PURINE AND PYRIMIDIN EMETABOLISM IN MAN VIIPart A : Chemotherapy, ATP Depletion,and Gout

R. Angus Harkness

Gertrude B. Elion

Nepomuk Zöllner

Advances in experimental medicine and biology ; v . 390A-B)

PART A

CHEMOTHERAPY

1 . Historical Development

Biochemical Approach to New Medications 1Nobel Laureate, G .H . Hitchings

2 . Cancer and AIDS Treatment

Antimetabolites in Cancer Chemotherapy 7J . Clarke, A .L . Jackman and K .R . Harrap

2-Chlorodeoxyadenosine Chemotherapy Trigger sProgrammed Cell Death in Normal and Malignan tLymphocytes 1 5C .J . Carrera, L.D . Piro, A . Saven, E . Beutler ,C . Terai and D .A . Carson

ICI D1694, an Inhibitor of Thymidylate Synthas efor Clinical Study 1 9A.L . Jackman, D .I . Jodrell, W. Gibson and T .C .Stephens

Action and Sequence Dependent Interaction o fAcivicin and 6-Thioguanine in the Human DerivedMaligant T-ALL and CALLA+ Cell Lines, 2 5R.C . Trueworthy, R .A . DeAbreu, L .H .J . Lambooy ,J .P.M. Bokkerink and E .H . Stet

Conversion of Acyclic Nucleoside Phosphonates t otheir

Diphosphate

Derivatives

by

5-Phosphoribosyl-l-Pyrophosphate (PRPP) Synthetase 2 9J . Balzarini and E . De Clercq

Derivation of New Drugs for Therapy of AIDS 3 3K .L . Powell and D .J . Purifoy

3 .Development and Effects of New Analogue s

Biochemical and Pharmacological Properties o fC1-972, a Novel 9-Deazaguanine Analog PurineNucleoside Phosphorylase (PNP) Inhibitor 4 1R .B . Gilbertsen, M .K . Dong, D .J . Wilburn, L.M.Kossarek, J .C . Sircar, C .R . Kostlan and M.C .Conroy

Pyrrolo[3,2-D]pyrimidines, a New Class of Purin eNucleoside Phosphyorylase (PNP) Inhibitors a sPotential T-cell Selective Immunosuppressiv eAgents 4 5J .C . Sircar, C .R . Kostlan, R.B. Gilbertsen, M .K .Dong and W .A . Centenko

Modulation of Metabolism and Anti-HIV-1 Activit yof Purine 2',3'-Dideoxynucleosides by IM PDehydrogenase Inhibitors 4 9L.L .Bondoc,Jr., B.L. Robbins, G .S . Ahluwalia, H .Mitsuya, D .G . Johns and A . Fridland

Acadesine (AICA Riboside) Inhibits PlateletAggregation in Human Whole Blood 5 5D .A . Bullough, C . Zhang and K.M . Mullane

Concentration and Time Dependent GrowthInhibition and Metabolism

in Vitro

by2 ' ,2 ' -Difluoro-deoyxcytidine (Gemcitabine) 5 7V.W .T . Ruiz van Haperen, G. Veerman, P .Noordhuis, J .B. Vermorken and G .J . Peters

4 . Analogue Effects and Metabolism

Thiopurine Methyltransferase Activity an dEfficacy of Azathioprine Immunosuppresion inTransplant Recipients 61P .R . Chocair, J .A . Duley, H .A . Simmonds and J .S .Cameron

Increase in 2',5'-Oligoadenylate Synthetas eCaused by Deoxycoformycin in Hairy Cel lLeukaemia 6 5K. Ganeshaguru, W .C .P . De Mel, G . Sissolak, D .Catovosky, C . Dearden, A .B. Mehta and A .V .Hoffbrand

A Dual Anti-Tumour Effect of a Combination ofInterferon-a and 5-Fluorouracil or2-Chiorodeoxyadenosine on Natural Killer (NK )Cell Mediated Cytotoxicity 6 9Z . Reiter, O . Ozes, S .Tomson, L .M .Blatt and M .W.Taylor

