THE
`CHEMOTHERAPY
`
`SOURCE BOOK
`
`SECOND EDITION
`
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`1 of 23
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`Genentech Exhibit 2051
`
`

`

`CHEMOTHERAPY
`SOURCE BOOK
`
`
`
`SECOND EDITION
`
`Michael C. Perry, MD, FACP
`Editor
`
`|
`
`Professor of Medicine
`Nellie B. Smith Chair of Oncology
`Director, Division of Hematology/Medical Oncology
`University of Missouri/Ellis Fischel Cancer Center
`Columbia, Missouri
`
`-
`
`cSANS
`
`TACHE
`
`Williams & Wilkins
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`A WAVERLY COMPANY
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`Managing Editor: Molly Mullen
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`Copyright © 1996 Williams & Wilkins .
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`Accurate indications, adverse reactions and dosage schedules for drugs are provided in this book, butit is
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`of the medications mentioned.
`
`Printed in the United States of America
`
`First Edition, 1992
`
`Library of Congress Cataloging-in-Publication Data
`
`The chemotherapy source book / Michael C.Perry, editor—2nded.
`p.
`cm
`Includes bibliographical references and index.
`ISBN 0-683-06868-7
`:
`I. Perry, Michael C. (Michael Clinton), 1945-
`2. Antineoplastic agents.
`1. Cancer—Chemotherapy.
`[DNLM:
`1.Neoplasms—drug therapy.
`2. Antineoplastic Agents—therapeutic use. QZ 267 C5186 1996]
`RC271.C5C446
`1996
`616.99'4061—dc20
`DNLM/DLC
`For Library of Congress
`
`:
`
`96-685
`CIP
`
`The publishers have made every effort to trace the copyright holders for borrowed material. If they have inadvertently
`overlooked any, they will be pleased to make the necessary arrangements atthefirst opportunity.
`To purchase additional copies of this book, call our CustomerService Departmentat (800) 638-0672 or fax orders
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`96
`97 98 99
`00
`6
`7
`'8
`9
`106
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`12 8
`
`4
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`65
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`wii
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`

`
`
`Contents
`
`
`
`Section One/ Principles of Chemotherapy:
`A/ Scientific Foundation of Chemotherapy
`
`1/ The Scientific Basis of Cancer Chemotherapy
`John W.Yarbro
`
`2/ Antineoplastic Drug Development
`Barbara A. Conley and David A. Van Echo
`
`3/ Principles of Pharmacology
`Antonius A. Miller, Mark J. Ratain, and Richard L. Schilsky
`
`4/ The Norton-Simon Hypothesis
`Larry Norton
`
`5/ Drug Resistance
`
`James H. Goldie
`
`6/ Adjuvant Chemotherapy
`’ Teresa Gilewski and Jacob D. Bitran
`
`7/ Combination Chemotherapy
`Michael L. Friedland
`
`8/ Combined Modality Therapy
`NancyL. Bartlett and Todd H. Wasserman
`
`9/ The Design and Interpretation of Clinical Trials
`Richard Simon and Michael A. Friedman
`
`10/ Hematopoietic Growth Factors
`Matthew L. Sherman and Marc B. Garnick
`
`11/ Biologic Response Modifiers: Principles of Immunotherapy
`Majd Chahin and Howard Ozer
`
`12/ Circadian Timing of Cancer Chemotherapy
`Patricia A. Wood and William J. M. Hrushesky
`
`B/ Routes of Administration
`
`13/ Intraventricular Therapy
`Arthur D. Forman and Victor A. Levin
`
`14/ Intraperitoneal Chemotherapy
`Maurie Markman
`
`3
`
`19
`
`oF
`
`43
`
`63
`
`79
`
`101
`
`109
`
`107
`
`141
`
`155
`
`177
`
`205
`
`219
`
`xvii
`
`4 of 23
`4 of 23
`
`

