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call loadScript javascripts\jsmol\core\package.js call loadScript javascripts\jsmol\core\core.z.js -- required by ClazzNode call loadScript javascripts\jsmol\J\awtjs2d\WebOutputChannel.js Jmol JavaScript applet jmolApplet0_object__900690825829079__ initializing getValue debug = null getValue logLevel = null getValue allowjavascript = null AppletRegistry.checkIn(jmolApplet0_object__900690825829079__) call loadScript javascripts\jsmol\core\corestate.z.js viewerOptions: { "name":"jmolApplet0_object","applet":true,"documentBase":"https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:27834","platform":"J.awtjs2d.Platform","fullName":"jmolApplet0_object__900690825829079__","display":"jmolApplet0_canvas2d","signedApplet":"true","appletReadyCallback":"Jmol._readyCallback","statusListener":"[J.appletjs.Jmol.MyStatusListener object]","codeBase":"https://www.ebi.ac.uk/chebi/javascripts/jsmol/","syncId":"900690825829079","bgcolor":"#000" } (C) 2012 Jmol Development Jmol Version: 13.2.7 $Date: 2013-10-01 11:35:15 -0500 (Tue, 01 Oct 2013) $ java.vendor: j2s java.version: 0.0 os.name: j2s Access: ALL memory: 0.0/0.0 processors available: 1 useCommandThread: false appletId:jmolApplet0_object (signed) starting HoverWatcher_1 getValue emulate = null defaults = "Jmol" getValue boxbgcolor = null getValue bgcolor = #000 backgroundColor = "#000" getValue ANIMFRAMECallback = null getValue APPLETREADYCallback = Jmol._readyCallback APPLETREADYCallback = "Jmol._readyCallback" getValue ATOMMOVEDCallback = null getValue CLICKCallback = null getValue ECHOCallback = null getValue ERRORCallback = null getValue EVALCallback = null getValue HOVERCallback = null getValue LOADSTRUCTCallback = null getValue MEASURECallback = null getValue MESSAGECallback = null getValue MINIMIZATIONCallback = null getValue PICKCallback = null getValue RESIZECallback = null getValue SCRIPTCallback = null getValue SYNCCallback = null getValue STRUCTUREMODIFIEDCallback = null getValue doTranslate = null language=en_US getValue popupMenu = null getValue script = null Jmol applet jmolApplet0_object__900690825829079__ ready call loadScript javascripts\jsmol\core\corescript.z.js call loadScript javascripts\jsmol\J\script\FileLoadThread.js starting QueueThread0_2 script 1 started starting HoverWatcher_3 starting HoverWatcher_4 The Resolver thinks Mol DCF - Ideal conformer Mrv1927 09142313133D starting HoverWatcher_5 Time for openFile(DCF - Ideal conformer Mrv1927 09142313133D 35 37 0 0 0 0 999 V2000 1.6930 -0.8210 -1.4210 N 0 0 0 0 0 0 0 0 0 0 0 0 1.4190 -0.5890 -0.1700 C 0 0 0 0 0 0 0 0 0 0 0 0 0.1950 -0.0100 -0.0920 N 0 0 0 0 0 0 0 0 0 0 0 0 0.6700 -0.4090 -2.1950 C 0 0 0 0 0 0 0 0 0 0 0 0 -0.2840 0.1080 -1.3870 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.4830 0.6640 -1.6790 N 0 0 0 0 0 0 0 0 0 0 0 0 -2.0260 0.8680 -2.8140 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.5170 0.5320 -4.0170 N 0 0 0 0 0 0 0 0 0 0 0 0 -0.1080 0.5840 -4.3530 C 0 0 2 0 0 0 0 0 0 0 0 0 0.6580 -0.5440 -3.6920 C 0 0 1 0 0 0 0 0 0 0 0 0 2.0040 -0.5340 -4.1720 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.3410 -0.7590 1.6800 C 0 0 2 0 0 0 0 0 0 0 0 0 -0.7910 -0.9890 3.1110 C 0 0 2 0 0 0 0 0 0 0 0 0 -1.8540 -1.2420 4.0310 O 0 0 0 0 0 0 0 0 0 0 0 0 1.6510 1.4380 4.6850 O 0 0 0 0 0 0 0 0 0 0 0 0 0.9970 0.1860 4.4630 C 0 0 1 0 0 0 0 0 0 0 0 0 -0.1000 0.3640 3.4130 C 0 0 1 0 0 0 0 0 0 0 0 0 0.4680 0.7470 2.1420 O 0 0 0 0 0 0 0 0 0 0 0 0 -0.4940 0.4040 1.1310 C 0 0 1 0 0 0 0 0 0 0 0 0 2.0610 -0.8180 0.6670 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.9880 1.3590 -2.8120 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.1350 0.2370 -4.7040 H 0 0 0 0 0 0 0 0 0 0 0 0 0.3020 1.5370 -4.0190 H 0 0 0 0 0 0 0 0 0 0 0 0 0.0040 0.5070 -5.4340 H 0 0 0 0 0 0 0 0 0 0 0 0 0.1930 -1.4930 -3.9590 H 0 0 0 0 0 0 0 0 0 0 0 0 1.9590 -0.6220 -5.1340 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.3930 -0.4800 1.7190 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.2040 -1.6510 1.0690 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.0660 -1.8040 3.1230 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.2970 -2.0480 3.7320 H 0 0 0 0 0 0 0 0 0 0 0 0 2.3340 1.2820 5.3520 H 0 0 0 0 0 0 0 0 0 0 0 0 1.7240 -0.5440 4.1090 H 0 0 0 0 0 0 0 0 0 0 0 0 0.5550 -0.1620 5.3960 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.8300 1.1020 3.7440 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.1330 1.2620 0.9230 H 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 0 0 0 0 1 4 1 0 0 0 0 2 3 1 0 0 0 0 2 20 1 0 0 0 0 3 5 1 0 0 0 0 3 19 1 0 0 0 0 4 5 2 0 0 0 0 4 10 1 0 0 0 0 5 6 1 0 0 0 0 6 7 2 0 0 0 0 7 8 1 0 0 0 0 7 21 1 0 0 0 0 8 9 1 0 0 0 0 8 22 1 0 0 0 0 9 10 1 0 0 0 0 9 23 1 0 0 0 0 9 24 1 0 0 0 0 10 11 1 0 0 0 0 10 25 1 1 0 0 0 11 26 1 0 0 0 0 12 13 1 0 0 0 0 12 19 1 0 0 0 0 12 27 1 0 0 0 0 12 28 1 0 0 0 0 13 14 1 0 0 0 0 13 17 1 0 0 0 0 13 29 1 6 0 0 0 14 30 1 0 0 0 0 15 16 1 0 0 0 0 15 31 1 0 0 0 0 16 17 1 0 0 0 0 16 32 1 0 0 0 0 16 33 1 0 0 0 0 17 18 1 0 0 0 0 17 34 1 1 0 0 0 18 19 1 0 0 0 0 19 35 1 6 0 0 0 M END): 18 ms reading 35 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. 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| Pentostatin (or deoxycoformycin, trade name Nipent, manufactured by SuperGen) is an anticancer chemotherapeutic drug. |
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Read full article at Wikipedia
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InChI=1S/C11H16N4O4/c16- 3-8-6(17)1-9(19-8)15-5-14-10-7(18)2-12-4-13-11(10)15/h4-9,16-18H,1-3H2,(H,12,13)/t6-,7+,8+,9+/m0/s1 |
| FPVKHBSQESCIEP-JQCXWYLXSA-N |
