Biochemical Pharmacology of Blood and Bloodforming Organs

597 Pages·1992·12.42 MB·English

by  J. W. Fisher (auth.)

Handbook of
Experimental Pharmacology
Volume 101
Editorial Board
G.Y.R. Born, London
P. Cuatrecasas, Ann Arbor, MI
H. Herken, Berlin
Biochemical Pharmacology
of Blood
and Bloodforming Organs
Contributors
K. Agrawal, Barbara S. Beckman, R.L. Capizzi
Marion Dugdale, A.C. Eaves, C.J. Eaves, J.W. Fisher
G .A. FitzGerald, R.A. Joyce, D.M. Kerins, R.D. Lange
M. Mason-Garcia, T. P. McDonald, D.C.B. Mills
J. Nakashima, P.J. Quesenberry, J.B. Smith
L.R. Solomon, J.L. Spivak
Editor
James W. Fisher
Springer-Verlag
Berlin Heidelberg New York London Paris
Tokyo Hong Kong Barcelona Budapest
JAMES W. FISHER, Ph.D.
Regents Professor and Chairman
Tulane University School of Medicine
Department of Pharmacology
1430 Tulane Avenue
New Orleans, LA 70112
USA
With 64 Figures and 47 Tables
ISBN-13: 978-3-642-75867-6 e-ISBN-13: 978-3-642-75865-2
DOl: 10.1007/978-3-642-75865-2
Library of Congress Cataloging-in-Publication Data Biochemical pharmacology of blood and blood
forming organs/contributors, K. Agrawal ... let al.]; editor, James W. Fisher. p. cm. - (Handbook
of experimental pharmacology; v. 101) Includes bibliographical references and index.
ISBN-13: 978-3-642-75867-6 1. Hematopoiesis. 2. Hematopoietic growth factors.
3. Erythropoietin. I. Agrawal, K. (Krishna) II. Fisher, James W. (James William), 1925-
III. Series. [DNLM: 1. Anemia-blood. 2. Anemia-drug effects. 3. Blood-drug effects. 4.
Hematopoiesis-drug effects. 5. Hematopoietic Cell Growth Factors-pharmacology. WI HA51L
v. 1011WH 140 B6143] QP905.H3 vol. 101 [QP92] 615'.1 s-dc20 [612.4'1] DNLM/DLC for Library
of Congress 91-5014 CIP
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© Springer-Verlag Berlin Heidelberg 1992
Softcover reprint of the hardcover 1st edition 1992
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List of Contributors
AGRAWAL, K., Department of Pharmacology, Tulane Medical Center,
School of Medicine, Tulane University, 1430 Tulane Avenue, New
Orleans, LA 70112, USA
BECKMAN, BARBARA S., Department of Pharmacology, Tulane Medical
Center, School of Medicine, Tulane University, 1430 Tulane Avenue,
New Orleans, LA 70112, USA
CAPIZZI, R.L., Executive Vice President US Bioscience Inc., One Tower
Bridge, 100 Front Street, West Conshohocken, PA 19428. Formerly,
Director, comprehensive Cancer Center of Wake Forrest University,
Winston-Salem, NC 27103, USA
DUGDALE, MARION, University of Tennessee Hemophilia Clinic, Division
of Hematology/Oncology, The University of Tennessee, College of
Medicine, 3 N. Dunlap, Memphis, TN 38163, USA
EAVES, A.C., Terry Fox Laboratory, B.C. Cancer Agency, 601 West 10th
Avenue, Vancouver, B.C., Canada V5Z 1L3, and Department of
Medicine and Pathology, University of British Columbia, Vancouver,
B.C., Canada
EAVES, C.J., Terry Fox Laboratory, B.C. Cancer Agency, 601 West 10th
Avenue, Vancouver, B.C., Canada V5Z 1L3 and Department of
Medical Genetics, University of British Columbia, Vancouver, B.C.,
Canada
FISHER, J.W., Department of Pharmacology, Tulane Medical Center, School
of Medicine, Tulane University, 1430 Tulane Avenue, New Orleans, LA
70112, USA
FITzGERALD, G .A., Center for Cardiovascular Science, Department of
Medicine and Experimental Therapeutics, University College Dublin,
Water Hospital, 41 Eccles St., Dublin 7, Ireland
JOYCE, R.A., Cancer Institute, Baptist Medical Center, Jacksonville, FL
32207, USA
VI List of Contributors
KERINS, D.M., Center for Cardiovascular Science, Department of Medicine
and Experimental Therapeutics, University College Dublin, Water
Hospital, 41 Eccles St., Dublin 7, Ireland
LANGE, R.D., Department of Medical Biology, The University of Tennessee
Medical Center at Knoxville, 1924 Alcoa Highway, Knoxville, TN 37920-
6999, USA
MASON-GARCIA, M., Department of Anatomy, Tulane Medical Center,
