PURINE AND PYRIMIDINE METABOLISM IN MAN VIII

ADV AN CES IN EXPERIMENTAL MEDICINE AND BIOLOGY

Editorial Board:

NATHAN BACK, State University ofNew York at Bujfalo

IRUN R. COHEN, The Weizmann Institute ofScience

DA VID KRITCHEVSKY, Wistar Institute

ABEL LAJTHA, N. S. Kline Institutefor Psychiatrie Research

RODOLFO PAOLETTI, University of Milan

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PURINE AND PYRIMIDINE METABOLISM IN MAN VIII

Edited by

Amrik Sahota Indiana University School ofMedicine Indianapolis, Indiana

and

Milton W. Taylor Indiana University Bloomington, Indiana

Springer Science+Business Media, LLC

L1brary of Congress Catalog1ng-1n-Publ1cat1on Data

Purine and pyrimidine metabolism in man VIII 1 edited Amrik Sahota, Milton W. Taylor.

p. cm. -- <Advances in experimental medicine and biology : v. 370> .

"Proceedings of the Eighth International Symposium on Purine and Pyrimidine Metabolism in Man, held May 22-27, 1994 in Bloomington, Indiana"--T.p. verso.

Includes bibliographical references and index. ISBN 978-1-4613-6105-3 ISBN 978-1-4615-2584-4 (eBook) DOI 10.1007/978-1-4615-2584-4

1. Purines--Metabolism--Disorders--Congresses. 2. Pyrimidines­-Metabolism--Disorders--Congresses. 3. Purines--Metabolism--Congresses. 4. Pyrimidines--Metabolism--Congresses. I. Sahota, Amrik. II. Taylor, Milton W. III. International Symposium on Purine and Pyrimidine Metabolism in Man (8th : 1994 : Bloom1ngton, Ind.> IV. Title: Purine and pyrimidine metabolism in man eight. V. Title: Purine and pyrimidine metabolism in man 8. VI. Series.

[DNLM: 1. Purines--metabolism--congresses. 2. Pyrimidines­-metabolism--congresses. W1 AD559 v.370 1994 I QU 58 P9855 1944] RC632.P87P87 1994 616.3'9--dc20 95-13913

CIP

Proceedings oftbe Eigbtb International Symposium on Purine and Pyrimidine Metabolism in Man, beld May 22-27, 1994, in Bloomington, Indiana

© 1994 Springer Science+Business Media New York Origina11y published by Plenum Press, New Y ork in 1994 Softcover reprint of the bardeover 1st edition 1994

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DEDICATION

These proceedings are dedicated to Dr. H. Anne Simmonds, whose contributions to inborn errors of purine and pyrimidine ~etabolism, especially those involving the renal and immune systems, have been exemplary and ourstanding. She has been a highly respected, and highly productive contributor to this field. Herresearch has influenced many scientists the world over, including the editors of this volume. It would be a rare event indeed if one did not see a new visiting scientist in her Iab every few months. Her collaborations with clinical colleagues have contributed immensely to patient care. The editors owe a personal debt of gratitude to her, since without the discovery of the clinical importance of the APRT gene (for which Anne was primarily responsible), they would not have studied this gene for so long and in such detail.

Anne was born and raised on a remote farm in North Auckland, New Zealand. She did not receive any formal primary education other than through Correspondence School. She had to go away to complete her high school education and went on to obtain a MSc in organic chemistry. She declined a schalarship for a PhD, believing that without practical experience it would be meaningless, and instead joined the Waikato Hospital as a trainee in clinical laboratory sciences. While studying for her MSc in clinical sciences, she organized the first local walking and skiing club. These recreational activities have been with her to this day. In fact, on the rare occasions Anne is not in the Iab or at a conference, she can most likely be found enjoying her favorite pastime. It has been noticed more than once that afterabrief time on the ski slopes, Anne approaches her research with even greater vigor and intensity.

After obtaining her degree in clinical sciences, Anne spent some time gaining postgraduale experience in various hospitallaboratories in Europe and North America, trying to figure out what she really wanted to do. She returned to New Zealand, andin ·1963 found herself in the renal unit of an Auckland hospital. This provided her with her first introduction

V

to pyrimidines and purines and, as everyone in the field knows, the rest is history. To quote Anne: "It all began when I was asked to help Dr. David Becroft, head of the Princess Mary Children's Hospital, to investigate a baby boy, half-Maori and half-Irish, who was failing to thrive, had an untreatable anemia, and was passing unidentifiable crystals. My job was to identify the crystals. This child is the Iongest survivor with the rare pyrimidine disorder, hereditary orotic aciduria." Anne then went on to study the effects of allopurinol on patients with renal disease, and during the course of these studies she developed methods for the separation and identification of purine and pyrimidine metabolites that would be considered nothing less than "gold standards." She then moved to Britain and continued this work at Guy's Hospital. It was for this work, supported by the Wellcome Foundation, that Anne received her PhD from London University.

In 1970, she was invited to set up the Purine Research Laboratory at Guy's Hospital to study purine metabolism in gout and renal failure. The laboratory has since become an ad hoc diagnostic center for diseases of purine and pyrimidine metabolism. Many of the frrst cases of specific genetic defects involving purines and pyrimidines in Britain and in many other countries have been diagnosed in her laboratory. Despite these successes, financial support for the laboratory has not been easy to come by. Support for the first three years came from an anonymous donor, and we should point out that the laboratory has been run for all these years on three-year contracts. This obviously placed a great deal of stress on Anne, but it is a testimony to her scientific acumen and her courage and stamina, that she continued to find support for herself, her research, and her staff. She has worked tirelessly to improve the career structure and working conditions for non-clinical scientists in clinical departments. One very important outcome of this effort has been the formation of the Association of Researchers in Medicine and Science (ARMS), an organization whose aim is to define and improve the career structure for basic scientists and clinicians in clinical research.

In addition to her independent description of APRT deficiency, Anne was the first to identify that deoxyadenosine, rather than adenosine, was the toxic metabolite accumulating in ADA deficiency, now the first enzyme deficiency for which gene therapy is being tested in humans. She has always been convinced of the importance of metabolism and has refused to be diverted to current bandwagons. She is also a dedicated European and was a founding member of the European Society for the Study of Purine and Pyrimidine Metabolism in Man (ESSPPM) with the objective of providing low cost meetings to attract and educate young investigators in this important field of metabolism.