| OC[C@H]1O[C@H](C[C@@H]1O)N1C=NC2=C1N=CNC[C@H]2O |
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Aspergillus nidulans
(NCBI:txid162425)
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of strain
Y 176-2
See:
DOI
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EC 3.5.4.4 (adenosine deaminase) inhibitor
An EC 3.5.4.* (non-peptide cyclic amidine C-N hydrolase) inhibitor that interferes with the action of adenosine deaminase (EC 3.5.4.4).
antimetabolite
A substance which is structurally similar to a metabolite but which competes with it or replaces it, and so prevents or reduces its normal utilization.
bacterial metabolite
Any prokaryotic metabolite produced during a metabolic reaction in bacteria.
Aspergillus metabolite
Any fungal metabolite produced during a metabolic reaction in the mould, Aspergillus .
nucleoside antibiotic
(via coformycins )
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antineoplastic agent
A substance that inhibits or prevents the proliferation of neoplasms.
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View more via ChEBI Ontology
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(8R)-3-(2-deoxy-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol
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pentostatin
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WHO MedNet
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pentostatina
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WHO MedNet
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pentostatine
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WHO MedNet
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pentostatinum
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WHO MedNet
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2'-deoxycoformycin
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ChEBI
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CI 825
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DrugBank
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CI-825
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DrugBank
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CI825
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ChEBI
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co-vidarabine
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DrugBank
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deoxycoformycin
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KEGG COMPOUND
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deoxycoformycin
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ChEBI
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PD 81565
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DrugBank
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PD-81565
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DrugBank
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PD-ADI
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DrugBank
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PD81565
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ChEBI
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YK-176
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DrugBank
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53910-25-1
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CAS Registry Number
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KEGG COMPOUND
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Rawat RS, Kumar S (2023)
Understanding the mode of inhibition and molecular interaction of taxifolin with human adenosine deaminase.
Journal of biomolecular structure & dynamics 41, 377-385 [PubMed:34851227]
[show Abstract]
Adenosine deaminase is a zinc+2 dependent key enzyme of purine metabolism which irreversibly converts adenosine to inosine and form ammonia. Overexpression of adenosine deaminase has been linked to a variety of pathophysiological conditions such as atherosclerosis, hypertension, and diabetes. In the case of a cell-mediated immune response, ADA is thought to be a marker, particularly in type II diabetes. Deoxycoformycin is the most potent ADA inhibitor that has been discovered so far, but it has several drawbacks, including being toxic and having poor pharmacokinetics. Taxifolin, a flavonoid derived from plants, was discovered to be a potent inhibitor of the human ADA (hADA) enzyme in the current study. Taxifolin bound at the active site of human ADA and showed fifty percent inhibition at a concentration of 400 µM against the enzyme. To better understand the interactions between taxifolin and human ADA, docking and molecular dynamic simulations were performed. In-silico studies using autodock revealed that taxifolin bound in the active site of human ADA with a binding energy of -7.4 kcal mol -1 and a theoretical Ki of 3.7 uM. Comparative analysis indicated that taxifolin and deoxycoformycin share a common binding space in the active site of human ADA and inhibit its catalytic activity similarly. The work emphasises the need of employing taxifolin as a lead chemical in order to produce a more precise and effective inhibitor of the human ADA enzyme with therapeutic potential.Communicated by Ramaswamy H. Sarma. | Dimitrova D, Kanakry JA (2022)
Beyond fludarabine: pentostatin plus cyclophosphamide are a well-tolerated alternative in reduced intensity conditioning.
Bone marrow transplantation 57, 1837-1838 [PubMed:36115868] | Tusup M, Kündig TM, Pascolo S (2022)
Epitranscriptomics modifier pentostatin indirectly triggers Toll-like receptor 3 and can enhance immune infiltration in tumors.