The Effect of Methotrexate on the Folat eCoenzyme Pools in Human Hepatoma Cells i nCulture 75J . Galivan, M . Rhee, D .G . Priest, M . Banni, J .H .Freisheim and J .M. Whitel y

Purine Nucleotide Biosynthesis in Leukemi cPromyelocytes Treated with Retinoids 7 9H . Tsutani, D . Kagawa, M. Uchida, T . Yoshimura ,T . Tanaka, T . Ueda and T . Nakamura

6-Mercaptopurine Metabolism in Two Leukemic CellLines 83E .H . Stet, R.A . De Abreu, Y .P .G . Janssen, J .P .M .Bokkerink and J .M.F . Trijbels

Synergistic Interaction of Methotrexate an d6-Mercaptopurine in Human Derived Malignant T-and CALLA+ Cell Lines 8 7R.A . De Abreu, F . van Strein, L .H .J . Lambooy andJ .P .M. Bokkerink

6-Thioguanine Metabolism in Human Erythrocytes 93A. Lucano, C . Crifo and C . Salerno

The Impact of Selected Nucleosides on theCytotoxicity of ARA-C in HL60 Cells 9 7J . Mejer

Effect

of

Chloroadenosine

on

thePhosphoinosotide

Turnover

in

Human

TLymphoblasts Activated through the T-cel lReceptor/CD3 Complex 101H .A . Buc, M . Hamet, A. Moncion and L .J .Perignon

Isolated Liver Perfusion versus Hepatic Arter yInfusion with 5-Fluorouracil in a Rat Model ;Effects on Thymidylate Synthase 105C .L . van der Wilt, A . Marinelli, K . Smid, J .Cloos, H .M . Pinedo and G .J . Peters

5 . Metabolic Studies in Cancer Cells

Changes of Purine Nucleotide Metabolism ofEhrlich Ascites Cells during the Transition o fTumour Growth 10 9T . Grune, W .G . Siems, R . Uhlig, P. Langen and G .Gerber

Purine Nucleotides, Nucleosides and Nucleobasesof Liver, Skeletal Muscle, Blood and Tumou rCells during the Growth of Ehrlich AscitesTumour in Mice 11 3W.G . Siems, T . Grupe, H . Schmidt, R .Uhlig, G .Gerber, Y .V . Tikhonov, A .M. Pimenov and R.T.Toguzov

Uridine Fluxes in Healthy ProliferatingT-Lymphocytes, MOLT-3 T-ALL Cell-Line Cells and

11 7Differentiated MOLT-3 CellsA .A. van den Berg, H. Van Lenthe, D . de Korte ,

D . Roos and A .H . van Gennip

Some Aspects of Purine Nucleotide Metabolism in

Human Lymphocytes : Nucleotide Content in Human

12 1Lymphoblastoid Lines, Transfected with HIV-1

A . Tabucchi, F . Carlucci, R. Pagan', F .Ciccomascolo, L . Lopalco and A .G . Siccardi

6 .Pyrimidine Analogue s

Metabolism and Action of 2', 2'-Difluoro -deoxycytidine :

Self

Potentiation

o fCytotoxicity 12 5

V. Gandhi, P . Huang, Yi-Z. Xu, V . Heinemann andW. Plunkett

Effect of Leucovorin on 5-Fluorouracil Induce dInhibition of Thymidylate Synthase in Patientswith Colon Cancer 13 1G.J . Peters, C .J . Van Groeningen, C .L . van derWilt, K . Smid, S . Meijer and H .M . Pinedo

7 .Hypouricaemic Compounds

A Novel Xanthine Dehydrogenase Inhibitor(BOF-4272) 13 5S . Sato, K. Tatsumi and T . Nishino