Anne is indeed a pioneer in purine and pyrimidine metabolism, and as so often happens to pioneers, recognition takes a long time to come. On behalf of the International Organizing Committee, the Local Planning Committee, and her friends and colleagues throughout the world, we dedicate this symposium and its proceedings to Dr. H. Anne Simmonds.

vi

PREFACE

These volumes record the presentations made at the VIII International Symposium on Purine and Pyrimidine Metabolism in Manheld at Indiana University, Bloomington, USA from May 22- May 27, 1994. This was a continuation of meetings held every three years with the idea of bringing clinicians and basic scientists together, which we hope results in cross-fertilization of ideas. Some of the papers presented in this volume represent oral contributions and others are from posters, but we emphasize that both are considered of equal merit.

As is obvious from a perusal of the titles of the papers there has been a shift in the focus of this meeting, which reflects a general shift in the area of purine and pyrimidine metabolism. The emphasis has definitely shifted to gene structure and molecular genetics, with the beginnings we hope of gene therapy as an important branch of this area of science. Although many of the inherited diseases discussed in this text can be treated with drugs, the major thrust in the futurewill be in gene therapy, where the gene (or cDNA) will be used to treat the patient with enzyme deficiency, particularly if the patient is young.

As can be seen from the Iist of authors there is a remarkable degree of international cooperation in this area across countries and continents. We thank the many participants who have attended these symposia many times, and we welcome the large group of scientists from Eastern Europe who are attending this meeting for the first time.

We would like to acknowledge the financial support from a number of companies, in particular Burroughs Wellcome, Gensia, and Amgen, which were the largest contributors. We also wish to thank Dr. M. Lowengrub, Dean of the College of Arts and Seiences for financial support, and hosting the meeting. Among other sponsors, we would like to mention the Indiana University Research and Graduate School. Other contributors included Agouran Pharmaceuticals, Berlex, Bioehern Therapeutics, British Bio-tech, Gilead Sciences, Harlan­Sprague, Marion Merrell Dow, Pfizer, Sterling Winthrop and the Upjohn Company. The availability of such funds allowed us to offer 22 full or partial travel grants. We also wish to thank the Monroe County Convention and Visitors Bureau for assistance in organizing trips in the area.

Organizing such a symposium involves many people and takes a considerable amount of effort. In particular, the review of abstracts, their organization into symposium topics, and selection of travel award recipients based on the quality of abstracts were formidable tasks. We thank the Abstract Review Committee (Drs. Jeff Davidson, Mitch Turker, Carol Caporelli and Joseph Cory) for doing a wonderful job. The overall planning of the program was organized by Dr. George Weber, with the day-to-day coordination being done by Dr. Milton Taylor and Dr. Amrick Sahota. We owe a debt of thanks to Kevin Knerr from the Indiana University Conference Bureau for his handling of day-to-day problems, and the amount of attention he has given to this meeting throughout the conference and its planning stages. We would also like to recognize Ginger Calloway, also from the conference bureau, for her excellent administrative skills. She was responsible for daily administrative matters including mailing lists, letters and faxes and receipt of manuscripts.

vii

We look forward to the 9th international meeting in Salzburg in 1997.

*Milton Taylor Department of Biology Indiana Uni versity Bloomington, IN 47405

Amrick Sahota Department of Medical and Molecular Generies Indiana University School ofMedicine Indianapolis, IN 46202

*Contact Editor

viii

CONTENTS

REVIEW

Diagnosis and Treatment of lnborn Errors of Purine and Pyrimidine Metabolism: An Overview ............................................................................................................. 1

H.A. Simmonds.

REGULATION OF PURINE AND PYRIMIDINE MET ABOLISM

CLINICAL

Determination of dihydropyrimidine dehydrogenase (dpd) in fibroblasts of a dpd deficient pediatric patient and family members using a polyclonal antibody to human dpd .. .. .... .. .. .... .. .. .... .. .. .. .. .. .... .. .. .... .. .... .. .. .. .. .. ...... .. .. .. . ... .. .. ...... .. .. .. ...... .. . 7

R.B. Diasio, A.B.P. V an Kuilenburg, Z. Lu, R. Zhang, H. Van Lenthe, H.D. Bakker, and A.H. V an Gennip.

The effect of partial hepatectomy on blood purine levels in rats and patients ..... .. .. .. ..... 11 M. Usarni, K. Furuchi, H. Kasahara, S. Haji, G. Kotani, A. Iso, K. Sun, E. Sou,

J.H. Zheng, K. Sakata, K. Ohta, T. Kanammaru, and Y. Saitoh.

Abnormal purine and pyrimidine metabolism in inherited superactivity of PRPP synthetase ............................................................................................................ 15

C. Bory, C. Chantin, and R. Boulieu.

Accelerated purine base salvage - a possible cause of elevated nucleotide pool in the erythrocytes of patients with uraernia ................................................................. 19

M. Marlewski, R.T. Smolenski, J. Swierczynski, B. Rutkowski, J.A. Duley, H.A. Simmonds, and M. Zydowo.

Quantitation of TKl mRNA in patients with chronic lymphatic leukemia .................... 23 T. Kristensen, H.K. Jensen, and B. Munch-Petersen.

Effect of hypouricemic agents on serum carbohydrate-deficient transferrin (cdt) in gouty patients ...................................................................................................... 27

K. Kaneko, S. Fujimori, H. Yamanaka, and I. Akaoka.

Renal hemodynamics in familial nephropathy associated with hyperuricemia (FNAH) ............................................................................................................... 31

F.A. Mateos, and J.G. Puig.

ix

Renal urate hypoexcretion in Polynesian warnen is not as severe as in United Kingdom (UK) warnen with familial juvenile hyperuricaemic nephropathy (FJHN) ........................ .............. ................ ..................................... 35

M.B. McBride, H.A. Simmonds, P.J. Hatfield, R. Graham, J. McCaskey, and M. Jackson.

Renal clearances of purine bases and oxypurinol during glucose infusion ..... ............... 39 Y. Moriwaki, T. Yamamoto, S. Takahashi, Y. Nasako, T. Hada, and K.

Higashino.

In vitro andin vivo study on the conversion of allopurinol and pyrazinamide .............. 43 Y. Nasako, T. Yamamoto, Y. Moriwaki, S. Takahashi, Z. Tsutsumi, T. Hada,

and K. Higashino.