Molecular therapy : the journal of the American Society of Gene Therapy 30, 1163-1170 [PubMed:34563676]
[show Abstract]
The adenosine deaminase inhibitor 2'-deoxycoformycin (pentostatin, Nipent) has been used since 1982 to treat leukemia and lymphoma, but its mode of action is still unknown. Pentostatin was reported to decrease methylation of cellular RNA. We discovered that RNA extracted from pentostatin-treated cells or mice has enhanced immunostimulating capacities. Accordingly, we demonstrated in mice that the anticancer activity of pentostatin required Toll-like receptor 3, the type I interferon receptor, and T cells. Upon systemic administration of pentostatin, type I interferon is produced locally in tumors, resulting in immune cell infiltration. We combined pentostatin with immune checkpoint inhibitors and observed synergistic anti-cancer activities. Our work identifies pentostatin as a new class of an anticancer immunostimulating drug that activates innate immunity within tumor tissues and synergizes with systemic T cell therapies. | Gao S, Zhang W, Barrow SL, Iavarone AT, Klinman JP (2022)
Temperature-dependent hydrogen deuterium exchange shows impact of analog binding on adenosine deaminase flexibility but not embedded thermal networks.
The Journal of biological chemistry 298, 102350 [PubMed:35933011]
[show Abstract]
The analysis of hydrogen deuterium exchange by mass spectrometry as a function of temperature and mutation has emerged as a generic and efficient tool for the spatial resolution of protein networks that are proposed to function in the thermal activation of catalysis. In this work, we extend temperature-dependent hydrogen deuterium exchange from apo-enzyme structures to protein-ligand complexes. Using adenosine deaminase as a prototype, we compared the impacts of a substrate analog (1-deaza-adenosine) and a very tight-binding inhibitor/transition state analog (pentostatin) at single and multiple temperatures. At a single temperature, we observed different hydrogen deuterium exchange-mass spectrometry properties for the two ligands, as expected from their 106-fold differences in strength of binding. By contrast, analogous patterns for temperature-dependent hydrogen deuterium exchange mass spectrometry emerge in the presence of both 1-deaza-adenosine and pentostatin, indicating similar impacts of either ligand on the enthalpic barriers for local protein unfolding. We extended temperature-dependent hydrogen deuterium exchange to a function-altering mutant of adenosine deaminase in the presence of pentostatin and revealed a protein thermal network that is highly similar to that previously reported for the apo-enzyme (Gao et al., 2020, JACS 142, 19936-19949). Finally, we discuss the differential impacts of pentostatin binding on overall protein flexibility versus site-specific thermal transfer pathways in the context of models for substrate-induced changes to a distributed protein conformational landscape that act in synergy with embedded protein thermal networks to achieve efficient catalysis. | Hagen NR, Nguyen ML, Williams JD, Bowlin TL, Gentry BG (2021)
Pentostatin antagonizes the antiviral activity of MBX-2168 by inhibiting the biosynthesis of the active compound.
Antiviral research 187, 105018 [PubMed:33476709]
[show Abstract]
MBX-2168 has a mechanism of action similar to that of acyclovir (ACV) and ganciclovir (GCV), but two unique steps differentiate this drug from ACV/GCV. First, MBX-2168 is, at least partially, phosphorylated by the endogenous cellular kinase TAOK3 to a monophosphate. The second involves the removal of a moiety at the 6-position of MBX-2168-MP by adenosine deaminase like protein-1 (ADAL-1). It has been previously demonstrated that co-incubation with pentostatin (dCF), an ADAL-1 inhibitor, antagonizes the anti-viral activity of MBX-2168. We therefore hypothesize that inhibiting ADAL-1 results in a reduction of active compound produced in virus-infected cells. To test this, we examined the effect dCF has on the conversion of MBX-2168 to a triphosphate in HSV-1 and HCMV-infected cells. Our results demonstrate incubation of MBX-2168 alone or with dCF in HCMV-infected cells resulted in 53.1 ± 0.7 and 39.4 ± 1.5 pmol triphosphate/106 cells at 120 h, respectively. Incubation of MBX-2168 alone or with dCF in Vero cells resulted in 12.8 ± 0.1 and 6.7 ± 0.7 pmol triphosphate/106 cells at 24 h, respectively. HSV-1-infected Vero cells demonstrated no statistical difference in triphosphate accumulation at 24 h (13.1 ± 0.3 pmol triphosphate/106 cells). As expected, incubation with dCF resulted in the accumulation of MBX-2168-MP in both HFF (9.8 ± 0.9 pmol MBX-2168-MP/106 cells at 120 h) and Vero cells (4.7 ± 0.3 pmol MBX-2168-MP/106 cells at 24 h) while no detectable levels of monophosphate were observed in cultures not incubated with dCF. We conclude that dCF antagonizes the anti-viral effect of MBX-2168 by inhibiting the production of triphosphate, the active compound. | Zhao M, Zhang H, Lou T, Zhao K, Wang S (2021)
[Simultaneous determination of pentostatin and 2'-amino-2'-deoxyadenosine in fermentation broth by high performance liquid chromatography-tandem mass spectrometry].