School of Medicine, Tulane University, 1430 Tulane Avenue, New
Orleans, LA 70112, USA
McDONALD, T.P., Department of Animal Science, University of Tennessee,
College of Veterinary Medicine, P.O. Box 1071, Knoxville, TN 37901-
1071, USA
MILLS, D.C.B., Thrombosis Research Center, Temple University Health
Sciences Center, 3400 North Broad Street, Philadelphia, PA 19140, USA
NAKASHIMA, J., Department of Pharmacology, Tulane Medical Center,
School of Medicine, Tulane University, 1430 Tulane Avenue, New
Orleans, LA 70112, USA
QUESENBERRY, P.J., Division of Hematology IOncology, Department
of Medicine, University of Virginia School of Medicine, Box 502,
Charlottesville, VA 22908, USA.
SMITH, J.B., Department of Pharmacology, Temple University Medical
School, 3420 North Broad Street, Philadelphia, PA 19140, USA
SOLOMON, L.R., The Connecticut Hospice, Inc., 61 Burban Drive,
Branford, CT 06405, USA
SPIVAK, J.L., Hematology Division, Department of Medicine, The Johns
Hopkins Hospital, 600 N. Wolfe Street, Baltimore, MD 21205, USA
Preface
A large number of chemical agents are known which affect blood and
blood-forming organs. The purpose of this volume is to review the sig
nificant advances made over the past several years regarding such chemical
agents. The purification, biological action, and therapeutic implications of
several widely used hematopoietic growth factors such as interleukin 3
(IL-3 or multi-CSF), granulocyte/macrophage colony stimulating factor
(GM-CSF), granulocyte colony stimulating factor (G-CSF), colony stimu
lating factor (CSF-I or M-CSF), thrombopoietin, and erythropoietin are
included in this volume. These factors are important in regulating several
hematopoietic cell lines such as neutrophils, monocytes, eosinophils,
macrophages, megakaryocytes, platelets, and erythrocytes.
People are exposed daily to numerous toxic chemical substances present
in our environment which produce a suppression of erythropoiesis, myelo
poiesis, lymphocytopoiesis, and megakaryocytopoiesis. Attempts have
been made in this volume to assess the therapeutic role of some of the
hematopoietic factors such as erythropoietin in the anemia of end stage
renal disease, as well as colony stimulating factors in other hematopoietic
abnormalities. In addition, some of the chemical factors in our environment
which suppress major hematopoietic lineages stimulated by erythropoietin,
macrophage colony stimulating factor, granulocyte colony stimulating factor,
interleukin I-alpha, interleukin I-beta, and interleukins 2, 3, 4, 5, 6, 7, and
9 are also included. An updating of the mechanism of action of each of these
factors on the major hematopoietic lineages is covered.
Erythropoietin is currently enjoying widespread use in the treatment of
the anemia of end stage renal disease, and the work included on it can
provide practicing hematologists and nephrologists with updated informa
tion on the mechanism of production and sites of action of erythropoietin.
Other uses of erythropoietin are the enemia of AIDS, cancer and cancer
therapeutic agents, rheumatoid arthritis, and autologous blood donors. This
volume also includes sections on the effects of arachidonic acid and its
metabolites on erythroid cell proliferation, iron deficiency and megaloblastic
anemia mechanisms and therapy; the humoral control of thrombocytopoiesis;
arachidonic acid, its metabolites, and other chemical agents which influence
platelets in thromboembolic diseases; an updated section on anticoagulant,
anti thrombotic , and thrombolytic agents in disease processes; chemical
VIII Preface
agents which suppress myelopoiesis; and finally an updated chapter on drugs
which are useful in the chemotherapy of acute leukemias. It is hoped that
this volume will prove useful to investigators in the fields of pharmacology,
physiology, nephrology, urology, hematology, pathology, endocrinology,
biochemistry, and molecular and cell biology.