Free oxypurines in plasma and urine of gout patients before and after a purine-free diet ....................................................................................................................... 47

B. Porcelli, D. Vannoni, R. Leoncini, M. Pizzichini, R. Pagani, and E. Marinello.

Analysis of the genotypes for aldehyde dehydrogenase 2 in Japanese patients with primary gout ....... .. ...... ........ ...... .............. ................................ .......... ................... 53

H. Yamanaka, N. Kamatani, M. Hakoda, C. Terai, R. Kawaguchi, and, S. Kashiwazaki.

Hypouricemia and an increased clearance of uric acid are observed in liver diseases ... 57 A. Pelatti, C.P. Quaratino, C. D'Amario, R. Tentarelli, G. Riario-Sforza, and

A. Giacomello.

The influence of allopurinol on renal deterioration in familial nepropathy associated with hyperuricemia (FNAH) ............................................................................... 61

M.E. Miranda.

Ultrasound imaging and colour doppler studies in familial nephropathy associated with hyperuricemia (FNAH) ............................................................................... 65

C. Prieto, and T. Berrocal.

Purine metabolism in female patients with primary gout ...... ......................................... 69 J.G. Puig, F.A. Mateos, \1.E. Miranda, R.J. Torres, E. de Miguel, C.

Perez de Ayala, and A. Gil.

Familial juvenile hyperuricaemic nephropathy in adolescents ............ .......... ................. 73 I. Sebesta, J. Krijt, K. Pavelka, J. Maly, H.A. Simmonds, and M.B. McBride.

Correlation of serum uric acid, cholesterol and triglyceride levels ................................ 77 N. Di Sciascio, C.P. Quaratino, C. Rucci, P. Ciaglia, M.N. Mariani, and A.

Giacomello.

Serum concentration of Lp(a) in patients with primary gout .......................................... 79 S. Takahashi, T. Yamamoto, Y. Moriwaki, Z. Tsutsumi, and K. Higashimo, K.

Study on Iipoprotein lipase and hepatic triglyceride lipase activities in patients with gout...................................................................................................................... 83

Z. Tsutsumi, S. Takahashi, T. Yamamoto, Y. Moriwaki, Y. Nasako, K. Hiroishi, T. Hada, and K. Higashimo.

Benzbromarone and fenofibrate are lipid lowering and uricosuric: A possible key to metabolic syndrome? .......................................................................................... 87

U. Gresser, B.S. Gathof, and M. Grass.

The normal range of serum urate levels and of fractional urate excretion ...................... 91 C.P. Quaratino, N. Di Sciasco, C. Rucci, P. Ciaglia, and A. Giacomello.

X

CANCER TREATMENT

Therapy related disturbances in nucleotides in cancer cells ... .... .... .. .... ...... .... .. .... ...... ... 95 G.J. Peters.

Comparison of 5-fluoro-2'-deoxyuridine and 5-fluorouracil in the treatment of murine colon cancer; effects on thymidylate synthase .................. ..................... 109

C.L. van der Wilt, J.A.M. van Laar, K. Smid, Y.M. Rustum, and G.J. Peters.

Intracellular pharmacology and biochemistry of methotrexate and 6-mercaptopurine in childhood acute lymphoblastic leukemia ....................................................... 115

C.W. Keuzenkamp-Jansen, J.P.M. Bökkerink, J.M.F. Trijbels, M.A.H. v.d. Heijden, and R.A. De Abreu.

Modulation of arbinosylcytosine metabolism during leukemia therapy ......................... 119 V. Gandhi, E. Estey, and W. Plunkett.

A new mechanism of toxicity of 2-chlorodeoxyadenosine (2CdA) ............................... 125 K. Fabianowska-Majewska, T.J. Wasiak, K. Warzocha, M. Marlewski,

L. Fairbanks, R.T. Smolenski, J. Duley, and A. Simmonds.

The influence of 2-chlorodeoxyadenosine (2-CdA) alone andin combination with cyclophosphamide or methotrexate on normal and leukemic hematopoiesis ..... 129

J. Gora-Tybor, and T. Robak.

Utilization of purine and pyrimidinein human gastric cancer cells (KATO III): Effect of a nucleotide and nucleosides mixture (OG-VI) solution on proliferation with coadministration of 5-fluorouracil .............................................................. 131

M. Usami, J-H. Zheng, J. Wang, I. Yasuda, S. Haji, G. Kotani, G., A. Iso, K. Sun, K. Sakata, K. Ohta, T. Kanamaru, H. Kasahara, and Y. Saitoh.

Inhibition of the proliferation of human cancer cells in vitro by substrate-analog inhibitors of dUTPase ......................................................................................... 135

P. Zalud, W.O. Wachs, P.O. Nyman, and M. Zeppezauer.

Synergistic interaction between cisplatin and gemcitabine in ovarian and colon cancer celllines . .. .. . ... .... .. . . .. . . .. .. .. .. . ... . . .. .. . . .. . . .. .. .. .. .. . . .. .. .. .. .. .. . . .... .. ... . .. .. .. .. .. .. .. .. .... .. .... ... 139

A.M. B~rgman, V.W.T. Ruiz van Haperen, G. Veerman, C.M. Kuiper, and G.J. Peters.

PURINE/PYRIMIDINE ENZYMES AS DRUG TARGETS

Antime~ab?l~t~s redu~e the ~ctivities of enzymes with short half-lives in addition to mh1b1t1ng the1r spec1fic targets ............................................................................ 145

G. Weber, N. Prajda, and R.L. Singhal.

Inhibition ofmurine amido phosphoribosyltransferase by folate derivatives ................. 151 S.L. Schoettle, and R.I. Christopherson.

Inosine 5'-monophosphate dehydrogenase as a chemotherapeutic target ....................... 155 T.J. Franklin, G. Edwards, and P. Hedge.

Pharmacokinetics/pharmacodynamics of CI-1000, a purine nucleoside phosphorylase (PNP) inhibitor, in rats and monkeys .................................................................. 161

H. Hallak, A. Hayes, M. Dong, R. Gilbertsen, and R. Guttendorf.

Blockade of nucleoside degradation in monkey whole blood in vitro by CI-1000, a purine nucleoside phosphorylase (PNP) inhibitor .............................................. 167

R.B. Gilbertsen, and M.K. Dong.

xi

Changes in monkey plasma purines induced by repeated doses of CI -1000, a novel inhibitor of purine nucleoside phosphorylase ..................................................... 173

D.G. Robertson, E.R. Urda, M.R. Bleavins, and N.D. Lalwani.

Inhibitors of thymidylate synthase and glycinamide ribonucleotide transformylase ..... 179 R.C. Jackson.