Se pu = Chinese journal of chromatography 39, 744-749 [PubMed:34227372]
[show Abstract]
An analytical method was established for the simultaneously determination the pentostatin and 2'-amino-2'-deoxyadenosine contents in fermentation broth by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). After high-speed centrifugation, aqueous solution dilution, vortex shock, and microfiltration, the fermentation broth samples were analyzed by HPLC-MS/MS. The samples were separated on a Waters Atlantis® T3 column (100 mm×2.1 mm, 5 μm) using a gradient elution program with 10 mmol/L ammonium formate (containing 0.1% formic acid) and methanol (containing 0.02% formic acid) as the mobile phases. Moreover, a chromatographic protection column (5 mm×2.1 mm, 5 μm) was added to preserve the column efficiency. The flow rate, column temperature, and injection volume were set at 0.3 mL/min, 25 ℃, and 10 μL, respectively. Qualitative and quantitative analyses of the target compounds were performed using an ESI+ source. MS parameters such as the collision energies and tube lens offsets of pentostatin and 2'-amino-2'-deoxyadenosine were optimized. The quantitative ion pairs of pentostatin and 2'-amino-2'-deoxyadenosine were m/z 269.17>153.20 and m/z 267.00>136.10, respectively; the corresponding collision energies were 11 V and 18 V. The external standard method was used for quantitative analysis. The established method was verified rigorously in terms of the linear range, limit of detection, limit of quantification, recovery rate, and precision. Pentostatin and 2'-amino-2'-deoxyadenosine showed good linear relationships in the range of 1.0-250 μg/L. The correlation coefficients ranged from 0.9969 to 0.9996, and the relative standard deviations (RSDs) ranged from 6.51% to 8.35% (n=8). This result indicated good accuracy and exactitude in the detection of the pentostatin and 2'-amino-2'-deoxyadenosine. The recoveries (n=6) at three spiked levels (1.0, 5.0, and 25 μg/L) were in the ranges of 97.94%-104.46% and 89.96%-107.21% for the pentostatin and 2'-amino-2'-deoxyadenosine, respectively; the corresponding RSDs were in the ranges of 3.74%-4.88% and 4.81%-13.29%. The limits of detection (LODs, S/N≥3) and limits of quantification (LOQs, S/N≥10) of the 2'-amino-2'-deoxyadenosine and pentostatin in the fermentation broth were 0.003-0.060 μg/L and 0.010-0.200 μg/L, respectively. The validated experimental method was used for the detection of actual samples, viz. the stored multiple pentostatin-producing mutagenic strains in our laboratory. The HPLC-MS/MS method for the determination of the pentostatin and 2'-amino-2'-deoxyadenosine in fermentation broth offered the advantages of small sampling volume, strong maneuverability, good stability, and high sensitivity. Compared with previously published methods, this systematically established and optimized method significantly reduced the detection time, and matrix effects were well suppressed. Moreover, the peak shape and stability of the target compounds were greatly improved. This method provides a methodological basis and meaningful reference for the detection of the pentostatin and 2'-amino-2'-deoxyadenosine in fermentation broth. | Song Z, Liu H, Duan X, Yang H, Wang C, Lu X, Tian Y (2021)
[Advances in the biosynthesis of pentostatin].
Sheng wu gong cheng xue bao = Chinese journal of biotechnology 37, 4158-4168 [PubMed:34984865]
[show Abstract]
Pentostatin is a nucleoside antibiotics with a strong inhibitory effect on adenosine deaminase, and is widely used in the clinical treatment of malignant tumors. However, the high cost hampers its application. In the past 10 years, the biosynthesis of pentostatin were focused on strain breeding, optimization of medium composition and fermentation process. To date, there are no reviews summarizing the elucidated biosynthetic mechanism of pentostatin. This review starts by introducing the various chemical route for production of pentostatin, followed by summarizing the mechanisms of pentostatin biosynthesis in different microorganisms. Finally, challenges for biosynthesis of pentostatin were discussed, and strategies for regulating and improving the microbial synthesis of pentostatin were proposed. | Alfayez M, Thakral B, Jain P, Ravandi F, Ferrajoli A, Jain N, Pemmaraju N, Wierda W, Kadia T (2020)
First report of clinical response to venetoclax combination with pentostatin in T-cell-prolymphocytic leukemia (T-PLL).
Leukemia & lymphoma 61, 445-449 [PubMed:31566032] | Krackeler ML, Broome C, Lai C (2020)
Complete remission of aggressive T-cell LGL leukemia with pentostatin therapy: first case report.
Stem cell investigation 7, 24 [PubMed:33437844]
[show Abstract]
This is the first report of a complete remission in aggressive T-cell large granular lymphocytic (T-LGL) leukemia after treatment with pentostatin. The aggressive variant of the disease is rare, and traditional therapies include immunosuppressive agents, however, there is no standard consensus for treatment. Cytotoxic chemotherapy has led to remission in a few reported cases. We present this unique case as an alternative treatment for individuals refractory to chemotherapy. A 55-year-old African American male with hypertension, type II diabetes mellitus, hyperlipidemia, and gout presented with symptoms of multiple ecchymosis, fatigue, and weight loss. He was found to have splenomegaly (SM) and significant leukocytosis to 101 k/µL with 30% blasts on peripheral smear. Following bone marrow aspiration and biopsy with flow cytometry, he was diagnosed with aggressive T-LGL leukemia. The chemotherapy regimen hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) was initially chosen based on his clinical presentation but was refractory to treatment. His therapy was changed to alemtuzumab; however, patient tolerated poorly and did not respond. Pentostatin was added to alemtuzumab with improvement in clinical symptoms and laboratory parameters. The patient was transitioned to pentostatin monotherapy and achieved complete remission after 1 month. This report provides support for pentostatin as an effective treatment for patients with aggressive T-cell malignancies refractory to cytotoxic chemotherapy. Pentostatin has previously been studied to treat T-cell prolymphocytic leukemia (T-PLL), hairy cell leukemia, and marginal zone lymphoma. This case suggests an alternative, well-tolerated option that could be considered for initial therapy of aggressive T-LGL leukemia. | Gozzetti A, Sammartano V, Bacchiarri F, Raspadori D, Bocchia M (2020)
A BRAF-Negative Classic Hairy Cell Leukemia Patient with Long-Lasting Complete Remission after Rituximab and Pentostatin
Turkish journal of haematology : official journal of Turkish Society of Haematology 37, 286-287 [PubMed:32539314] | Kempin S, Sun Z, Kay NE, Paietta EM, Mazza JJ, Ketterling RP, Frankfurt O, Claxton DF, Saltzman JN, Srkalovic G, Callander NS, Gross G, Tallman MS (2019)
Pentostatin, Cyclophosphamide, and Rituximab Followed by Alemtuzumab for Relapsed or Refractory Chronic Lymphocytic Leukemia: A Phase 2 Trial of the ECOG-Acrin Cancer Research Group (E2903).
