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Biochemical Aspects Ofmercaptopurine Inhibition and Resistance*

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Biochemical Aspects of Mercaptopurine Inhibition and Resistance* R. W. BROCKMAN (Kettering-Meyer Laboratory, Southern Research institute, Birmingham, Alabama) SUMMARY The observed effects of 6-mercaptopurine on purmne synthesis de novo can be at tributed to inhibition by 6-mercaptopurmne ribonucleotide of phosphoribosylamine synthesis. Azaserine-induced accumulation of@ formyiglycinamide ribonucleotide (FGAR) in human tumor cellsin culture was inhibitedby low concentrationsof 6- mercaptopurine and 6-thioguanine; such inhibition of FGAR accumulation did not occur in a mercaptopurmne-resistant subline that lacked inosinic and guanylic acid pyrophosphorylase activities, the enzyme system by which 6-mercaptopurmne ribo nucleotide and 6-thioguanylic acid are formed. Resistance to mercaptopurmne has been seen to be accompanied frequently by decrease or loss of these enzyme activities. Such loss of enzyme activity appears to be a genetically stable and heritable characteristic of resistant cells. Resistance to mercaptopurine by means other than loss of capacity for ribonucleotide formation is also evident. INTRODUCTION of the metabolism of mercaptopurine, mechanisms Elion and Hitchings (28) described the syn by which it inhibits nucleic acid synthesis, and thesis of 6-mercaptopurmne over a decade ago. mechanisms by which biological systems may be Early reports of the inhibitory effects of mercapto come resistant to this analog. It is hoped that this purmne on microorganisms (29), experimental tu presentation may provide a framework for die mors (28), and mouse leukemias (48) were fol cussion, since aspects of the mechanisms of action lowed by extensive studies of the biological and of mercaptopurine and other purinethiols and of biochemical effects of this purine analog (56). resistance to these inhibitors are still under active investigation. Mercaptopurine is known to be metabolized by pathways of hypoxanthine metabolism and to METABOLISM OF MERCAPTOPURINE interfere with the synthesis and interconversion of Mercaptopurine closely follows the known purine nucleotides (see 1, 10, 11, 75). The analog pathways for the anabolism and catabolism of also suppresses immune responses (71). purine bases. The analog was oxidized to thiouric Considered in the present discussion are aspects acid by microorganisms and by mammalian cells S The experimental work reported herein was supported (20, 30, 52, 56). The rate of oxidation of mer by the Cancer Chemotherapy National Service Center, Na captopurine by milk xanthine oxidase was relative tional Cancer Institute, under the National Institutes of ly slow, and the analog was a competitive inhibi Health Contract No. SA-43-ph-2483, and by grants from the tor of xanthine oxidation (72). Mercaptopurine Charles F. Kettering Foundation and the Alfred P. Sloan Foundation. was metabolized to hypoxanthine and to purine The abbreviations used are those accepted as standard by nucleotides in microorganisms (4, 20) ; desulfuriza the Journal of BiOlOgical Chemistry with certain additions or tion also occurred in miceasindicated by sulfate. exceptions. Su excretion and labeling of nutleic acid adenine AMP, GMP, IMP: adenosine-, guanosine-, and inOSine-5'- monophosphates. and guanine from mercaptopurine-8-C'4 (56). 6- ATP, GTP, UTP, CTP: adenosine-, guanosine-, uridine Methylmercaptopurmne was identified as an excre and cytidine-5'-triphosphates. tion product of the metabolism of mercaptopurine @ dUTP: deoxyuridine-5'-triphosphate. (68). Chart 1 summarizessome of the known dTTP: thymidine-5'-triphosphate. pathways of metabolism of 6-inerciaptopurine.' PRPP: 5-phosphoribosyl-1-pyrophosphate. FGAR: formylglycinamide ribonudeotide. 1 Elion et aL considered catabolism of tbiopuzine In their @@@ MP: 6-mercaptopurine. contribution to this conference. :. 1191 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1963 American Association for Cancer Research. 1192 Cancer Research Vol. 23, September 1963 Purine nucleoside phosphorylase was active for Carter (21) showed that mercaptopurine and the formation of mercaptopurine ribo- and deoxy hypoxanthine competed for a partially purified E. ribonucleosides (31, 81). Evidence that mercapto coli purine ribonucleotide pyrophosphorylase that purine inhibited inosine phosphorylase was oh was also active for guanine. Competition of mer tamed in E. coli (82) and in neoplasms grown in captopurmne and hypoxanthine for IMP pyrophos cell culture.2 Paterson (62) found that mercapto phorylase probably accounts for the observed in purine ribonucleoside was rapidly cleaved to the hibition of conversion of hypoxanthine to nucleo base by Ehrlich ascites cells, suggesting the action tides in microbial