The antitumor activity of ZD9331 a non-polyglutamatable quinazoline thymidylate synthase inhibitor . .. .. .. .... .. .. .. .. .... .. .. .... .. .. ...... .. .... .. .. .. .... ...... .. .. .. .. .. .. .. .......... .. ....... 185

A. Jackman, R. Kimbell, M. Brown, L. Brunton, K.R. Harrap, J.M. Wardelworth, and F.T. Boyle.

Cross-resistance to thymidylate synthase inhibitors in P-glycoprotein and non-P-glycoprotein celllines .............................................................................. 189

B. van Triest, F. Telleman, H.M. Pinedo, C.L. van der Wilt, and G.J. Peters.

Nucleotide metabolism: Mode of action of thiopurines in leukemia .............................. 195 R.A. De Abreu.

Mitochondrial versus cytosolic activities of deoxyribonucleoside salvage enzymes ..... 201 J.C.F. Söderlund, E.S.J. and Amer.

Does low-dose allopurinol, with azathioprine, cyclosporin, and prednisolone, improve renal transplant immunosuppression? ................................................... 205

P.R. Chocair, J.A. Duley, J.S. Cameron, S. Arap, L. Ianhez, E. Sabbaga, and H.A. Simmonds.

NUCLEOTIDE MET ABOLISM AND CANCER

Purine nucleotide interconversion enzymes in childhood leukemia: Relation with cell cycle and clinical outcome .. .. .. ...... .. .... .. .. ...... .. .. .. ........ .. .. .. ........ .. .. ...... ......... 209

D.C. van Oostveen, R. Pieters, G.J. Peters, and A.J.P. Veerman, A.J.P.

Behaviour of enzymes involved in purine nucleotide metabolism in tumors ................. 213 L. Lorenzini, A. De Martino, W. Testi, F. Sorbellini, E. Dispensa, A. Tabucchi,

F. Carlucci, and F. Rosi.

Purine and pyrimidine metabolism in human gliomas, melanomas and colon carcinoma xenografts, relation to their cytogenetic profile ................................ 219

V. Bardot, A.M. Dutrillaux, J. Beaumatin, D. Lefrancois, F. Apiou, B. Dutrillaux, and C. Luccioni.

Ecto -5'-nucleotidase activity in lymphocytes from healthy and leukemia patients ....... 227 A.B. Agostinho, F. Rosi, F. Carlucci, R. Pagani, M. Pizzichini, E. Marinello,

P. Galieni, E. Dispensa, and R. Leoncini.

Endo-5'-nucleotidase activity in lymphocytes from healthy subjects and leukemia patients ................................................................................................................ 231

F. Rosi, A.B. Agostinho, A. Tabucchi, R. Pagani, M. Pizzichini, E. Marinello, R. Leoncini, P. Galieni, and E. Dispensa.

Purine nucleotide content of the leukocytes of leukemia patients .................................. 237 F. Carlucci, A. Tabucchi, E. Consolmagno, E. Dispensa, P. Galieni, R. Pagani,

M. Pizzichini, R. Leoncini, and E. Marinello.

AMP-deaminase from human uterine muscle neoplasm (leiomyoma) ........................... 243 K. Kaletha, G. Nagel-Starczynowska, Z. Chodorowski, T. Gos, and

W. Makarewicz.

xii

Regulation of gene expression of adenosine deaminase, purine nucleoside phosphorylase and terminal deoxynucleotidyl transferase by dexamethasone and cAMP in human leukemic cells ................................................................... 249

C. Fernandez-Mejia, 0. Peralta-Zaragoza, J. Cerezo-Roman, C. Navarro-Duque, R. Barrera-Rodriguez, H. Martinez-Valdez, and V. Madrid-Marina.

Altered Substrate and inhibitor specificity of purified human adult thymidine kinases (TK2) from leukemic cells ..................................................................... 253

B. Munch-Petersen, C. Volker, L. Cloos, R. Hofbauer, B.T. Mortensen, and G. Tyrsted.

Elevated ratio between deoxycytidine kinase and thymidine kinase 2 in CLL lymphocytes compared to control cells ............................................................... 257

S.E. Nielsen, B. Munch-Petersen, and J. Mejer.

The roles of uridine-cytidine kinase and CTP synthetase in the synthesis of CTP in malignant human T-lymphocytic cells ................................................................ 261

A.H. van den Berg, H. van Lenthe, A.B.P. van Kuilenberg, and A.H. van Gennip.

Metabolism ofUDP-N-acetyl-hexose and UDP-hexoses in normal human T-lymphocytes and molt-3 T-leukemia cells ...................................................... 265

A.A. van den Berg, H. van Lenthe, and A.H. van Gennip.

Pattern of methylated purine bases in urine of cancer patients: Analysis by mass spectrometry .... . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . 269

L. Lorenzini, A. De Martino, W. Testi, F. Sorbellini, S. Catinella, P. Traldi, E. Marinello, and B. Porcelli.

Cytotoxicity of deoxycoformycin on human colon carcinoma celllines ....................... 275 M. Camici, M. Turriani, G. Turchi, M.G. Tozzi, J. Cos, C. Alemany, V. Noe,

and C.J. Ciudad.

Imbalance between the pyrimidine and ribonucleotide pools in rat rhabdomyosarcoma R1 cells ................................................................................................................ 279

R.J. Slingerland, A.B.P. van Kuilenburg, J. Bodlaender, H. van Lenthe, E. Kreuk, P.A. Voute, and A.H. van Gennip.

Compartmentation ofribonucleotides in PC-12 cells: Free and protein bound ribonucleotides .................................................................................................... 283

R.J. Slingerland, A.B.P. van Kuilenburg, J. Bodlaender, H. van Lenthe, E. Kreuk, P.A. Voute, and A.H. van Gennip.

ISCHEMIA

The effect of ischemic preconditioning on nucleotide metabolism and function of rat heart after prolonged cold storage ................................................................. 287

H. Ogino, R.T. Smolenski, A.M.L. Seymour, and M.H. Yacoub.

Does adenosine deaminase inhibition protect ischemic myocardium? ........................... 291 K.P. Gallagher, T.B. McClanahan, B.J. Martin, L.J. Saganek, D.P. Ignasiak,

T.E. Mertz, D.G.L. V an Wylen, and J. Vinten-Johansen.

Is hypoxanthine a useful marker ofperinatal hypoxia? .................................................. 295 T. Grune, R. Mueller, M. Jakstadt, H. Schmidt, and W.G. Siems.