Acta haematologica 142, 224-232 [PubMed:31336367]
[show Abstract]
Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) may benefit from salvage chemoimmunotherapy (CIT). To explore further the use of CIT in the pre-novel agent era, ECOG-ACRIN undertook a phase 2 trial (E2903) for R/R CLL utilizing pentostatin, cyclophosphamide, and rituximab (PCR) followed by a consolidation course of alemtuzumab. This trial enrolled 102 patients with a median age of 64 years. Treatment consisted of 6 cycles of PCR followed by alemtuzumab for either 4 or 18 weeks depending on the initial response to PCR. The overall response after PCR (complete remission, CR, nodular partial remission, nPR, and partial remission, PR) was 55%. Major responses (CR or nPR) were achieved in 6%. The median overall survival (OS) and the median progression-free survival were 28 and 12 months, respectively. The most serious nonlethal adverse events were myelosuppression, febrile neutropenia, fatigue, nausea, and hyponatremia. PCR is an effective and well-tolerated nucleoside-based regimen for heavily pretreated CLL patients with R/R disease. The addition of alemtuzumab to CLL patients with a minor response (PR) or stable disease did not result in a significant number of higher responses (CR or nPR) nor an improvement in OS. | Wellham PAD, Kim DH, Brock M, de Moor CH (2019)
Coupled biosynthesis of cordycepin and pentostatin in Cordyceps militaris: implications for fungal biology and medicinal natural products.
Annals of translational medicine 7, S85 [PubMed:31576294] | Khashab T, Hagemeister F, Romaguera JE, Fanale MA, Pro B, McLaughlin P, Rodriguez MA, Neelapu SS, Fayad L, Younes A, Feng L, Vega F, Kwak LW, Samaniego F (2019)
Long-term overall- and progression-free survival after pentostatin, cyclophosphamide and rituximab therapy for indolent non-Hodgkin lymphoma.
British journal of haematology 185, 670-678 [PubMed:30820940]
[show Abstract]
In a prospective phase II trial, pentostatin combined with cyclophosphamide and rituximab (PCR) induced strong responses and was well-tolerated in previously untreated patients with advanced-stage, indolent non-Hodgkin lymphoma (iNHL). After a median patient follow-up of more than 108 months, we performed an intent-to-treat analysis of our 83 participants. Progression-free survival (PFS) rates at 108 months for follicular lymphoma (FL), marginal zone lymphoma (MZL) and small lymphocytic lymphoma (SLL) were 71%, 67% and 15%, respectively, and were affected by clinicopathological characteristics. Ten-year PFS rates for those with beta-2-microglobulin levels <2·2 and ≥2·2 mg/l prior to treatment were 71% and 21%, respectively. Patients without bone marrow involvement had 10-year PFS rates of 72% vs. 29% for those with involvement. At time of analysis, the median overall survival (OS) had not been reached. The OS rate was 64% at 10 years and differed significantly based on histology: 94% for FL, 66% for MZL and 39% for SLL. Long-term toxicities included 18 (21·7%) patients with second malignancies and 2 (2·4%) who developed myelodysplastic syndrome after receiving additional lines of chemotherapy. Our 10-year follow-up analysis confirms that PCR is an effective, robust and tolerable treatment regimen for patients with iNHL. | do Carmo GM, de Sá MF, Grando TH, Gressler LT, Baldissera MD, Monteiro SG, Henker LC, Mendes RE, Stefani LM, Da Silva AS (2019)
Cordycepin (3'-deoxyadenosine) and pentostatin (deoxycoformycin) against Trypanosoma cruzi.
Experimental parasitology 199, 47-51 [PubMed:30825499]
[show Abstract]
The aim of this study was to evaluate in vitro the efficacy of cordycepin and pentostatin (alone or combined) against Trypanosoma cruzi, as well as the therapeutic efficiency of protocols of cordycepin and pentostatin combinations in mice experimentally infected with T. cruzi. In vitro, the cordycepin (3'-deoxyadenosine) and pentostatin (deoxycoformycin) exerted potent trypanocidal effect against T. cruzi (Colombian strain), similarly to benznidazole, which is the reference drug. For epimastigotes, the lethal dose of cordycepin capable of killing 50% (LD50) and 20% (LD20) of the parasites was 0.072 and 0.031 mg/mL, respectively and for trypomastigotes was 0.047 and 0.015 mg/mL, respectively. The combined use of cordycepin and pentostatin resulted in a LD50 and LD20 for epimastigotes of 0.068 and 0.027 mg/mL, respectively, as well as 0.056 and 0.018 mg/mL for trypomastigotes, respectively. In vivo, the combined use of cordycepin and pentostatin did not show the expected curative effect, however it was able to control the parasitema in the peak period. In summary, the combination of cordycepin and pentostatin showed no curative effect in mice infected by T. cruzi, despite the in vitro reduction of epimastigotes and trypomastigotes. | Zhao X, Zhang G, Li C, Ling J (2019)
Cordycepin and pentostatin biosynthesis gene identified through transcriptome and proteomics analysis of Cordyceps kyushuensis Kob.
