Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Coformycin”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources
PubMed2000

Direct measurement of adenosine release during hypoxia in the CA1 region of the rat hippocampal slice.

We have used an enzyme-based, twin-barrelled sensor to measure adenosine release during hypoxia in the CA1 region of rat hippocampal slices in conjunction with simultaneous extracellular field recordings of excitatory synaptic transmission. When loaded with a combination of adenosine deaminase, nucleoside phosphorylase and xanthine oxidase, the sensor responded linearly to exogenous adenosine over the concentration range 10 nM to 20 microM. Without enzymes, the sensor when placed on the surface of hippocampal slices recorded a very small net signal during hypoxia of 40 +/- 43 pA (mean +/- s.e.m.; n = 7). Only when one barrel was loaded with the complete sequence of enzymes and the other with the last two in the cascade did the sensor record a large net difference signal during hypoxia (1226 +/- 423 pA; n = 7). This signal increased progressively during the hypoxic episode, scaled with the hypoxic depression of the simultaneously recorded field excitatory postsynaptic potential and was greatly reduced (67 +/- 6.5 %; n = 9) by coformycin (0.5-2 microM), a selective inhibitor of adenosine deaminase, the first enzyme in the enzymic cascade within the sensor. For 5 min hypoxic episodes, the sensor recorded a peak concentration of adenosine of 5.6 +/- 1.2 microM (n = 16) with an IC(50) for the depression of transmission of approximately 3 microM. In slices pre-incubated for 3-6 h in nominally Ca(2+)-free artificial cerebrospinal fluid, 5 min of hypoxia resulted in an approximately 9-fold greater release of adenosine (48.9 +/- 17.7 microM; n = 6). High extracellular Ca(2+) (4 mM) both reduced the adenosine signal recorded by the sensor during hypoxia (3.5 +/- 0.6 microM; n = 4) and delayed the hypoxic depression of excitatory synaptic transmission.

Adenosine↗
PubMed1985

Effects of adenosine deaminase inhibitors on lymphocyte-mediated cytolysis.

Four compounds that inhibit adenosine deaminase, erythro-9-(2-hydroxy-3-nonyl)adenine, 2'-deoxycoformycin, coformycin, and 9-(1-hydroxy-2-octyl)adenine have been studied in an in vitro lymphocyte-mediated cytolysis assay. At low concentration (congruent to 10 microM) these agents enhance the activities of a number of inhibitory purine nucleosides, including adenosine and 2'-deoxyadenosine. The LMC-inhibitory activity of Ado but not dAdo is further enhanced by 5-iodotubercidin, uridine, 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone, or L-homocysteine and is antagonized by theophylline. The inhibition of LMC by Ado and dAdo is increased by nitrobenzyl-thioinosine. Lymphocyte-mediated cytolysis was inhibited by EHNA or HOA alone (IC50 congruent to 150 microM), but not by dCF and CF (even at 400 microM). Inhibition of LMC by EHNA, HOA, Ado, or dAdo could not be attributed to changes in nucleoside 5'-triphosphate or S-adenosylhomocysteine levels. Inhibition of LMC by Ado appears to be related to increases in lymphocyte cAMP levels, while the mechanism of action of dAdo remains obscure. Lymphocyte-mediated cytolysis may be inhibited by EHNA and HOA through modulation of cAMP metabolism.

Adenine↗
PubMed1981

Role of adenosine deaminase in activation of macrophages.

The intracellular adenosine deaminase activity of induced macrophages was twice that of resident cells. Coformycin, a specific inhibitor of adenosine deaminase, inhibited the activation of macrophages, as measured by superoxide generation.

Adenosine Deaminase↗
PubMed1988

Interstitial transudate concentration of adenosine and inosine in rat and guinea pig hearts.