Endothelial cells responses to hypoxia and reperfusion ................................................. 299 A. Griesmacher, A. Windischbauer, and M.M. Muller.

xiii

Inhibition of Iipid peroxidation by purines and analogs of purine .................................. 303 Y. Nishida.

A study of anoxia in rat hepatocytes .............................................................. ................. 307 A. Schwende\, H.G. Holzhutter, T. Grune, and W. Siems.

Adenine nucleotide Ievels and Iipid peroxidation at hypoxia and reoxygenation in different cell types ............................................................................................... 313

W.G. Siems, T. Grune, and A. Schwende!.

Purine and pyrimidine catabolite production in the postischemic rat heart - effect of adenosine supply during reperfusion .................................................................. 319

R.T. Smolenski, H.A. Simmonds, and D.J. Chambers.

The AMP - adenosine cycle is active during normoxia and impaired in A TP depletion in isolated rabbit cardiomyocytes .. .. ...... ........ .. .......... .. .... .. .. .... .. .. .. .... .. .. ........ .. .. . 323

D.R. Wagner, F. Bontemps, and G. van den Berghe.

DIAGNOSIS AND TREATMENT OF INHERITED DISEASES

Search for the mechanisms of high incidence of APRT deficiency among Japanese .... 327 N. Kamatani, H. Yamanaka, M. Hakoda, C. Terai, and S. Kashiwazaki.

Genetic an~ ~lini_cal heterogeneity in hypoxanthine phosphoribosyltransferase deficiencies .......................................................................................................... 331

R. Burgemeister, W. Gutensohn, G. V an den Berghe, and J. Jaeken.

Molecular mechanisms of the second female Lesch-Nyhan patient ............................... 337 Y. Yamada, H. Goto, T. Yukawa, H. Akazawa, and N. Ogasawara.

Clinical symptoms of patients with partial HPRT deficiency .... .. .. .. .. .. .... .. .. .. ........ .. .. ..... 341 B.S. Gathof, D. Jurgens, and U. Gresser.

Normalhypoxanthine and ammonia release from working muscle in partial HPRT deficiency . .. .. . . .. .. .. .... .. .... .. .... .. .. . . .. .. .. .. .. .. . ... .. .. . . .. .. .. .. .. .. .. .. .. .. .. .. .... .. .. .... .. .. .. .. ....... 345

M. Gross, B.S. Gathof, and U. Gresser.

Altered pyrimidine metabolism in the erythrocytes of a mentally retarded infant with partial HPRT deficiency ...................................................................................... 349

V. Micheli, M. Pescaglini, M. Rocchigiani, S. Sestini, G. Jacomelli, G. Hayek, and G. Pompucci.

Treatment ofLesch-Nyhan syndrome with AICAR ....................................................... 353 T. Page, B. Barshop, AL. Yu, and W.L. Nyhan.

Plasma and urinary oxypurines in Lesch-Nyhan patient after allopurinol treatment. .... 357 G. Roscioni, M.A. Farnetani, R. Pagani, M. Pizzichini, E. Marinello, and

B. Porcelli.

Adenylosuccinate Iyase deficiency: An update ............................................................. 363 G. Van den Berghe, F. V an den Bergh, M.F. Vincent, and J. Jaeken.

Adenylosuccinate Iyase deficiency in a Czech girl and two siblings ............................. 367 J. Krijt, I. Sebesta, A. Svehlakova, A. Zumrova, and J. Zeman.

Anomalous response to intravenous fructose tolerance test in a case of deficit of adenylosuccinate Iyase ........................................................................................ 371

C. Salerno, C. Crifo, E. Capuozzo, and 0. Giardini.

xiv

Effect of allopurinol on the xanthinuria in a patient with molybdenum cofactor deficiency ............................................................................................................ 375

A.H. van Gennip, H. Mandel, L.E.M. Stroomer, and A. G. van Cruchten.

Differential diagnosis of the main rheumatic diseases in man........................................ 379 M. L. Sorgi, C.P. Quaratino, C. Rucci, P. Ciaglia, A. Zoppini, and A. Giacomello.

Dihydropyrimidinuria: The first case in Japan ............................................................... 383 S. Ohba, K. Kidouchi, S. Sumi, M. Imaeda, N. Takeda, H. Yoshizumi,

A. Tatematsu, K. Kodama, K. Yamanaka, M. Kobayashi, and Y. Wada.

Normal uric acid concentrations in a purine nucleoside phosphorylase (PNP) deficient child presenting with severe chicken pox, possible immuno-deficiency and developmental delay .................. ...... .................. .. ....................... 387

R. J. Ballett, S.M. Cronin, G. Morgan, J.A. Duley, L.D. Fairbanks, and H.A. Simmonds.

GENE THERAPY

Biochemical and immunological status following gene therapy and PEG-ADA therapy for adenosine deaminase (ADA) deficiency .......................................... 391

L.D. Fairbanks, H.A.Simmonds, P.M. Hoogerbrugge, V.W. van Beusechem, D. Valerio, A. Moseley, R.J. Levinsky, H.B. Gaspar, G. and Morgan.

Genetic manipulation of hematopoietic stem cells in adenosine deaminase deficiency ... ........ .. ...... .. ...... .... ...... .. .... .. .... .......... .. .... .. .......... .. ...... .. ..................... 395

D.A. Williams, and T. Moritz.

ADENOSINE REGULATORY AGENTS

Al adenosine receptors in human neutrophils: Electron microscopic localization using a colloidal cha-gold-albumin probe ........................................................... 401

C. Martini, U. Montali, L. Giusti, M. Fiorini, A. Falleni, V. Gremigni, and A. Lucacchini.

A2 adenosine receptors in neutrophils from healthy volunteers and patients with rheumatoid arthritis .... ...................... ...... .... ............ ........ .......... .......... ................. 407

C. Martini, P. Tacchi, L. Bazzichi, M. Fiorini, F. Bondi, M.L. Ciompi, and A. Lucacchini.

The antiinflammatory effects of methotrexate are mediated by adenosine .................... 411 B.N. Cronstein, D. Naime, and E. Ostad.

Endogenous adenosine formation can regulate human neutrophil function ................... 417 J. Barankiewicz, R. Jimenez, J. Uyesaka, E. Colmerauer, and G.S. Firestein.

Acadesine: Preclinical overview ....... .. ...... ...... .... ...... ...... ...... .. .. ........ ........ .. ................... 423 H.E. Gruber.

Regulation of endogenous adenosine Ievels in the CNS: Potential for therapy in stroke, epilepsy and pain ............ ...... .... .......... ...... ........ .. .......... .................. ......... 427

A.C. Foster, L.P. Miller, and J.B. Wiesner.