`

`xviii Contents
`
`15/ ContinuousIntravenous Infusion Chemotherapy
`Robert W. Carlson
`
`16/ Intraarterial Therapy
`
`17/ Perfusion Therapy
`
`William D. Ensminger
`
`William G. Kraybill
`
`18/ Bone Marrow Transplantation
`Julie M. Vose and James O. Armitage
`
`Section Two/ Chemotherapeutic Drugs
`19/ Covalent DNA-Binding Drugs
`Louise B. Grochow
`
`20/ Antimetabolites
`John C. Gutheil and Christine M. Kearns
`
`21/ Antitumor Antibiotics and Related Compounds
`Charles E. Riggs,Jr.
`
`22/ Microtubule-Targeting Drugs
`Eric K. Rowinsky and Ross C. Donehower
`23/ DNA TopoisomeraseInhibitors
`Part 1. DNA TopoisomeraseI Inhibitors
`Nasir Shahab and MichaelC. Perry
`Part 2. DNA Topoisomerase II Inhibitors
`Ross C. Donehowerand Eric K. Rowinsky
`
`24/ Differentiation Agents
`
`Raymond P. Warrell, Jr.
`
`25/ Hormones and Enzymes
`Part 1. Hormonal Agents
`Joseph Aisner, Robert J. Fram, Mario Eisenberger, and Joseph A. Fontana
`Part 2. L-Asparaginase
`
`Alan P. Lyss
`
`26/ Investigational Drugs
`Daniel R. Budman and Stuart M. Lichtman
`
`Section Three/ Management of Drug Toxicity
`27/ Hematologic Complications of Cancer Chemotherapy
`H. Clark Hoagland and Dennis A. Gastineau
`
`28/ Oral Toxicity
`
`Douglas E. Peterson and Mark M. Schubert
`
`29/ Dermatologic Toxicity
`
`Antoinette F. Hood
`
`5 of 23
`5 of 23
`
`225
`
`253
`
`271
`
`281
`
`293
`
`317
`
`345
`
`387
`
`425
`425
`
`434
`
`447
`
`459
`459
`
`476
`
`479
`
`559
`
`571
`
`595
`
`

`

`30/ Extravasation
`
`Gerald H. Clamon
`
`31/ Hypersensitivity Reactions
`Raymond B. Weiss
`
`32/ Ocular Side Effects of Chemotherapy
`Linda J. Burns
`
`33/ Cardiotoxicity of Chemotherapeutic Drugs
`Michael S. Ewer and Robert S. Benjamin
`
`34/ Pulmonary Toxicity of Chemotherapeutic Drugs
`David W. Koh and Mario Castro
`
`35/ Gastrointestinal Toxicity of Chemotherapeutic Agents
`William F, Maule
`
`36/ Hepatotoxicity of Chemotherapeutic Agents
`Paul D. King and Michael C. Perry
`
`37/ Renal and Electrolyte Abnormalities Due to Chemotherapy
`William P. Patterson and Garry P. Reams
`
`38/ Neurotoxicity of Chemotherapeutic Agents
`David R. Macdonald
`
`39/ Vascular Toxicity
`
`Donald C. Doll and John W. Yarbro
`
`40/ Second Malignancies after Chemotherapy
`John D. Boice, Jr., and Donna A. Shriner
`
`41/ Chemotherapy in Pregancy
`Donald C. Doll and John W. Yarbro
`
`42/ Gonadal Complications and Teratogenicity of Cancer Therapy
`Catherine E. Klein
`
`43/ Toxicity of Biologic Response Modifiers
`Ernest C. Borden,Jeffrey Crawford, Alan Cross, Robert O. Dillman,
`Marc Ernstoff, Michael J. Hawkins, and Meyer Heyman
`
`Section Four/ Combination Chemotherapy Programs
`44/ Chemotherapy Programs
`Victoria J. Dorr, Debra Morris, and Mary Lorber
`
`Section Five/ Drug Administration
`45/ Central Venous Access for Chemotherapy
`Steven B. Standiford
`
`46/ Safe Handling of Cytotoxic Drugs
`Bruce R. Harrison
`
`6 of 23
`6 of 23
`
`Contents
`
`xix
`
`607
`
`613
`
`635
`
`649
`
`665
`
`697
`
`709
`
`727
`
`745
`
`767
`
`785
`
`803
`
`813
`
`833
`
`845
`
`891
`
`905
`
`