Interstitial transudate (IT) was sampled from the surface of isolated constant pressure-perfused guinea pig and rat hearts. With endogenous adenosine (AR) formation, IT concentrations (Crr) of AR and inosine (IR) were 4- to 6.5-fold higher than those in the venous effluent. The AR-to-IR ratio varied between 0.5 and 0.1. During normoxic perfusion, CIT-AR reached a basal level of 0.18 microM. During maintained hypoxia, CIT-AR was elevated only initially up to 0.63 microM. Subsequently, it decreased to basal values, whereas coronary flow remained elevated. With repetitive hypoxia, CIT-AR decreased to basal values, with little alteration in the coronary flow response. Addition of 1,000 U/l adenosine deaminase reduced CIT-AR below 0.2 microM, with no change in coronary flow response to hypoxia. High concentrations of coformycin (Streptomyces antibioticus), an adenosine deaminase inhibitor (greater than 1 microM), were necessary to increase the AR-to-IR ratio to unity, indicating an intracellular site of action. During administration of 0.1 microM dipyridamole, no close correlation between CIT-AR and coronary flow was found. Administration of 1 microM AR did not induce a detectable change in Crr-AR despite a distinct coronary flow response. We conclude that at least in our heart preparation, interstitial adenosine seems to play no primary role in coronary flow regulation.

Adenosine↗
PubMed1988

Adenosine transport by the lung.

Adenosine, a nucleoside and potent vasodilator, has been found to be taken up by the lung and converted by deamination into inosine and hypoxanthine. In a single circulation through an isolated rat lung, 69.3 +/- 3.3% of infused [14C]adenosine (10 microM) was removed from the circulation. Uptake of [14C]adenosine remained unchanged when deamination of adenosine was inhibited by 8-azaguanine or coformycin. In a single passage of adenosine through the pulmonary artery, very little of the deaminated products appeared in the pulmonary circulation, but when adenosine was recirculated through the pulmonary circulation inosine and hypoxanthine appeared in the venous effluent. These adenosine metabolites were also taken up by the lung. A major portion of the circulating adenosine was transported into the lung, where it was used to synthesize adenine nucleotides. Inhibition of adenosine kinase by iodotubercidin resulted in reduced formation of ATP and ADP. Uptake of adenosine by the lung was saturable on a concentration gradient and was a passive process because it was not affected by the absence of glucose or the presence of ouabain. Km and Vmax for adenosine transport were 0.227 mM and 4.6 mumol.min-1.g lung-1, respectively. Adenosine transport was inhibited by adenosine analogues, and the inhibitions were found to be competitive in nature. These results suggest that a specific and rate-limiting transport system exists in the lung for adenosine.

Adenosine↗
PubMed1982

Suppression by adenine compounds of histamine-induced contraction in isolated guinea pig tracheal rings.

The effects of purine compounds on the contraction of isolated guinea pig tracheal pigs induced by histamine were studied in vitro. Adenosine, at 0.1-1 mM concentrations, suppressed the contraction induced by histamine in the isolated guinea pig tracheal rings in a concentration-dependent manner. ATP, AMP and adenine were also effective in blocking tracheal constriction induced by histamine. The other purine compounds such as inosine, guanosine, guanine and hypoxanthine had no effect on tracheal smooth muscle. Coformycin, which is a competitive inhibitor of adenosine deaminase, did not potentiate adenosine action. Dipyridamole, which blocks adenosine uptake, did not impair the suppression caused by adenosine. These results suggest that adenosine action on tracheal smooth muscle cells may be mediated by direct action on cell surface receptors. In addition, it seems that adenosine is an important modulator of tracheal smooth muscle cell function.

Adenine↗
PubMed2002

Enhancement of cellular adenosine triphosphate levels in PC12 cells by extracellular adenosine.

To elucidate the biological significance of extracellular adenine compounds, the effects of adenosine (Ado) on cellular levels of adenine compounds, especially adenosine triphosphate (ATP), in PC12 cells were studied. Ado and inosine but not adenosine 5'-monophosphate, adenosine 5'-diphosphate, ATP, guanosine, cytosine, thymidine, and uridine, significantly enhanced cellular ATP levels in PC12 cells in time- and dose-dependent manners. Various P1 receptor agonists of Ado did not enhance the ATP level. In addition, theophylline, an antagonist of P1 receptors, did not inhibit the Ado-evoked ATP enhancement. These results suggest that the Ado receptor is not involved in the augmentation of the cellular ATP level induced by Ado in PC12 cells. The ATP-enhancing effect of Ado was potentiated by dipyridamole, an inhibitor of Ado uptake, or coformycin, an inhibitor of Ado deaminase. The effect of Ado on the ATP level was also observed when PC12 cells were incubated in glucose-free medium. Together these results suggest that enhancement of cellular ATP levels in PC12 cells by extracellular Ado might be acceleration of ATP synthesis through the Ado salvage system using hypoxanthine-guanine phosphoribosyltransferase rather than Ado kinase since 5'-iodotubercidin, an inhibitor of Ado kinase, had no effect on the enhancement elicited by Ado.