Enzymes of adenosine metabolism in the heart, cardiomyocytes and endothelium ....... 431 Z. Kochan, R.T. Smolenski, A-M.L. Seymour, and M.H. Yacoub.

Adenosine uptake and metabolism in human endothelial cells ..... ................................. 435 Smolenski, R.T., Kochan, Z., McDouall, R., Seymour, A-M.L. and Yacoub, M.H.

XV

Sah-hydrolase activity in haemolysate and intact erythrocytes; the effect of adenosine analogs ..... .. .. ........ ............ .... ........ ...... .. .... .. ........ ........ .. .. ........ .. .. ...... ...... .. ...... .. ... 439

K. Fabianowska-Majewska, R.T. Smolenski, M. Marlewski, J.A. Duley, H.A. Simmonds.

VIRUS AND NUCLEOSIDE ANALOGS

Chemotherapeutic options in HIV infection ................................................................... 443 S. Cox, S. Palmer, K. Aperia, and B. Wahren.

Changes of purine nucleotide content in lymphocytes from patients infected with human immunodeficiency virus .......................................................................... 453

C.A. Boggiano, F. Carlucci, A. Taucchi, R. Pagani, E. Marinello, M. Pizzichini, and R. Leoncini.

Anti-retroviral and pharmacological properties of 9-(2-phosphonylmethoxyethyl) adenine (PEMA) .. .... .. .... .... .. .... .. .. .. .. .. .. .. .. .. .. .. .. .. .. ...... .. .... .. .... .. .. ...... .. .. .......... .. .. . 459

J. Balzarini.

Properties of mitochondrial DNA metabolising enzymes; implication for chemotherapy . .. ...... ...... .... .. .. .. .. ... . .. .. .... .. .... .. .. .... .. .. ...... .. .... .. ...... .. .. ...... .. .. ........... 465

S. Eriksson, B. Xu, and D.A. Clayton.

Adenosine deaminase (ADA) deficiency as the unexpected cause of CD4+ T-lymphocytopenia in two HIV-negative adult female siblings ......................... 471

L.D. Fairbanks, H.A. Simmonds, A.D.B. Webster, C.L. Shovlin, and J.M.B. Hughes.

Serum guanase activity in hepatitis C virus infection ..................................................... 475 T. Shaw, J. Li, D.S. Bowden, G. Cooksley, and S. A. Lacarnini.

Ganciclovir nucleotide analysisinhuman myocardial tissue. Usefulness in the diagnosis of cytomegalovirus myocarditis .......................................................... 483

R. Boulieu, N. Bleyzac, and 0. Bastien.

PARASITOLOGY

Toxicity of adenosine analogs against human rüalaria (Plasmodium falciparum) ........ 487 A.M. Gero, A.M. Wood, and D.W. Coomber.

Altered purine nucleoside transport as a target for malaria chemotherapy ..................... 493 A.M. Gero, and J.M. Upston.

Quantitative deterrnination of Trypanosoma cruzi growth inside host cells in vitro and effect of allopurinol . .... .... .. .... .. .. .. .... .. ...... .... ...... .. .. .. .. .... .. ...... .. .. ...... .. .. ...... .. . 499

T. Aoki, J. Nakajima-Shimada, and Y. Hirota.

Polyamine content of Acanthamoeba polyphaga at different stages of development and the effect of pentarnidine ................................... ........................................... 503

S.A. Asiri, P.O.J. Ogbunude, and D.C. Warhurst

Specific enzyme synthesizing adenosine from adenine and ribose-1-phosphate in invertebrates . .. .. .. .. .. .... .. .. .. .. .. . . .. .. .. . ... .. .. . . .. .. .. .. .. .. .. .. .... .. .... .. ... . .. .... .. .. .. ........ .. ....... 509

H. Trembacz, and M.M. Jezewska.

Molecular characterization of a carbamoyl-phosphate synthetase II (CPS II) gene from Trypanosoma cruzi ..................................................................................... 513

T. Aoki, R. Shimogawara, K. Ochiai, H. Yamasaki, and J. Shimada.

xvi

ENZYMES OF PURINE MET ABOLISM

Development of a mouse model for the study of human purine metabolism ................. 517 T.S. Barnes, G.L. Brodsky, G.J. Barela, J.H. Bleskan, and D. Patterson.

Effect of galactosamine on adenine and uracil nucleotide Ievels in isolated hepatocytes of young and old rats .... .. .. .... .. .. .. .... .. .... .. ...... .. .. .. .. ........ .. .. .. .. .. ......... 523

Z. Kmiec, M. Marlewski, R.T. Smolenski, and H.A. Simmonds.

Influence of purines on endothelial high energy phosphates ... .. .. .. ...... .. .. .. .... .. ........ .. ..... 527 A. Griesmacher, R.A. De Abreu, and M.M. Muller.

Ribose 1-P-dependent ADP and A TP formation in rat Ii ver .......................................... 531 R. Leoncini, D. Vannoni, E. Marinello, and R. Pagani.

Myocardial 5'deoxy-5'methylthioadenosine phosphorylase ........................................... 537 K. Ruckemann, P. Jagodzinski, and R.T.Smolenski.

A nucleoside mixture and its sparing effect on de novo purine nucleotide synthesis .... 541 H. Yokoyama, K. Okamoto, H. Nogawa, S. Naitou, and M. Itakura.

ENZYMES OF PYRIMIDINE MET ABOLISM

De novo pyrimidine nucleotide biosynthesis in synchronized Chinese hamster ovary cells .. .. .. .. . . .. .. .. .... .. .... .... .. . . .. .. .. .... .. .. .. .. .. .. .. .. .. .. .. .. .. .... .. .. .. .. .. .. .. .. .. ...... ......... 545

K. Bein, and D.R. Evans.

The catalytic mechanism of hamster dihydroorotase ...................................................... 549 N.K. Williams, E.L. Isaac, Y. Peide, and R.I. Christopherson.

Stimulation by 6-azauridine of de novo pyrimidine biosynthesis in BHK 165-23 cells 555 K. Bein, and D.R. Evans.