Changes Caused by Ethanol Intake on Metabolismof

Hypouricemic Agents

(Combination

ofAllopurinol and Benzobromarone) 13 9K . Kaneko, S . Fujimori and I . Akaoka

Allopurinol in Breast Milk 143I . Kamilli, U . Gresser, C . Schaefer and N.Zöllner

Pharmacokinetics of Benzbromarone : Evidence fora Biliary-Intestinal Biliary-Recirculation 14 7U. Gresser, H . Empl, I . Kamilli and N . Zöllner

Analysis of Uric Acid Transport in Renal Tubule sUsing Benzbromarone and Pyrazinamide 15 1Y . Moriwaki, T . Yamamoto, S . Takahashi, M . Suda ,O .E . Agbdedana, T . Hada and K. Higashino

Deficient Benzbromarone Elimination from Plasma :Evidence for a New Genetically Determine dPolymorphism with an Autosomal Inheritance 15 7U . Grasser, M . Adjan and N. Zöllner

8 . Parasitic Diseases

Nucleotide Status in Erythrocytes of Rat sInfected with Plasmodium berghei 16 1G . Jacobasch, A . Werner, W. Siems and C . Gerth

Hypoxanthine Depletion Induced by Xanthin eOxidase Inhibits Malaria Parasite Growth i nVitro 16 5P .A . Berman and L . Human

New Nucleoside Transport Pathways Induced in th eHost Erythrocyte Membrane of Malaria and Babesi aInfected Cells 16 9A .M . Gero and A .M . Wood

9 .Enzyme Replacement

Effect of Polyethylene Glycol-Modfied AdenosineDeaminase (PEG-ADA) Therapy in Two ADA-Deficien tChildren :

Measurement

of

ErythrocyteDeoxyadenosine Triphosphate as a Useful Tool 17 3C. Bory, R . Boulieu, G . Souillet, P . Guibaud andM .S . Herschfield

B . GOUT AND URIC ACI D

Urate Transport in the Proximal Tubule of Huma nKidney 17 7D. Werner, B . Guisan and F . Roch-Ramel

The Genetics of Renal Excretion of Urate in Man 18 1B .T . Emmerson, S . L . Nagel, J . O'Conner, D .L .Duffey and N .G . Martin

What is the Pathogenesis of Familial Juvenil eGouty Nephropathy? 18 5J .S . Cameron, F . Moro and H .A . Simmonds

Renal Urate Hypoexcretion Preceding Rena lDisease in a New Kindred with Familial GoutyNephropathy (FJGN) 19 1M .B . McBride, V . Raman, C .S . Ogg, C . Chantler ,J .S . Cameron, J .A . Duley and H .A. Simmonds

Familial Nephropathy and Gout : Which Come sFirst? 195J .C . Puig, M .E . Miranda Cards, F .A . Mateos ,M .L . Picazo, M .L. Jimemez and J .O. Vazque z

Does Allopurinol Affect the Progression i nFamilial Juvenile Gouty Nephropathy? 19 9F . Moro, H .A . Simmonds, J .S . Cameron, C .S . Ogg ,G .D . Williams, M .B . McBride and P .M. Davis

Congenital

Chloride

Losing

EnteropathyAssociated with Tophaceous Gouty Arthritis 20 3G . Nuki, M .L . Watson, B .C . Williams,

H .A .Simmonds and R .C . Wallace

The Role of Lead in Gout Nephropathy Reviewed :Pathogenic or Associated Factor? 20 9M .E . Miranda, J .G . Puig, F .A . Mateos, T .H.Ramos, E . Herrero, A . Gonzalez, A . Gil and J .O.Vazquez

Myogenic Hyperuricemia in Hypoparathyroidism 21 3T . Nishimura, I . Mineao, T . Shimizu, M . Kawachi ,A . Ono, H . Jakanima, M . Kuwajima, N . Kono and S .Tarui

Lipoprotein Metabolism in Primary Gout -Influence of Alcohol Intake and Body Weight 217S . Takahashi, T . Yamamoto, Y . Moriwaki, M . Suda ,O .E . Agbedana and K . Higashino

Serum Urate and Uric Acid Excretion 22 3N . Di Sciascio, C . Crognale, M . Golato, C .P .Quaratino, M .B . di Sciascio, M . Lucarelli and A .Giacomell o

Gout and Main Rheumatic Diseases in Man 227M .L. Sorgi, C .P . Quaratino, F . Savini, A .Zoppinni and A . Giacomello .