Adenosine↗
PubMed1987

Effect of concanavalin A on 5'-nucleotidase activity of rabbit blood platelets.

Ecto-5'-nucleotidase (ecto-5'-NU) of platelets was enhanced by concanavalin A (Con A). This effect of Con A was antagonized by alpha-methyl-D-mannose, a specific antagonist of Con A binding to glycoprotein. Coformycin, an adenosine deaminase inhibitor, did not change the effect of Con A on the ecto-5'-NU. Uptake of adenosine by platelets was not affected by Con A. It was suggested that the ecto-5'-NU of platelet might be a direct and primary site of action of Con A.

5'-Nucleotidase↗
PubMed1991

Herbicidal nucleosides from microbial sources.

The structures of five naturally-occurring herbicidal nucleosides have been determined by spectral analysis. Three (5'-deoxyguanosine, coaristeromycin and 5'-deoxytoyocamycin) are novel natural products while the remaining two (coformycin and adenine 9-beta-D-arabinofuranoside) are known natural products which have not previously been reported to be herbicidal.

Actinomycetales↗
PubMed2000

Adenosine-mediated killing of cultured epithelial cancer cells.

Because micromolar concentrations of adenosine (Ado) have been documented recently in the interstitial fluid of carcinomas growing in animals, we examined the effects of low concentrations of Ado on the growth of cultured human carcinoma cells. Ado alone had little effect upon cell growth. In the presence of one of a number of Ado deaminase (ADA) inhibitors, Ado led to significant growth inhibition of all cell lines tested. Similar effects were found when ATP, ADP, or AMP was substituted for Ado. Surprisingly, the ADA inhibitor coformycin (CF) had a much greater potentiating effect than did 2'-deoxycoformycin (DCF), although DCF is a more potent ADA inhibitor. The growth inhibition of the Ado/CF combination was not abrogated by pyrimidines or caffeine, a nonspecific Ado receptor blocker. Toxicity was prevented by the addition of the Ado transport inhibitor dipyridamole or the Ado kinase inhibitor 5'-amino 5'-deoxyadenosine. S-Adenosylhomocysteine hydrolase is not involved because neither homocysteine thiolactone nor an S-adenosylhomocysteine hydrolase inhibitor (adenosine dialdehyde) potentiated toxicity of the Ado/CF combination. Unexpectedly, substitution of 2'-deoxyadenosine (the toxic moiety in congenital ADA deficiency) for Ado, did not lead to equivalent toxicity. The Ado/CF combination inhibited DNA synthesis and brought about morphological changes consistent with apoptosis. Together, these findings indicate that the Ado-mediated killing proceeds via an intracellular route that requires the action of Ado kinase. The enhanced cofactor activity of CF may be attributable to its being a more potent inhibitor of AMP deaminase than is DCF.

Adenine↗
PubMed1992

Adenosine deaminase from bovine brain: purification and partial characterization.

Bovine brain adenosine deaminase cytoplasmatic form was purified about 450 fold by salt fractionation, column chromatography on DEAE-cellulose, octyl-sepharose 4B and affinity chromatography on CH-sepharose 4B 9-(p-aminobenzyl)adenine. The purified enzyme was homogeneous on disc gel electrophoresis; the enzyme had a molecular mass of about 65 kDa with an isoelectric point at pH 4.87. The Km values for adenosine and 2'-deoxyadenosine were 4 x 10(-5) and 5.2 x 10(-5) M, respectively. The enzyme showed a great stability to temperature with a half life of 15 hours at 53 degrees C significantly different compared to that known for other mammalian forms of this enzyme. Aza and deaza analogs of adenosine and erythro-9-(2-hydroxy-3-nonyl) adenine were good inhibitors of the bovine brain enzyme with little difference with respect to those reported for the adenosine deaminases purified from other sources. Kinetic constants for the association and dissociation of coformycin and 2'-deoxycoformycin with the bovine brain adenosine deaminase are reported.