Microbiological research 218, 12-21 [PubMed:30454654]
[show Abstract]
Cordyceps kyushuensis is the only species of cordyceps growing on the larvae of Clanis bilineata Walker, and has been demonstrated that there are lots of pharmacological components including cordycepin. Cordycepin shows lots of pharmacological action but it could be converted to 3'-deoxyinosine by adenosine deaminase in vivo, which weakens the efficiency of cordycepin. That pentostatin, which has been reported to inhibit adenosine deaminase, combining cordycepin could enhance the efficiency of cordycepin in vivo. During transcriptome and proteomics analysis of Cordyceps kyushuensis, a single gene cluster including four genes we named ck1-ck4 which can synthesis both cordycepin and pentostatin has been identified using BLAST. Meanwhile, KEGG, KOG, GO analysis and differentially expressed genes were analyzed in transcriptome and proteomics. This study first sequenced transcriptome and proteomics of C. kyushuensis, and demonstrated that there is a single gene cluster related to biosynthesis of cordycepin and pentostatin, which can be employed to improve the yield of cordycepin and find more functional proteins. | Bar M, Flowers MED, Storer BE, Chauncey TR, Pulsipher MA, Thakar MS, Bethge W, Storb R, Maloney DG, Sandmaier BM (2018)
Reversal of Low Donor Chimerism after Hematopoietic Cell Transplantation Using Pentostatin and Donor Lymphocyte Infusion: A Prospective Phase II Multicenter Trial.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 24, 308-313 [PubMed:29032276]
[show Abstract]
In a multicenter, prospective, phase II study we evaluated the safety and efficacy of pentostatin followed by donor lymphocyte infusion (DLI) in patients with low donor Tcell chimerism after allogeneic hematopoietic cell transplantation (HCT). Thirty-six patients with low donor blood CD3 chimerism were enrolled in this study. Thirty-five patients received a total of 41 DLIs after a dose of pentostatin, and 1 patient received pentostatin only. Median donor CD3 chimerism prompting the initiation of pentostatin and DLI was 28% (range, 5% to 47%). Responses (defined by increases in donor CD3 chimerism ≥10% maintained to day 56 post-DLI) were seen in 16 patients (44.4%) with a median rise in CD3 donor chimerism to 64% (range, 48% to 100%). There was a trend for better responses among 21 patients who received first treatment within 100 days after transplant (57% response rate) compared with15 patients who received first treatment more than 100 days after HCT (27% response rate, P = .07). Fourteen patients (39%) developed grades II to IV acute graft-versus-host disease (GVHD) at a median of 10 days (range, 0 to 83) after DLI. Ten patients (28%) developed extensive chronic GVHD. Seventeen patients (47%) developed new grade 4 cytopenias after DLI. There was no difference in relapse between nonresponders and responders. Twenty-eight patients (78%) died, most (n = 21) because of relapse. Five of 16 responders (31%) are alive, all disease-free, at a median of 60 months (range, 21 to 132) after DLI. Six of 20 nonresponders (30%) are alive at a median of 47 months (range, 16 to 100) after DLI, 3 in complete remission. Pentostatin and DLI had acceptable toxicity and appeared to increase low donor CD3 chimerism after HCT but had no impact on mortality. | Ragon BK, Mehta RS, Gulbis AM, Saliba RM, Chen J, Rondon G, Popat UR, Nieto Y, Oran B, Olson AL, Patel K, Hosing CM, Qazilbash MH, Shah N, Kebriaei P, Shpall EJ, Champlin RE, Alousi AM (2018)
Pentostatin therapy for steroid-refractory acute graft versus host disease: identifying those who may benefit.
Bone marrow transplantation 53, 315-325 [PubMed:29269797]
[show Abstract]
We report outcomes of 60 patients with steroid-refractory (SR)-aGVHD treated with pentostatin. Almost half (47%) of patients had grade 4 GVHD-22% had stage 3-4 liver GVHD and 51% had stage 3-4 lower gastrointestinal tract (LGI) GVHD. Patients received a median of 3 courses (range, 1-9) of pentostatin. Day 28 overall response rate (ORR) was 33% (n = 20) (complete response 18% (n = 11), partial response 15% (n = 9)). Non-relapse mortality was 72% (95% confidence interval (CI) 61-84%) and overall survival (OS) was 21% (95% CI 12-32%) at 18 months. On univariate analysis, age >60 years (HR 1.9, 95% CI 1.01-3.7, p = 0.045) and presence of liver GVHD (HR 1.9, 95% CI 1.9, 95% CI 1.5-3.3, p = 0.03) were significant predictors of poor OS while patients with LGI GVHD had superior OS than those without (HR 0.4, 95% CI 0.2-0.8, p = 0.01). On stratified analysis, patients <60 years with isolated LGI GVHD had the best outcomes with an ORR of 48% and OS of 42% at 18 months. Among older patients, OS was 14% in those with isolated LGI aGVHD and 0% in others. Pentostatin remains a viable treatment option for SR-aGVHD, especially in patients 60 years or younger with isolated LGI involvement. | Alsuliman T, Lassoued K, Belghoul M, Debbache K, Choufi B (2018)
Durable Resolution of Severe Psoriasis in a Patient Treated with Pentostatin for Hairy Cell Leukemia: A Case Report.
Dermatology and therapy 8, 165-169 [PubMed:29196889]
[show Abstract]
IntroductionPentostatin (2'-deoxycoformycin) and cladribine (2-chlorodeoxyadenosine) are adenosine analogues widely used to treat lymphoid malignancies, mainly hairy cell leukemia (HCL). Oral or parenteral adenosine analogues have been also used as immunomodulatory agents in multiple sclerosis and in acute graft-versus-host disease.Case reportHere, we report the case of a 43-year-old patient with a history of extensive psoriasis who later developed HCL.ResultsThe patient had achieved complete remission of both psoriasis and HCL after receiving intravenous infusions of pentostatin. It is worth noting that cladribine has already been reported to treat plaque psoriasis lesions in two patients with HCL and in a third patient with gastric marginal zone B cell lymphoma [1].ConclusionWe believe that adenosine analogues constitute a promising therapeutic option for moderate to severe psoriasis, especially for severe and refractory psoriasis, as well as for patients with adjacent lymphoid malignancies. | Kay NE, LaPlant BR, Pettinger AM, Call TG, Leis JF, Ding W, Parikh SA, Conte MJ, Bowen DA, Shanafelt TD (2018)
Cumulative experience and long term follow-up of pentostatin-based chemoimmunotherapy trials for patients with chronic lymphocytic leukemia.
