to 6-mercapto- amounts of radioactive uric acid and allantoin purine (89). L5178-Y is the L5178 ascites tumor cell line of Law which was passed through tissue culture by Dr. Glenn remaining in sensitive and resistant cells under Fischer, Yale University. the experimental conditions used. In in vivo ex- Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1960 American Association for Cancer Research. BROCKMAN—ResistancetoMercaptopurine 645 periments such as these it is not possible to L1210 may well be derived from the large pools specify how much of the degradation products of radioactive nucleotides present in the sensitive were formed in the ascites cells and how much cells. might have been formed in cells of the host. Metabolism of hypoxanthine-8-Cu in vivo : label Results of the enzyme studies discussed below ing of nucleic acid purines.— Hypoxanthine-8-C14 suggest that soluble enzyme preparations from extensively labels the nucleic acid purines of L1210
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