Adenosine↗
PubMed1990

Catalytic and regulatory site composition of yeast AMP deaminase by comparative binding and rate studies. Resolution of the cooperative mechanism.

Yeast AMP deaminase is allosterically activated by ATP and MgATP and inhibited by GTP and PO4. The tetrameric enzyme binds 2 mol each of ATP, GTP, and PO4/subunit with Kd values of 8.4 +/- 4.0, 4.1 +/- 0.6, and 169 +/- 12 microM, respectively. At 0.7 M KCl, ATP binds to the enzyme, but no longer activates. Titration with coformycin 5'-monophosphate, a slow, tight-binding inhibitor, indicates a single catalytic site/subunit. ATP and GTP bind at regulatory sites distinct from the catalytic site and their binding is mutually exclusive. Inorganic phosphate competes poorly with ATP for the ATP sites (Kd = 20.1 +/- 4.1 mM). However, near-saturating ATP reduces the moles of phosphate bound per subunit to 1 PO4, which binds with a Kd = 275 +/- 22 microM. In the presence of ATP, PO4 cannot effectively compete with ATP for the nucleotide triphosphate sites. The PO4 which binds in the presence of ATP is competitive with AMP at the catalytic site since the Kd equals the kinetic inhibition constant for PO4. Initial reaction rate curves are a cooperative function of AMP concentration and activation by ATP is also cooperative. However, no cooperativity is observed in the binding of any of the regulator ligands and ATP binding and kinetic activation by ATP is independent of substrate analog concentration. Cooperativity in initial rate curves results, therefore, from altered rate constants for product formation from each (enzyme.substrate)n species and not from cooperative substrate binding. The traditional cooperative binding models of allosteric regulation do not apply to yeast AMP deaminase, which regulates catalytic activity by kinetic control of product formation. The data are used to estimate the rates of AMP hydrolysis under reported metabolite concentrations in yeast.

AMP Deaminase↗
PubMed1988

2',3'-Dideoxyadenosine is selectively toxic for TdT-positive cells.

The 2',3'-dideoxynucleosides (ddNs) are currently undergoing clinical evaluation as antiretroviral agents in HIV-infected individuals. When phosphorylated, the ddNs (ddNTPs) function as chain-terminating substrate analogues with reverse transcriptase, thereby inhibiting HIV replication. These nucleoside analogues can also inhibit, by chain-terminating additions, the primitive lymphoid DNA polymerase, terminal deoxynucleotidyl transferase (TdT). To determine the effect of possible intracellular chain-terminating additions of ddNMPs by TdT, we exposed a series of TdT-positive and TdT-negative cell lines to 2',3'-dideoxyadenosine (ddA), a representative ddN. At ddA concentrations 25-fold higher than required for inhibition of HIV replication, progressive dose-related cytotoxicity was observed in the TdT-positive cell lines. This was accentuated by the adenosine deaminase inhibitor Coformycin (CF), presumably by enhancing the intracellular generation of ddATP from ddA. A central role of TdT in mediating the ddA/CF cytotoxicity was suggested by studies in a pre-B-cell line rendered TdT positive by infection with a TdT cDNA-containing retroviral vector. After a 48-hour continuous exposure period to 250 mumol/L ddA and 30 mumol/L CF, 30% cell death was observed in the TdT-negative parental line, whereas 90% cell death was observed in the TdT-positive daughter line. Exposure of fresh TdT-positive leukemic cells to ddA/CF for 72 hours ex vivo resulted in cytotoxicity (six cases of acute lymphocytic leukemia [ALL]) while not affecting TdT-negative acute leukemic cells (six cases). We conclude that ddA/CF selectively damages TdT-positive cells, presumably by chain-terminating additions of ddAMP, and that this may have therapeutic relevance in TdT-positive malignant disease.

Cell Division↗
PubMed1985

Inhibition of utilization of hypoxanthine and guanine in cells treated with the carbocyclic analog of adenosine. Phosphates of carbocyclic nucleoside analogs as inhibitors of hypoxanthine (guanine) phosphoribosyltransferase.