Expert review of hematology 11, 337-349 [PubMed:29460654]
[show Abstract]
Background7 regimens of pentostatin based chemoimmunotherapy (CIT) for progressive previously untreated CLL primarily with long term follow-up to update both efficacy and toxicity.Research design and methodsPrognostic markers including assessment of IGVH and FISH status were done on all. Response rates and 95% binomial confidence intervals were calculated for each regimen and in the combined cohort. Overall survival and treatment-free survival were evaluated using Kaplan-Meier methods.ResultsThe initial CIT trial was pentostatin (2 mgs/m2), cyclophosphamide (600 mg/m2) and rituximab (PCR) but subsequent P based CIT trials with modifications in subsequent trials. The cohort (n = 288) included 52% with unmutated IGVH status and del17p (4.5%) and del11q (14.9%). Toxicity profiles were primarily hematologic and no patient has developed MDS or AML after a median follow-up of 6.4 years. The overall response rate across all trials was found to be over 90% with a 41% complete response rate. We validated that the CLL IPI model segregates progressive CLL patients into 4 risk groups associated with OS and TFS.ConclusionsThe high overall and complete response levels in favorable genetic risk CLL along with favorable toxicity profiles provide rationale for consideration of a PC based strategy for previously untreated progressive CLL. | Xia Y, Luo F, Shang Y, Chen P, Lu Y, Wang C (2017)
Fungal Cordycepin Biosynthesis Is Coupled with the Production of the Safeguard Molecule Pentostatin.
Cell chemical biology 24, 1479-1489.e4 [PubMed:29056419]
[show Abstract]
Cordycepin (COR) and pentostatin (PTN) are adenosine analogs with related bioactivity profiles as both mimic adenosine and can inhibit some of the processes that are adenosine dependent. Both COR and PTN are also natural products and were originally isolated from the fungus Cordyceps militaris and the bacterium Streptomyces antibioticus, respectively. Here, we report that not only is PTN produced by C. militaris but that biosynthesis of COR is coupled with PTN production by a single gene cluster. We also demonstrate that this coupling is an important point of metabolic regulation where PTN safeguards COR from deamination by inhibiting adenosine deaminase (ADA) activity. ADA is not inhibited until COR reaches self-toxic levels, at which point ADA derepression occurs allowing for detoxification of COR to 3'-deoxyinosine. Finally, we show that using our biosynthetic insights, we can engineer C. militaris to produce higher levels of COR and PTN. | do Carmo GM, Doleski PH, de Sá MF, Grando TH, Azevedo MI, Manzoni AG, Leal DBR, Gressler LT, Henker LC, Mendes RE, Baldissera MD, Monteiro SG, Stefani LM, Da Silva AS (2017)
Treatment with 3'-deoxyadenosine and deoxycoformycin in mice infected by Trypanosoma cruzi and its side effect on purinergic enzymes.
Microbial pathogenesis 113, 51-56 [PubMed:29051060]
[show Abstract]
The aim of this study was to evaluate the efficacy of 3'-deoxyadenosine and deoxycoformycin combination in the treatment of mice infected by T. cruzi, as well as to verify the influence of the treatment on purinergic enzymes. Heart and serum samples were collected from 60 mice (30 infected and 30 uninfected) at day 12 post-infection. To verify treatment efficacy, parasitemia was monitored, and the treatment with 3'-deoxy adenosine and deoxycoformycin combination was able to reduce it, but had no curative effect on mice. Seric activities of NTPDase (ATP and ADP substrate) and ADA were increased significantly in untreated mice infected by T. cruzi compared to the negative control, as well as mice treated with 3'-deoxyadenosine and deoxycoformycin (alone or combined) modulated the activity of NTPDase (ATP and ADP substrate), preventing them from increasing in infected animals (activity similar to healthy animals). Treatment with deoxycoformycin alone and associated with 3'-deoxyadenosine modulated the activity of ADA preventing them from increasing in infected animals. However, seric activities of ADA in mice treated with 3'-deoxyadenosine (cordycepin) alone does not modify the ADA activity compared with infected and non-treated mice. However, the 5'-nucleotidase activity decreased significantly in infected untreated animals and the same occurred in infected and treated animals with deoxycoformycin and 3'-deoxyadenosine. However, treatment with deoxycoformycin associated with 3'-deoxyadenosine preventing them from decreasing the 5'-nucleotidase activity. Therefore, we conclude that the treatments did not have curative success for mice infected by T. cruzi. However, the treatments were able to modulate the purinergic enzymes during the infection by T. cruzi, which may contribute to reduce the inflammatory damage in heart. | Solimando DA, Waddell JA (2016)
Pentostatin, Cyclophosphamide and Rituximab (PCR) Regimen.
Hospital pharmacy 51, 888-893 [PubMed:28057947]
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The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr., President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, email: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net. The information presented in this review is based on published data and clinical expertise and includes information not included in the product labeling. Incorporation of such published data provides a more robust assessment of the drugs and assists pharmacists in evaluation of orders for off-label use of these agents. | Dalla Rosa L, da Silva AS, Gressler LT, Oliveira CB, Dambrós MG, Miletti LC, França RT, Lopes ST, Samara YN, da Veiga ML, Monteiro SG (2013)
Cordycepin (3'-deoxyadenosine) pentostatin (deoxycoformycin) combination treatment of mice experimentally infected with Trypanosoma evansi.