Observed resistance to pyrimidine analogs and sensitivity to uracil in Drosophila is attributed to deregulation of pyrimidine metabolism .......................................... 559

J. Piskur, L. Sondergaard, Z. Gojkovic, B. Stokbro. C. Hjulsager, J. Davidson, E. DeMoll, J. Rawls, and E. Bahn.

Expression of de novo pyrimidine biosynthesis genes during Sperrnatogenesis in Drosophila melanogaster .................................................................................... 567

L. Porter, J. Yang, and J. Rawls.

Regulation of calf thymus cytosolic 5' -nucleotidase nucleoside phosphotransferase .... 575 M.G. Tozzi, M. Camici, R. Pesi, S. Allegrini, C. Baiocchi, M. Torriani,

C. Scolozzi, and P.L. Ipata.

GENE REGULATION

Diverse genetic regulatory elements are required to direct the proper tissue specific and developmental expression of the murine adenosine deaminase gene . ......... 579

J.H. Winston, L. Hong, S. Akroyd, G. Hanten, K. Waymire, P. Overbeek, and R.E. Kellems.

The muscle and nonmuscle isozymes of adenylosuccinate synthetase are encoded by separate genes with differential patterns of expression ...................................... 585

O.M. Guicherit, B.F. Cooper, F.B. Rudolph, and R.E. Kellems.

xvii

Expressing enzymatic domains of hamster cad in cad-deficient Chinese hamster ovary cells .. . . .. . . .. . . . . .. . . . . .. .. . . . . .. .. . . . . . . .. . . . . .. . . . . .. .. .. .. .. . . . . . . .. .. . . . . .. .. . . . . .. . . .. .. . . .. .. .. .. . ... .. . 591

J.N. Davidson, R.S. Jamison.

Homology and mutagenesis studies of hamster dihydroorotase ..................................... 597 N.K. Williams, S. O'Donoghue, and R.l. Christopherson.

Evolution of the GATase, CPSase, DHOase like, A TCase multifunctional protein in eukaryotes: Genetic and molecular approaches with yeasts S. cerevisiae and S. pornbe . .. .. ...... .. ............ .... ...... .. ...... .. ...... .. ...... ........ ...... ...... .......... .. ...... .. .. ......... 603

M. Lollier, L. Jacquet, T. Nedeva, F. Lacroute, S. Potier, and J.L. Souciet.

ENZYME STRUCTURE AND PURIFICATION

Nucleoside diphosphate kinase: An old enzyme with new functions? .. ...... .. .. ........ ....... 607 M. Veron, A. Tepper, M. Hildebrandt, I. Lascu, M-L. Lacombe, J. Janin,

S. Morera, J. Cherfils, C. Dumas, and M. Chiadmi.

Production of adenosine and nucleoside analogs by an exchange reaction catalyzed by adenosine kinase ............................................................................................ 613

M. Mimouni, F. Bontemps, and G. V an den Berghe.

Different substrate specificity of two isozymes of cytosolic 5'-nucleotidase from rabbit heart ................................................................................................................ 617 A.C. Skladanowski, C.S. Hoffmann, J.D. Krass, W. Makarewicz, and B. Jastorff.

Human placental cytosolic purine 5'-nucleotidase is effectively reactive with an anti-chicken liver enzyme antibody ........................................................................... 623

J. Oka.

Characterization of the adenine phosphoribosyltransferase from Saccharomyces cerevisiae . .. .. .. . . .. .. . ... .. . . . . . . .. .. . . .. .. .. .. .. . ... . . . ... . . .. .. .. .. . . .. .. . . .. .. . . . . . . .. .. .. . . .. .. . . . . . ... .. .. .. .. . 627

J. Alfonzo-Garcia, A. Sahota, and M.W. Taylor.

Differential substrate properties of mammalian ribonucleotide reductase ..................... 631 J.G. Cory, A.H. Cory, and D.L. Downes.

Altered kinetic properties of recombinant human cytosolic thymidine kinase (TK 1) as compared with the native form ....................................................................... 637

H.K. Jensen, H., and B. Munch-Peterson.

MOLECULAR BIOLOGY AND GENE STRUCTURE

The promoter of the CHO APRT gene contains three regulatory regions ...................... 641 B.R. She, and M.W. Taylor.

The mouse APRT gene as a model for studying epigenetic gene inactivation ............... 647 M. Turker, P. Mummaneni, and G.E. Cooper.

Analysis of in vivo somatic mutations at the APRT locus .............................................. 653 P.K. Gupta, A. Sahota, S.A. Boyadjiev, S. Bye, J.P. O'Neill, T.C. Hunter,

R.J. Albertini, and J.A. Tischfield.

ldentification ofpolymorphic markers flanking the human APRT gene ........................ 657 S.A. Boyadjiev, A. Sahota, and J.A. Tischfield.

xviii

Germline and somatic mutation at the APRT locus of mice and man ........................... 661 J.A. Tischfield, S.J. Engle, P.K. Gupta, S. Bye, S. Boyadjiev, C. Shao,

P. O'Neill, R.J. Albertini, P.J. Stambrook, and A.S. Sahota.

Isolation and characterization of mutations in the mouse APRT gene that encode functional enzymes with resistance to toxic adenine analogs .. .. .. .... .. .. .. ...... ....... 665

N.H. Khattar, C.D. Jennings, K.A. Walker, and M.S. Turker.

Analysis of APRT mutations by reverse-transcription PCR ........................................... 671 S. Bye, S., A. Sahota, J. Chen, and J.A. Tischfield.

Molecular characterization of a novel mutation in APRT heterozygotes ........................ 675 A. Sahota, S. Bye, J. Chen, N. Khattar, M.S. Turker, F. Moro, H.A. Simmonds,

B.T. Emmerson, R.B. Gordon, and J.A. Tischfield.

Direct evidence for a hot spot germline mutation at the HPRT locus ............................. 679 S. Fujimori, T. Tagaya, N. Yamaoka, H. Saito, N. Kamatani, and I. Akaoka.

Regulation of low Km (Ecto-) 5'-nucleotidase gene expression in leukemic cells ......... 683 J. Spychala, and B.S. Mitchell.

Ecto-5'-nucleotidase (CD73): Genomic cloning and characterization of regions upstream of the translation start site ................................................................... 689

KR. Hansen, R. Resta, C.F. Webb, and L.F. Thompson.

Molecular cloning and sequence analysis of rat Ii ver dihydroorotate dehydrogenases ................................................................................................... 693

A. Rotgeri, and M. Loffler.

Mutagenesis studies of conserved residues in mammalian dihydroorotase .................... 699 B.H. Zimmermann, N.M. Kernling, and D.R. Evans.

Genemutations for human erythrocyte AMP deaminase deficiency ............................. 703 Y. Yamada, H. Goto, T. Murase, and N. Ogasawara.