cells (13). The data summarized of purine nucleoside phosphorylase or hydrolase. in Table 1 show that in our studies the inhibition Kinase activity for inosine and mercaptopurine by mercaptopurine of nucleotide formation in S. ribonucleoside has not yet been demonstrated, al faecalis was specific for hypoxanthine and guanine though indirect evidence for its existence was oh under the experimental conditions used (see also tained in a study of the metabolism of inosine to [5]). Mercaptopurine was metabolized to the cor purine nucleotides in bacterial cells deficient in the responding ribonucleotide by mouse neoplasms capacity to metabolize hypoxanthine to IMP. and other tissues in vivo, but no evidence for the Anobotism NP ribonucleoside @ phosphory,@@@@ pyrophosphorylas ‘...(kinose) @ 6-Mercaptopurins @.—.—& NP rsbonucleottde I' 1/ ‘:ii Inosinic polyphosphotcc acid polynucleotides Co tabolism zanthins zanthine @ midase oxidase @ 6-Nercaptopurine 6-thioxonthins 6-thiouric acid L__,@6-methylmercaptopurine @ sulfate; hypoxanthin.;anabolic and catabolic products of purine metabolism Ca4ur 1.—Metabolism of 6-mercaptepurine in rim SH ®-OCH2 SH formation of the ribonucleoside di- and triphos + PPi phates was obtained in these studies (9, 60). How c:x + ever, Way et al. (85) obtained indirect spectro photometric evidence for further phosphorylation of mercaptopurine ribonucleoside-5'-phosphate by pork kidney enzyme preparations. OH OH Some radioactivity from mercaptopurine-S36 CHART 2.—Enzymatic synthesis of 6-mercaptopurine ribo and from mercaptopurine-8-C'4 was incorporated nucleotide by reaction of the base with 5-phosphoribosyl-1- into the nucleic acid fraction isolated from mouse pyrophosphate. tissues (7, 56), but unequivocal evidence of in corporation of the analog as the nucleotide, and From the results obtained it appeared that MP thus as an integral part of the nucleic acid chain, resistant Streptococcus faeca& (SF/MP) utilized has not yet been presented. No evidence was oh inosine for nucleotide formation equally as well as tamed for incorporation of mercaptopurmne into did the parent sensitive strain (SF/0).3 the nucleic acids of microorganisms (20) or of Mercaptopurine, like natural purine bases, was mouse leukemia cells in vivo (9) or in cell culture converted to the nucleotide by enzyme-catalyzed (16)@Hansenet at. (38, 39) observedthat radio reaction with 5-phosphoribosyl-1-pyrophosphate activity from mercaptopurmne-S35 associated with (PRPP) (53, 86) (Chart 2). ribonucleic acids was significantly decreased by 3 G. P. Wheeler and B. Bowden (personal communication, treatment of the nucleic acid fraction with hydro 1962). gen sulfide. This was so whether the tracer was ad 3B.W.Brockman,P.Chambers,C.S.Debavadi(unpub ministered in vivo and the nucleic acid subsequent lished observations). ly isolated or whether ribonucleic acid was directly Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1963 American Association for Cancer Research. BROCKMAN—ASpecIS of Mercaptopurine Inhibition and Resistance 1193 exposed to mercaptopurine-S35 in vitro. Certain cursors such as formate, glycine, carbon dioxide, metal ions increased the radioactivity associated and ammonium salts (see [38]). Gots (83) showed with the nucleic acid fraction. Thus, some of the that exogenous purines, particularly adenine and mercaptopurine associated with the nucleic acid hypoxanthine, inhibited the accumulation of 5- fraction may be nonspecifically bound. amino-4-imidazolecarboxamide ribonucleoside in Anomalous nucleotides are known to be enzy a purine-requiring mutant, Escherichia coli B-96. matically incorporated into polynucleotides. For In a subsequent study with an adenine-requiring example, bromodeoxyuridine-5'-triphosphate and mutant it appeared that adenine, or adenine con dUTP can substitute for dTTP, and deoxyinosine geners, specifically prevented the formation of .5'-triphosphate can partially substitute for dGTP aminoimidazolecarboxamide derivatives (84) . Hen as substrates for DNA polymerase (6). Similarly, derson (41) observed that natural purine bases and .5-ribosyl-UTP, thymine ribonucleoside-5'-triphos nucleosides inhibited azaserine-induced formyl phate, 5-fiuorouridine-5'-triphosphate, and 5-bro TABLE 1 mouridine-.5'-triphosphate substitute completely or partially for UTP as substrates for microbial EFFECT OF MERCAPTOPURINE ON THE UTTL@ATION OF RNA polymerase; azaguanosine-5'-triphosphate EXOGENOUS PURINES FOR NUCLEOTIDE FORMA and inosine-5'-triphosphate also substitute partial TION BY Streptococcus faecaiis ly for GTP as substrates for this enzyme (44). Mercaptopurine nucleotides have not yet been re NUcLEOTTDESt IN TEE ported to be substrates for DNA or RNA poly FRACTIONCouut,/sec;SOLUBLE merase. Carbon (19) studied mercaptopurine ribo mercaptopurine-treated
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