In cell cultures treated with the carbocyclic analog of adenosine (C-Ado, (+/-)-aristeromycin), the utilization of hypoxanthine and guanine has been observed to be blocked. In an attempt to define the mechanism of this inhibition, we have reexamined the metabolism of C-Ado and its effects on the metabolism of guanine and hypoxanthine. In cultures of L1210 cells, C-Ado at a concentration of 25 microM inhibited the utilization of hypoxanthine and guanine for nucleotide synthesis by more than 90% but produced little or no inhibition of the utilization of these bases in cultures of L1210/MeMPR cells which lack adenosine kinase and cannot phosphorylate C-Ado. In cultures of mammalian cells (L1210, HEp-2, and colon-26 cells), C-Ado was converted to the triphosphate (as previously observed) and also to the triphosphate of the carbocyclic analog of guanosine. The presence of coformycin in the medium at a concentration sufficient to inhibit AMP deaminase almost completely prevented the formation of carbocyclic GTP; thus, the deamination of C-Ado monophosphate is essential for the formation of phosphates of carbocyclic guanosine. Since hypoxanthine (guanine) phosphoribosyltransferase is known to be subject to end product inhibition, it was considered likely that phosphates of carbocyclic guanosine or carbocyclic inosine, present in C-Ado-treated cells, were responsible for inhibition of utilization of hypoxanthine and guanine. The 5'-phosphates of the carbocyclic analogs of inosine and guanosine were synthesized and found to be effective inhibitors of the phosphoribosyltransferase. Carbocyclic GMP was a better inhibitor than carbocyclic IMP and was also superior to GMP and IMP; the concentration of C-GMP that produced a 50% inhibition of GMP formation was approximately 1 microM. It is probable that the presence of phosphates of carbocyclic guanosine accounts for the inhibition of utilization of hypoxanthine and guanine in C-Ado-treated cells.

Adenosine↗
PubMed1986

Mechanisms of adenosine 5'-monophosphate catabolism in human erythrocytes.

Uncertainties regarding the role of pyrimidine nucleotidase (PyrNase) in AMP catabolism were resolved by studies of erythrocytes from normal controls, controls with young mean cell ages, and patients with hereditary hemolytic anemia due to severe deficiency of PyrNase. Hemolysates from the latter exhibited undiminished capacity to dephosphorylate AMP over a broad range of pH, indicating that PyrNase was not directly involved. In each subject group, the rates of AMP dephosphorylation between pH 5.1 and 8.3 were indistinguishable from those of IMP, suggesting a potential role for AMP-deaminase, an erythrocyte enzyme that was stimulated by coformycin at pH 7.2. Quantitative analysis of catabolites in incubated hemolysates confirmed that AMP degradation preferentially occurred via deamination to IMP with subsequent dephosphorylation by another erythrocyte nucleotidase isozyme, deoxyribonucleotidase. Both AMP-deaminase and deoxyribonucleotidase have acidic pH optima with minimal activities at physiologic pH, suggesting that this pathway of AMP catabolism could accelerate depletion of the adenine nucleotide pool and thereby mediate the demise of senescent erythrocytes sequestered in the spleen.

5'-Nucleotidase↗
PubMed1986

Changes in nucleoside transport of HL-60 human promyelocytic cells during N,N-dimethylformamide induced differentiation.

The rate of nucleoside transport decreased profoundly in human promyelocytic leukemia HL-60 cells after myeloid differentiation was induced by 5-6 days of exposure to 0.8% N,N-dimethylformamide (DMF). The facilitated diffusion of 100 microM radiolabeled adenosine and 2'-deoxyadenosine, measured by rapid transport assays, decreased 10- to 20-fold. The transport of 2 microM coformycin or 2'-deoxycoformycin, which is mediated by the same mechanism and was monitored by the adenosine deaminase titration assay, decreased 29-fold. The reduction in nucleoside transport capacity after DMF treatment was confirmed by a 19-fold decrease in the number of specific binding sites per cell (from 24-30 X 10(4) to 1.2-1.7 X 10(4)) for [3H]-6-p-nitrobenzylthioinosine, a nucleoside transport inhibitor. The binding affinity of 6-p-nitrobenzylthioinosine was not altered significantly and nucleoside transport remained sensitive to the transport inhibitors, 6-p-nitrobenzylthioinosine, dipyridamole, and dilazep after DMF-induced maturation. Time-dependence studies showed that the rate of 100 microM deoxyadenosine transport was unchanged for the first 24 h of exposure to DMF but fell to about 36% of control rates at 24-26 h and then gradually decreased further to about 4-5% of control rates after 5-6 days. In contrast, transport rates of the purine bases were reduced only 2- to 3-fold in HL-60 cells after 5 days of DMF treatment. The rates of adenosine and deoxyadenosine transport were unchanged or reduced by no more than 2-fold after 5-6 days of exposure to 0.8% DMF in the following human tumor cell lines that are not inducible with DMF: ARH-77 (multiple myeloma), KG-1 (acute myelogenous), and K-562 (chronic myelogenous). Thus, changes in nucleoside transport may serve as an early, membrane-associated marker of differentiation of the HL-60 cell line.