I gratefully acknowledge the technical assistance of Mr. Jesse Brookins,
Mr. Eugene Maulet, and Ms. Judy Wigginton for their assistance in the
preparation of this book. This volume is dedicated to my loving wife, Mrs.
Carol B. Fisher, who has over the years been patient with me in the time
that I have had to sacrifice away from my family in the preparation of this
work.
New Orleans JAMES W. FISHER
Contents
CHAPTER 1
Introduction
J.W. FISHER ............ . 1
CHAPTER 2
Fundamental Control of Hematopoiesis
C.J. EAVES and A.C. EAVES. With 4 Figures. . . . . . . . . . . . . . . . . . 5
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
B. Hierarchical Organization of Hematopoietic Cells. . . . . . . . . . . . 9
C. Assay and Characterization of In Vitro Clonogenic Cells . . . . . .. 12
D. Use of In Vitro Clonogenic Cell Assays . . . . . . . . . . . . . . . . .. 17
E. Newer Assays for More Primitive Cells. . . . . . . . . . . . . . . . . .. 20
F. Regulatory Mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . .. 23
G. Future Outlook. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 24
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 25
CHAPTER 3
Kidney Regulation of Erythropoietin Production
J.W. FISHER and J. NAKASHIMA. With 13 Figures 33
A. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 33
B. Model for the Control of Erythropoietin Production . . . . . . . . .. 33
C. Hypoxia and Erythropoietin Production . . . . . . . . . . . . . . . . .. 36
D. Adenosine and Erythropoietin Production . . . . . . . . . . . . . . .. 40
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 46
x Contents
CHAPTER 4
The Mechanism of Action of Erythropoietin: Erythroid Cell Response
1.L. SPIVAK. With 2 Figures. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 49
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 49
I. The Erythropoietin Gene .. . . . . . . . . . . . . . . . . . . . .. 50
II. The Erythropoietin Molecule. . . . . . . . . . . . . . . . . . . .. 51
III. Erythropoietin-Responsive Cells. . . . . . . . . . . . . . . . . .. 55
IV. The Erythroid Burst-Forming Unit . . . . . . . . . . . . . . . .. 58
V. The Colony-Forming Unit Erythroid. . . . . . . . . . . . . . .. 59
B. Model Systems for Studying the Interaction of Erythropoietin
with Erythroid Progenitor Cells. . . . . . . . . . . . . . . . . . . . . . .. 60
I. The Erythropoietin Receptor . . . . . . . . . . . . . . . . . . . .. 64
C. Interaction of Other Growth and Development Factors with
Erythroid Progenitor Cells. . . . . . . . . . . . . . . . . . . . . . . . . .. 74
D. The Erythroid Differentiation Program . . . . . . . . . . . . . . . . .. 79
I. Gene Expression During Erythroid Cell Differentiation. . .. 80
E. Signal Transduction in Erythroid Progenitor Cells ........... 84
F. Erythropoietin as a Competence or Progression Factor ........ 90
G. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 93
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 94
CHAPTERS
The Arachidonic Acid Cascade and Erythropoiesis
B.S. BECKMAN and M. MASON-GARCIA. With 8 Figures 115
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 115
I. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 115
II. Classification of Eicosanoids and Their Chemistry . . . . .. 117
1. Prostaglandins. . . . . . . . . . . . . . . . . . . . . . . . . . .. 117
2. Thromboxanes . . . . . . . . . . . . . . . . . . . . . . . . . .. 118
3. Hydroperoxy/Hydroxy Fatty Acids. . . . . . . . . . . . .. 118
4. Leukotrienes .. . . . . . . . . . . . . . . . . . . . . . . . . .. 119
5. Diglyceride, Phosphatidic Acid, and Lysophosphatidic
Acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 119
III. Erythropoiesis and Eicosanoids. . . . . . . . . . . . . . . . . .. 120
B. Evidence for the Roles of Arachidonic Acid Metabolism in
Erythropoiesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 120
I. Criteria for Implicating Eicosanoids. . . . . . . . . . . . . . .. 120
II. Target Cell Responses . . . . . . . . . . . . . . . . . . . . . . .. 122
III. Cell-Cell Interactions . . . . . . . . . . . . . . . . . . . . . . . .. 125
IV. Specific Involvement of the Lipoxygenase Pathway. . . . .. 126
C. Future Directions for Research . . . . . . . . . . . . . . . . . . . . . .. 129
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 130
Contents XI
CHAPTER 6
Iron Deficiency and Megaloblastic Anemias
L.R. SOLOMON. With 6 Figures. . . . . . . . . . . . . . . . . . . . . . . . .. 137
A. Iron-Deficiency Anemia . . . . . . . . . . . . . . . . . . . . . . . . . .. 137
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 137
II. Iron Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . .. 137
1. Iron Absorption . . . . . . . . . . . . . . . . . . . . . . . . .. 138
a) Nonheme Iron Absorption . . . . . . . . . . . . . . . .. 139
b) Heme Iron Absorption. . . . . . . . . . . . . . . . . . .. 142
c) Regulation of Iron Absorption . . . . . . . . . . . . . .. 143
2. Iron Transport . . . . . . . . . . . . . . . . . . . . . . . . . .. 145
3. Intracellular Iron Metabolism. . . . . . . . . . . . . . . . .. 148
4. Iron Storage. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 148
III. Biochemical and Physiologic Roles of Iron
in Mammalian Tissues. . . . . . . . . . . . . . . . . . . . . . . .. 149
IV. Iron-Deficiency Anemia . . . . . . . . . . . . . . . . . . . . . .. 150
1. Clinical Aspects. . . . . . . . . . . . . . . . . . . . . . . . . .. 150
2. Diagnosis of Iron Deficiency .................. 151
3. Management of Iron Deficiency . . . . . . . . . . . . . . .. 154
a) Oral Iron Therapy .......... _ . . . . . . . . . . .. 155
b) Parenteral Iron Therapy . . . . . . . . . . . . . . . . . .. 155
B. Megaloblastic Anemias . . . . . . . . . . . . . . . . . . . . . . . . . . .. 157
I. Definition and Differential Diagnosis. . . . . . . . . . . . . .. 157
II. Clinical Manifestations. . . . . . . . . . . . . . . . . . . . . . .. 158
III. Biochemistry of Folic Acid and Vitamin B\2 . . . . . . . . .. 159
IV. Vitamin B\2 Deficiency. . . . . . . . . . . . . . . . . . . . . . .. 164
1. General Considerations. . . . . . . . . . . . . . . . . . . . .. 164
2. Vitamin B\2 Metabolism. . . . . . . . . . . . . . . . . . . .. 164
a) Vitamin B\2 Binding Proteins . . . . . . . . . . . . . .. 164
b) Vitamin B\2 Absorption . . . . . . . . . . . . . . . . . .. 167
c) Transport and Intracellular Metabolism
of Vitamin B\2 . . . . . . . . . . . . . . . . . . . . . . . .. 169
3. Causes of Vitamin B\2 Deficiency. . . . . . . . . . . . . .. 169
4. Diagnosis of Vitamin B12 Deficiency . . . . . . . . . . . .. 171
5. Management of Vitamin B12 Deficiency. . . . . . . . . .. 173
V. Folate Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . .. 174
1. General Considerations. . . . . . . . . . . . . . . . . . . . .. 174
2. Folate Metabolism . . . . . . . . . . . . . . . . . . . . . . . .. 176
a) Folate Absorption. . . . . . . . . . . . . . . . . . . . . .. 176
b) Transport and Intracellular Metabolism of Folate. .. 178
3. Causes of Folate Deficiency. . . . . . . . . . . . . . . . . .. 179
4. Diagnosis of Folate Deficiency . . . . . . . . . . . . . . . .. 181
5. Management of Folate Deficiency . . . . . . . . . . . . . .. 182
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 183