Pointmutations in PRPS 1, the gene encoding the PRPP synthetase (PRS) 1 isoform, ~n~e~lie X-l~nked PRS superactivity associated with purine nucle6tide Inhibitor-resistance .............................................................................................. 707

M.A. Becker, J.M. Nosal, R.L. Switzer, P.R. Smith, T.D. Palella, and B.J. Roessler.

2,3'-dideoxycytidine phosphorylation by recombinant mouse and human deoxycytidine kinase ........................................................................................... 711

M. Johansson, and A. Karlsson.

Feedback of S. cerevisae CPSase-ATCase: Selection, cloning and sequencing of n1utant alleles ...................................................................................................... 715

L. Jaquet, M. Lollier, 0. Navratil, A. Schoendorf, V. Brondani, J.L. Souciet, and S. Potier.

Gene structure and regulation of the expression of the R 1 and R2 subunits of mouse ribonucleotide reductase ..................................................................................... 721

E. Johansson, S. Björklund, and L. Thelander.

Molecular characterization of IMP dehydrogenase in acquired resistance to mycophenolic acid . .... .. .. .. .. .. .. .. .. .. .... .. . . .. .. .. .. .. .. .. .. .. . ... .. .. . .. . .. .. .. .. .. .. .. .. .... .. .. ......... 725

F.F. Snyder, T. Lightfoot, and S.D. Hodges.

xix

Function of the polypeptide chain segment connecting the dihydroorotase and asparatate transcarbamylase domains in the mammalian multifunctional CAD .................................................................................................................... 729

H.l. Guy, and D.R. Evans.

Mapping a gene that determines erythrocytic guanosine-5'-triphosphate concentration on mouse chromosome 9 . .... .. .. ...... .. ...... .. ...... ........ .. .. ........ .. .. ....... 735

F.F. Snyder, J.P. Jenuth, J.L. Noy, and E. Fung.

Regulation of mammalian serine hydroxymethyltransferase .......................................... 739 S.K. Whitehouse, P.C. Byrne, P. Sanders, and K. Snell.

DIFFERENT AT ION

Regulation and role of inosine-5'-monophosphate dehydrogenase in cell replication, malignant transformation, and differentation ...................................................... 741

E. Huberman, D. Glesne, and F. Collart.

Reciprocal alterations of enzymic phenotype of purine and pyrimidine metabolism in induced differentiation of leukemia cells ............................................................ 747

Y. Yamaji, T. Shiotani, H. Nakamura, Y. Hata, Y. Hashimoto, M. Nagai, J. Fujita, and 1. Takahara.

Extracellular concentrations of oxypurines in xanthine oxidase-deficient hepatoma-derived cellline HuH-7 ....................................................................................... 753

T. Yamamoto, Y. Moriwaki, O.E. Agtedana, S. Takahashi, Y. Nasako, Y. Yokoyama, and K. Higashino.

Induction of cell differentiation by IMPDH an antisense oligomer in HL-60 and K562 human leukemia celllines ......................................................................... 757

H. Tsutani, K. Inai, S. Imamura, T. Veda, and T. Nakamura.

Inhibition of CTP synthetase induces differentiation of HL-60 cells and down-regulation of the c-myc oncogene ....................................................................... 761

A.B.P. V an Kuilenburg, A.A. van den Berg, J.R. Meinsma. R.J. Slingerland, and A.H. van Gennip.

NUCLEOSIDE TRANSPORT

Adenosine transport and metabolism in cardiomyocytes of hyperthyroid rat ................ 765 R.T. Smolenski, A-M.L. Seymour, and M.H. Yacoub.

Nuleoside transport and metabolism in lymphocytes, polymorphonuclear cells and cerebral synaptosomes ........................................................................................ 769

M. Staub, M. Sasvari-Szekely, M. Solymossy, and K. Szikla.

Inhibition of nucleoside transport by reactive oxygen species in bovine heart microvascular endothelial cells ........................................................................... 775

J. Barankiewicz, 1. Uyesaka, W. Kossenjans, and Z. Rymaszewski.

Novel nucleoside transport inhibitors of natural origin .................................................. 779 Y -S. Zhen, J. Su, Y.-C. Xue, C.Q. Qi, and J.-L. Hu.

XX

CYTOKINES

Modification of tumor necrosis factor (TNF) production and survival rate by a nucleoside mixture in lipopolysaccharide-injected rats ...................................... 783

H. Yokoyama, S. Kano, K. Okamoto. and Y. Shinagawa.

The effect of dietary nucleic acid deficiency and the administration of a nucleotide and nucleosides mixture solution on endotoxin shock in rats ............................. 787

S. Haji, M. Usami, G. Kotani, A. Iso, K. Ohta, K. Sakata, E. Sou, K. Sun, T. Kanamaru, H. Kasahara, and Y. Saitoh.

METHODS

Radioimmunoassay of folic acid and its correlation with age ........................................ 791 L. Lorenzini, A. De Martino, W. Testi, F. Sorbellini, L. Bisozzi, L.Terzuoli,

R. Leoncini, M. Pizzichini, E. Marinello, R. Pagani, and B. Procelli.

Uric acid and allantoin in rat liver after oxonic acid and 14c-formate .......................... 795 M. Pizzichini, L. Arezzini, G. Cinci, M.L. Pandolfi, L. Terzuoli, A. Tabucchi,

E. Marinello, and R. Pagani.

The measurement of deoxynucleotide (dNTP) pools by radioimmunoassy (RIA) ........ 801 W. Aherne, A. Hardcastle, L. Kelland, and A. Jackman.

Rapid simultaneous measurement of nucleotides, nucleosides and bases in tissues by capillary electrophoresis ..................................................................................... 805

T. Grune, and D. Perrett.

Application of capillary zone electrophoresis for rapid screening of enzymatic defects in purine metabolism ... .. .... .. .... .. .... .. .. .. .. .. .. .. ...... .. .. ...... .. .. ...... .. ........ .. ..... 811

C. Salemo, and C. Crifo.

A reverse-p~a.se J:IPLC method for cyclic nucleotide phosphodiesterases activity and classificatJon ........................................................................................................ 815

G. Spoto, S. Beradi, G. Ajerba, and V. De Laurentis.

Determination of the activity of recombinant human phosphoribosylpyrophosphate synthetase isoform 1 by a non-isotopic, one-step method .................................. 821

R. Torres, F. Mateos, J.G. Puig, and M.A. Becker.

Author Index ................................................................................................................... 825

Subject Index ................................................................................................................... 831

xxi