Adenosine↗
PubMed1995

2',3'-Dideoxyadenosine killing of TdT-positive cells is due to a trace contaminant.

We have previously reported that the chain-terminating nucleoside analogue 2',3'-dideoxyadenosine (ddA) is specifically cytotoxic for TdT-positive cells in the co-presence of the adenosine deaminase (ADA) inhibitor coformycin (CF). Further studies with ddA/CF revealed that cytotoxicity occurs only if ddA is supplied from the Calbiochem or Fluka companies. ddA supplied from other commercial sources (Pharmacia, Sigma) or the NCI Pharmaceutical Resources Branch is non-cytotoxic. To explore the basis for this difference, ddA from various sources was subjected to reverse-phase high-pressure liquid chromatography (HPLC) analysis. The Calbiochem and Fluka ddA had a unique HPLC peak, with a retention time of 12.8 min, representing a contaminant of less than 0.1% of the bulk material applied to the C-18 HPLC column. Study of all HPLC peaks resolved from the bulk material showed cytotoxic activity in only the 12.8 min peak. To identify the nature of the unknown compound, we compared HPLC characteristics of the synthetic intermediates and byproducts of ddA synthesis to the peak eluting at 12.8 min. Of these, only 3'-deoxyadenosine (cordycepin) had similar HPLC characteristics. In addition, in the co-presence of CF, cordycepin was specifically cytotoxic (IC50 < 0.5 microM) for all TdT-positive cell lines tested. Cytotoxicity was seen in TdT-negative cells only at concentrations 10-100-fold higher. We conclude that our previous report on ddA/CF as a TdT-specific cytotoxic combination was due to contamination of the ddA supplied by Calbiochem by cordycepin. ddA itself is non-cytotoxic for TdT-positive cells. Cordycepin in the co-presence of an ADA inhibitor may be effective in the treatment of TdT-positive hematological malignancies.

Cell Survival↗
PubMed1997

The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine.

The purine nucleoside adenosine (9-beta-D-ribofuranosyladenine) inhibits a number of lymphocyte functions in vitro, including the ability of activated T lymphocytes and natural killer cells to adhere to and kill tumor targets. Solid tumors, such as adenocarcinomas of the lung and colon, are frequently hypoxic and are, therefore, likely to exhibit increased adenine nucleotide breakdown through the 5'-nucleotidase pathway, yielding adenosine. We examined whether the concentration of adenosine in the extracellular fluid of such tumors is adequate to cause immunosuppression. Murine tumors grown in syngeneic hosts or human tumors grown in immunodeficient nu/nu mice were subjected to microdialysis, and adenosine levels in the microdialysate were measured by high-performance liquid chromatography. Treatment of the tumor microdialysates with adenosine deaminase eliminated the adenosine peak. Recovery of adenosine ranged from 15 to 29%, depending on the microdialysis probe, and concentrations of adenosine in tumors ranged from 0.2 to 2.4 microM with a mean of 0.5 microM. In contrast, the adenosine concentration measured s.c. at the same location was 30 +/- 5 nM (mean +/- SE). Inclusion of the adenosine deaminase inhibitor coformycin (10 microM) and the adenosine kinase inhibitor 5'-iodotubercidin (0.1 microM) in the microdialysis perfusion buffer increased extracellular adenosine concentration in tumors to as high as 13 microM. These data show that extracellular adenosine levels in solid tumors are sufficient to suppress the local antitumor immune response and that interference with pathways of adenosine metabolism causes marked increases in tumor extracellular adenosine concentration.

Adenosine↗