Importance of Confounding Factors Age and Sex i nthe Correlation of Serum Uric Acid, Cholestero land Triglyceride Levels 23 1B .S . Gathof, M .A . Schreiber, U . Gresser, I .Kamilli and N . Zöllner

Changes in Urate Metabolism after Castration o fPatients Suffering from Carcinoma of th eProstate 23 5L .G. Darlington, J .G . Ainsworth, A . Blight, M .D.Khong, T .A .N . Mann, R .D . Waldon, and E .A . Warburton

Renal Hypouricemia Associated withHyperoxypurinemia due to Decreased RenalExcretion of Oxypurines : A New Defect in Rena lPurine Transport 23 9M . Kawachi, N . Kono, I . Mineo, H . Kiyokawa, H .Nakajima, T . Shimizu, A . Ono, T . Nishimura, S .Yorifuji, M . Kuwajima and S . Taur i

Significance of Hypouricemia 24 3G . Riario Sforza, C . Di Cosmo, A .L . Di Mele, E .Morelli, C . Romano, C .P . Quaratino and A .Giacomello

Organic Distribution and Interrelationships o fLesions Occuring in Laying Hens Suffering fro mGout and Urolithiasis 247G . Sönmez

Biochemical Investigations on Chicken Gou tObserved in the Marmara Region in Turkey 25 1N . Mert

Production of Uric Acid and Allantoin inPerfused Rat Liver 25 5R . Pagani, R . Leoncini, M . Pizzichini, G . Cinci ,E . Marinelo and R . Fulceri

C .ATP DEPLETION

1 .Biochemistry of ATP Depletion

Dynamics in the Purine Nucleotides of Live rduring Various Periods of Hypoxia/Ischaemia andReoxygenation 25 9G . Gerber, W . Siems, A . Werner, W . Dubiel, T .Grune, W . Henke, W . Schneider and M. Ziegler

Adenosine Origin and Clinical Roles 26 5A .C . Newby

Oxypurines in Extracellular Fluids from Pigletsduring Hypoxemia and Reoxygenation 27 1J .P . Poulsen and O .D . Saugstad

Regulation of Adenosine Concentrations b yAcadesine

(AICA-Riboside)

in

HumanB-Lymphoblasts 27 5J . Barankiewicz, R . Jimenez, J . Uyesaka and H .E .Gruber

Preservation of Adenine Nucleotides followin gIschemia and Reperfusion : Correlation withFunctional Recovery 27 9P . Mankad, R . Lachno and M . Yacoub

An Alternative Pathway of Adenylate and ATPSynthesis 28 5C . Montero, R .T . Smolenski, J .A . Duley and H .A .S immonds

Preservation of Nucleotide Pool during HeartTransplantation and Evaluation of AdenylateCatabolic Pathways in the Human Heart 28 9R .T . Smolenski, A. Suitters, D .R . Lachno andM .H . Yacoub

The Influence of Acetate on Adenine Nucleotide sin Rat Liver 29 3M .M . Zydowo, R.T . Smolenski and J . Swierczynsk i

Purine Nucleotide Catabolism in Rat Liver afte rCastration 29 7L. Terzouli, M . Pizzichini, A . Di Stefano, B .Porcelli, A . Tabucchi and R . Pagani

Adenine Nucleotide Metabolism in Liver Ischemia :Effect of Allopurinol 301F .A. Mateos, M .V . Diaz, J .G . Puig, T .H . Ramos ,M .L. Jimenez, E . Diaz and E . Burgos