`

`xx Contents
`
`47/ Stability and Compatibility of Intravenous Oncology Drugs
`(Modified from Cetus Corporation)
`
`48/ Patient Education
`Mary H. Johnson and Verna A. Rhodes
`
`49/ Nursing Implications in the Administration of Cancer
`Chemotherapy
`
`Connie Henke Yarbro
`
`Section Six/ Current Therapy of Specific Solid Tumors
`50/ Chemotherapy of Melanoma
`Faith E. Nathan, David Berd, and MichaelJ. Mastrangelo
`
`51/ Chemotherapy of Primary Brain Tumors
`Roy A. Patchell
`
`52/ Head and Neck Cancer
`
`Everett E. Vokes
`
`53/ Chemotherapy of Lung Cancer
`Mohammad Jahanzeb and Daniel C. Ihde
`
`54/ Chemotherapy of Breast Cancer
`Carl G. Kardinal and John T. Cole
`
`55/ Chemotherapy of Gastrointestinal Cancer
`John D. Wilkes
`
`56/ Chemotherapy of Endocrine Tumors
`Richard J. McKittrick and Ronald L. Stephens
`
`57/ Chemotherapy of Genitourinary Cancers
`Bruce E. Brockstein and Nicholas J. Vogelzang
`
`58/ Chemotherapy of Gynecologic Cancer
`J. Tate Thigpen
`
`59/ Chemotherapy of Sarcomas of Bone and Soft Tissue
`Haralambos Raftopoulos and Karen H. Antman
`
`60/ Chemotherapy of Carcinoma of UnknownPrimary Site
`John D. Hainsworth and F, Anthony Greco
`
`61/ Chemotherapy of Pediatric Solid Tumors
`Donald K. Strickland and Nasrollah Hakami
`
`Section Seven/ Chemotherapy of Hematologic Malignancies
`62/ Chemotherapy of Hodgkin's Disease
`Dan L. Longo
`
`63/ Chemotherapy of Non-Hodgkin's Lymphoma
`James O. Armitage, Philip J. Bierman, and Julie M. Vose
`
`7 of 23
`7 of 23
`
`947
`
`1007
`
`1029
`
`1043
`
`1071
`
`1083
`
`1103
`
`1125
`
`1185
`
`1201
`
`1215
`
`1289
`
`1317
`
`1333
`
`1345
`
`1361
`
`

`

`64/ Chemotherapy of Acute Leukemia in Adults
`Clive S. Zent and Richard A. Larson
`
`65/ Chemotherapy of Chronic Lymphocytic Leukemia and Hairy Cell
`Leukemia
`
`Kanti R. Rai and Dilip V. Patel
`
`66/ Chemotherapy of the Myelodysplastic Syndromes
`Bruce D. Cheson
`
`67/ Chemotherapy of Myeloproliferative Disorders
`James K. Weick
`
`68/ Chemotherapy of Multiple Myeloma and Related Plasma Cell
`Dyscrasias
`.
`Mehdi Farhangi and Ali Khojasteh
`
`Appendix/ WHOToxicity Guidelines
`Michael C. Perry
`
`Index
`
`Contents
`
`xxi
`
`1379
`
`1399
`
`1409
`
`1423
`
`1431
`
`1447
`
`1457
`
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`8 of 23
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`