Parasitology 140, 663-671 [PubMed:23361035]
[show Abstract]
The aim of this study was to evaluate the anti-trypanosomal effect of treatment with 3'-deoxyadenosine (cordycepin) combined with deoxycoformycin (pentostatin: inhibitor of the enzyme adenosine deaminase) in vitro by using mice experimentally infected with Trypanosoma evansi. In vitro, a dose-dependent trypanocidal effect of cordycepin was observed against the parasite. In the in vivo trials, the two drugs were used individually and in combination of different doses. The drugs when used individually had no curative effect on infected mice. However, the combination of cordycepin (2 mg kg-1) and pentostatin (2 mg kg-1) was 100% effective in the T. evansi-infected groups. There was an increase in levels of some biochemical parameters, especially on liver enzymes, which were accompanied by histological lesions in the liver and kidneys. Based on these results we conclude that treatment using the combination of 3'-deoxyadenosine with deoxycoformycin has a curative effect on mice infected with T. evansi. However, the therapeutic protocol tested led to liver and kidney damage, manifested by hepatotoxicity and nephrotoxicity. | Larson ET, Deng W, Krumm BE, Napuli A, Mueller N, Van Voorhis WC, Buckner FS, Fan E, Lauricella A, DeTitta G, Luft J, Zucker F, Hol WG, Verlinde CL, Merritt EA (2008)
Structures of substrate- and inhibitor-bound adenosine deaminase from a human malaria parasite show a dramatic conformational change and shed light on drug selectivity.
Journal of molecular biology 381, 975-988 [PubMed:18602399]
[show Abstract]
Plasmodium and other apicomplexan parasites are deficient in purine biosynthesis, relying instead on the salvage of purines from their host environment. Therefore, interference with the purine salvage pathway is an attractive therapeutic target. The plasmodial enzyme adenosine deaminase (ADA) plays a central role in purine salvage and, unlike mammalian ADA homologs, has a further secondary role in methylthiopurine recycling. For this reason, plasmodial ADA accepts a wider range of substrates, as it is responsible for deamination of both adenosine and 5'-methylthioadenosine. The latter substrate is not accepted by mammalian ADA homologs. The structural basis for this natural difference in specificity between plasmodial and mammalian ADA has not been well understood. We now report crystal structures of Plasmodium vivax ADA in complex with adenosine, guanosine, and the picomolar inhibitor 2'-deoxycoformycin. These structures highlight a drastic conformational change in plasmodial ADA upon substrate binding that has not been observed for mammalian ADA enzymes. Further, these complexes illuminate the structural basis for the differential substrate specificity and potential drug selectivity between mammalian and parasite enzymes. | Braiteh F, Ng C, Kurzrock R (2006)
Refractory Hodgkin lymphoma responds to pentostatin (2'-deoxycoformycin).
Leukemia & lymphoma 47, 373-375 [PubMed:16321875] | Dillman RO (2004)
Pentostatin (Nipent) in the treatment of chronic lymphocyte leukemia and hairy cell leukemia.
Expert review of anticancer therapy 4, 27-36 [PubMed:14748654]
[show Abstract]
Pentostatin (Nipent), formerly known as deoxycoformycin, is a profound inhibitor of the enzyme adenosine deaminase, resulting in the accumulation of metabolites that inhibit ribonucleotide reductase, which in turn inhibits DNA synthesis. Pentostatin was the first of the purine analogs to undergo extensive testing as an anticancer agent and the first to receive US Food and Drug Administration approval for a treatment indication. It is highly effective as first-line monotherapy in hairy cell leukemia, with a complete response rate of 80% and a 10-year survival rate of around 80%. Pentostatin is also active in chronic lymphocyte leukemia as a single agent, but appears even more promising in combination approaches with the alkylating agents chlorambucil or cyclophosphamide. Due to the increasing recognition of delayed severe stem cell and immune suppression following therapy with other purine analogs, there has been renewed interest in pentostatin, especially in combination with chemotherapy and/or the monoclonal antibody rituximab (Rituxan) in chronic lymphocyte leukemia. | Kurzrock R (2000)
Pentostatin (Nipent) in T-cell lymphomas.
Seminars in oncology 27, 64-66 [PubMed:10877055]
[show Abstract]
Pentostatin (Nipent; SuperGen, San Ramon, CA), which is highly lymphocytotoxic, is an active agent in hairy cell leukemia. We therefore initiated a trial of this agent in T-cell lymphomas. Pentostatin was administered at a dose of 3.75 or 5.0 mg/m2/d intravenously for 3 days every 3 weeks to heavily pretreated patients with cutaneous and peripheral T-cell lymphomas. To date, there are 24 evaluable patients in the trial. Seventeen of these individuals have responded (complete or partial remission). The most common toxicities included granulocytopenia, nausea, renal insufficiency, CD4 suppression, and delayed herpes zoster. Pentostatin is an active agent in this group of diseases and merits further exploration. | Wang Z, Quiocho FA (1998)
Complexes of adenosine deaminase with two potent inhibitors: X-ray structures in four independent molecules at pH of maximum activity.
Biochemistry 37, 8314-8324 [PubMed:9622483]
[show Abstract]
Adenosine deaminase, which catalyzes the irreversible hydrolytic deamination of adenosine nucleosides to inosine nucleosides and ammonia, is a key enzyme in purine metabolism and lymphoid development. The X-ray structures of murine adenosine deaminase with bound potent inhibitors (Ki values approximately 10(-13) M) (8R)-hydroxyl-2'-deoxycoformycin (pentostatin), a transition state analogue, and (6S)-hydroxyl-1,6-dihydropurine riboside, a reaction coordinate analogue, have been determined and refined to resolutions of 2.6 and 1.95 A, respectively. Crystals of both complexes were obtained at pH 7, where the enzyme is fully active, in an identical space group with the asymmetric unit containing four molecules. In addition to the very high degree of similarity between the four independent molecules in each complex structure, there is also considerable structural similarity of the complex with the dihydropurine riboside with that of an identical complex previously determined at pH 4.2 where the enzyme is 20% active. The interactions between the enzyme and the two analogues are extremely similar. These include the coordination of the 8R- or 6S-hydroxyl group of the analogues to the Zn2+ which mainly contributes to the strong potency and very high degree of stereospecificity of inhibition by these analogues. The interactions are further indicative of the structural and chemical requirements of substrates. These structures and recent site-directed mutagenesis have further shed light on the catalytic mechanism of the enzyme. |
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