Effect of Pulsed Electromagnetic Fields on theAdenine Nucleotide Pool and Energy Charge i nCells in Culture 30 5A . Conte, M. Petrini, P . Zaniol and G . Ronca

Mechanism Accounting for Changes of Adenin eNucleotide Content in Mitochondria at Ischemia 309 .W . Henke, M. Ziegler, W . Dubiel and K. Jung

New Aspects of Purine Nucleotide Metabolism :Formation of ADP from Inorganic Phosphate duringDegradation of AMP 31 3D. Vanoni,

R. Leoncini, M. Pizzichini, L .Terzuoli, E . Marinello and R . Pagani

Phosphorylation of Adenosine by an Exchang eReaction between AMP and Adenosine in AnoxicHepatocytes 317F. Bontemps, M . Mimouni and G . van den Berghe

Hypoxanthine and Inosine Metabolism in CulturedRat Cardicmyocytes 32 1E. Zoref-Shani, Y . Bromberg, C . Shirin, Y . Sidiand O . Sperling

2 .1 Xanthine Oxidase and Reperfusion Injury

The Mechanism of Conversion of XanthineDehydrogenase to Oxidase and the Role of theEnzyme in Reperfusion Injury 32 7T . Nishino and I . Tamura

Purification of Xanthine Oxidase from HumanMilk 335R . Harrison, S . Abadeh and M. Benboubetra

Mechanisms of Protection of Hepatocytes atAnoxia and Reoxygenation by the XanthineOxidase Inhibitor Oxypurinol 33 9W. Schneider, W .G . Siems, T . Grune, C . Schneiderand G . Gerber

Oxypurinol Reduced Ischaemic Brain Injury in theGerbil and Rat 34 3J .W. Phillips and Y . Lin

Acadesine (AICA Riboside) Attenuates Reperfusion

Injury and Oxidant-Induced Damage of the Heart, 347E .K . Metzner, M .H . Fox, S . Potter, K.M . Mullaneand D .A. Bullough

Effects of H2 02 and CHPO on ATP, CP Content and14 C-HX Uptake by HUVECS 34 9A . Griesmacher, G . Weigel, A . Windischbauer andM .M . Müller

Absence of Xanthine Oxidoreductase Activity i nHuman Myocardium 35 3T . Podzuweit, A . Muller, H . Beck, H.H . Scheldand W . Schaper

Lower Xanthine Oxidoreducatase Activity i nIsolated Perfused Hearts if Xanthine Replace sHypoxanthine as Substrate 357M . Janssen, J .W . de Jong, A .S . Nieukoop and E .Keijer

Evidence

from

in

Vitro

Studies

thatDihydroorotate Dehydrogenase May Be a Source o fToxic Oxygen Species 36 1G . Lakaschus, H . Kruger, D. Heese and M .Löffler

Influence of Oxipurinol on Colitis Induced i nRat Colon by Trinitrobenzensulfonic Aci dTreatment 36 5W . Siems, T . Grune, A. Werner, G . Gerber, P .Buntrock and W . Schneider

A Xanthinuric Family - the Proposita havingImmunologically Reactive Xanthine Oxidase but n oXanthine Oxidase Activity 36 9T . Yamamoto, Y . Moriwaki, S . Takahashi, T. Hada ,M .

Suda, H .