`
`
`a
`Principles of Pharmacology
`
`Antonius A. Miller, Mark J. Ratain, and Richard L. Schilsky
`
`
`The effective use of cancer chemotherapy
`benefits from a comprehensive understandingof
`the principles of pharmacology and tumorbiol-
`ogy along with detailed knowledge ofthe natu-
`ral history of the disease being treated and in-
`sight by the physician into the goals and
`expectations of the patient and family.In clinical
`practice, the selection of a particular chemother-
`apy program depends on many factors. These
`include clinical experience, an understanding of
`the pharmacology of the drugs to be used, the
`potential for drug interactions, the likelihood of
`drug-resistantcells in the tumor, the physiologic
`status of the patient, and the presence of sanc-
`tuary sites or other unusualcharacteristics of the
`tumor that may influence the dose, schedule, or
`route of administration of a particular drug. Of
`great importanceis the recognition of those fac-
`tors that may result in diminished antitumorac-
`tivity (e.g., poor absorption of orally adminis-
`tered drugs) or excessive toxicity (e.g., abnormal
`renal function in a patient receiving methotrex-
`ate) in individual patients. This chapter reviews
`the principles of pharmacology as they apply to
`antineoplastic drugs andillustrates how an un-
`derstanding of these principles can lead to an
`improvementin the therapeutic index of cancer
`chemotherapy.°
`
`GENERAL MECHANISMS
`OF DRUG ACTION
`
`Membrane Transport
`The initial requirement for drug action is ad-
`equate drug delivery to the target site (Fig. 3.1).
`This dependslargely on bloodflow in the tumor
`bed and the diffusion characteristics of the drug
`in tissue but mayalso be influenced by the extent
`of plasma protein binding and,for orally admin-
`istered drugs, by absorption andfirst-pass me-
`tabolism in the liver. To produce cytotoxicity,
`
`—
`
`most anticancer drugs require uptake into the
`cell. A notable exception is L-asparaginase, a bac-
`terial enzymethatinhibits cell growth by deple-
`tion of circulating L-asparagine.
`the
`for
`A number of mechanisms exist
`passage of drugs across the plasma membrane,
`including passive diffusion,facilitated diffusion,
`and active transport systems(1). Passive diffu-
`sion of drugs through thelipid bilayer structure
`of the plasma membraneis a function of the size
`andlipid solubility of the drug molecule.If the
`extracellular drug concentration is constant, then
`drug accumulation bythe cell will continue until
`the rate of drug uptake from the extracellular
`space is equal to the rate of drug exit from the
`cell. At this point, a dynamic equilibrium is
`reached,and intracellular and extracellular drug
`levels are equal. As drugis cleared from the ex-
`tracellular space, intracellular drug levels will
`decline if the drug is not bound or metabolized
`intracellularly. An important feature of the pas-
`sive diffusion process is that it does not saturate
`(Fig. 3.2). That is, as the extracellular drug con-
`centration increases, influx into the cell increases
`proportionally, and high intracellular drug lev-
`els can be achieved. Passive diffusion, however,
`is a highly inefficient and nonspecific process,
`although it may be particularly important
`when carrier-mediated processes are lost or non-
`functional, such as occurs in some cases of
`methotrexateresistance.
`The passage of physiologically important
`hydrophilic compoundsacross the plasma mem-
`brane is usually mediated by a specific recep-
`tor or carrier in the plasma membranethatfacil-
`itates the translocation of the substance into or
`out of the cell. Carrier-mediated transport sys-
`tems are distinguished from passive diffusion by
`having a high degree of specificity and by being
`saturable at high extracellular drug concentra-
`tions owing to the presence of a finite number of
`
`27
`
`9 of 23
`9 of 23
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`