Imanishi, O .E . Agbedana, M .Nanahoshi and K . Higashino

Human Hepatic Peroxisomes with Crystalloid CoresAssociated with Urate Oxidase Activity 37 3L .A. De Netto, P .S . Tappia, Z . Malik, A .J . Wood ,V .M. Mann, C .J .P . Jones, K . Burdett, J .P .Neoptolemnos and M .J . Connock

Structural Analysis of the Rat Uricase Gene an dEvidence that Lysine 164 Is Involved in th eSubstrate-Binding Site of the Enyzme 37 7M . Ito, M . Nakamura, S . Kato, H . Ogawa and Y .Takagi

2 .DNA Repair

Study of DNA Repair in Peripheral Bloo dLymphocytes of Patients with Rheumatic Disease sUndergoing Treatment 383A . Luksiene and R . Filipaviciüte

3 . Nucleoside Transport

Nucleoside Transport in Lymphocytes fromAlcoholics and Non-Alcoholics 38 7

A .S . Gordon, S .W . Krauss, L . Nagy and I .Diamond

Initial Rate Measurements of Cellular Nucleosid eTransport : Time Course, Initial Curvature o fTime Curves and Metabolism 391

H .P . Baer, P .O .J . Ogbunude, A . Moorji and V .Serignese

Relationships between Metabolic Enzymes and th eNucleoside Transport 395R. Franco, C . Lluis, E .I . Canela, J . Mallol ,J .J . Centelles, J .M . Aran, B . Blanco and J .Sayos

Active Transport of Adenosine into Primar yCultures of Brain Cells and its Methodologica lConsequences 39 9L . Hertz

Intestinal Transport and Metabolism of Purineand Pyrimidine Nucleosides 40 3J .R . Bronk, P .A . Helliwell and R .A . Stow

Guanine Uptake by Human Erythrocytes 40 7G. Spoto, C .P . Quaratino and A . Giacomello

Radioligand Binding Studies on the Nucleosid eTransport Protein 41 1A.P . IJzermand, A. Voorschuur, M . Kruidering ,I .M . Pirovano, H . Van Bell and C . Janssen

Nucleoside Transport in Guinea-Pig Myocardium 41 5A .R . Conant and S .M. Jarvis

Comparison of the Existing Nucleoside TransportInhibitors : in Vitro and in Vivo 41 9H. Van Belle, J . Wynants and K . Ver Donck .

Effect of Membrane Lipid Composition on th eFunctional Activity of a ReconstitutedNucleoside Transporter Derived from Ehrlic hAscites Cells 42 3J . R . Hammond

Antibodies and Proteases as Probes of theStructures of Mammalian Nucleoside Transporters 42 7F .Y .P . Kwong, H .E . Fincham, A. Davies, P .J .F .Henderson, S .A. Baldwin and J .D. Young

Expression

of

Sodium Dependent-NucleosideTransporters in Xenopus Oocytes 43 1D .A . Griffith and S .M . Jarvis

Control of Nucleoside Transport in Neural Cells .Effect of Protein Kinase C Activation 43 5M .T . Miras-Portugal, E .G . Delicado, T . Casillasand R.P . Sen

Isolation

of

Nucleoside

Permeases

fromEscherichia coil 43 9M .P . Gallagher, Y . Zhang and J . Craig

Murine Erythroleukemia Cells and Resistant t oPeriodate-Oxidised Adenosine

have LoweredLevels of Nucleoside Transporter 44 3J . Hoffman

4 .Adenosine Receptor s

Effect of Ischemia on Cardiac Adenosine BindingSites 44 7S . Tonca-Testoni, R. Zucchi, U . Limbruno, P .Galbani, G . Ronca and M . Mariani

A

Ferritin-Cyclohexyladenosine

Probe

forElectron Microscopical Localization of A lAdenosine Receptor 45 1C . Martini, U . Montali, L. Giusti, G .Giannaccini, A . Falleni, V . Gremigni and A .Lucacchini

Effect of Adenosine on the Membrane Potentia lChanges of Human Neutrophils Triggered by th eTripeptide F-Met-Leu-Phe 45 5E . Capuozzo, W . Siems, C . Salerno and C . Crifo

A2 Adenosine Receptors in Neutrophils fromHealthy Volunteers and Patients with Rheumati cDisease 45 9C . Martini, S . Di Sacco, P . Tacchi, L . Bazzichi ,A . Soletti, M .L. Ciompi and F . Bondi

Index 463