`

`28 Section One / Principles of Chemotherapy: Scientific Foundation of Chemotherapy
`
`
`DRUG DELIVERY
`BLOOD FLOW
`DIFFUSION
`
`TRANSMEMBRANE
`MOVEMENT
`Passsive Diffusion
`Carrier-Mediated
`
`‘
`
`INTRACELLULAR
`ACTIVATION
`Normal Tissues
`
`Ad
`
`
`CELLULAR TARGETS
`DNA, Enzymes,
`Membranes,Microtubules,
`Hormone/Growth Factor Receptors
`
`aA
`REPAIR
`
`Figure 3.1. Essential steps in drug action,
`
`receptor molecules within the membrane. Once
`all carrier sites become occupied, further in-
`creases in extracellular drug concentration will
`not produce further increments in drug influx,
`unless a componentof passive diffusion comes
`into play. Theaffinity of the carrier for the sub-
`strate can be estimated from the K,,, the drug
`concentration required to achieve one-half max-
`imal transport. The lower the K,,, the higher the
`carrier affinity.
`While all carrier-mediated systems enhance
`the rate of influx into the cell, not all carriers are
`able to translocate compounds against electro-
`chemical forces and to ultimately develop gra-
`dients such that the intracellular concentration
`exceeds the extracellular druglevel. To do so re-
`quires the expenditure of energy and the cou-
`
`Tumor Cells
`
`pling of carrier-mediated transport to an energy-
`generating reaction, usually hydrolysis of
`adenosine triphosphate (ATP).
`Manyantineoplastic drugs, particularly those
`that are structural analogues of natural com-
`pounds, gain entry into the cell by carrier-me-
`diated mechanisms. Nucleosides such as cyto-
`sine arabinoside are transported by facilitated
`diffusion (2, 3), and methotrexate transport is an
`active energy-dependent carrier-mediated pro-
`cess (4). L-Phenylalanine mustard utilizes at least
`two aminoacid transport systems, andits influx
`can be inhibited by the amino acid substrates
`specific for these transport carriers (5).
`The importance of transmembrane move-
`ment of a drug to its pharmacologic effect de-
`pends on several factors, including the rate of
`drug delivery to the tissue, the affinity of the
`transport process, and the nature of the intracel-
`lular biochemical events required for drug ac-
`tion. Although membrane transport can be the
`rate-limiting event in drug action because it
`limits the rate at which the drug gains access to .
`intracellular targets, this is not always the case.
`If drug delivery to a cell is slow relative to the
`rate of membrane transport, then the drug effect
`will be limited primarily by extracellular concen-
`tration, i.e., blood flow and diffusion of the drug.
`Similarly, if a drug requires intracellular activa-
`tion—for example, phosphorylation—before it
`can exert a cytotoxic effect, then the rate-limiting
`step in drug action maybe activation, rather than
`transport,if the rate of activationis slow relative
`to the rate of influx into the cell. Finally, it is
`important to remember that membrane trans-
`port is frequently bidirectional, with the final
`drug concentration inthe cell representing the
`balance between drug influx and drug efflux.
`These processes may utilize differentcarrier sys-
`tems and operate at different rates. While many
`efflux systems have not been carefully defined,
`one that appears to have great importance in
`cancer chemotherapy is the P-glycoprotein sys-
`tem that mediates multidrug resistance (6).
`
`Intracellular Activation
`
`Manyanticancer drugs require activation in-
`tracellularly before they are able to exert a cy-
`totoxic effect (Table 3.1). The activation process
`may occur by chemical or enzymatic reactions in
`either normal or tumortissues. Cisplatin, for ex-
`ample, undergoes a chemicalreaction with water
`molecules intracellularly, resulting in the gen-
`eration of a positively charged aquated species
`
`10 of 23
`10 of 23
`
`

`

`Chapter 3 / Principles of Pharmacology 29
`
`
`
`DrugInflux
`
`Vinax 4
`
`1/2 Vmax
`
`
`
`Carrier Mediated
`
`and Passive Diffusion
`
`
`
`
`Carrier Mediated
`
`Passive Diffusion
`
`
`
`
`
` pt !
`so ad
`a
`10
`15
`20
`25
`
`Extracellular Concentration
`
`Figure 3.2. Relationship between drug influx and extracellular concentration. The owerlineillustrates the linear
`relationship for a passive diffusion process that does not saturate. For carrier-mediated processes,initial influx is
`rapid; K,, is equal to the extracellular concentration at which theinflux rate is 1/2 maximal. Saturation occursat high
`extracellular concentrations. For transport processes with a componentof carrier-mediated influx and passive dif-
`fusion, the diffusion process dominates influx once saturation of the carrier occurs.
`
`Table 3.1. Intracellular Activation of Anticancer
`Drugs
`
`Activation
`Site of
`
`Drug
`Reaction
`Activation
`
`cilitates its binding to a number of enzymatic
`sites (9, 10).
`,
`The rate of formation of the activated drug
`species in the cell depends on a number of vari-
`ables: the rate of transmembrane influx of the
`drug, the amount and affinity of the activating
`Antimetabolites
`_Polyglutamation Tumorcells
`Methotrexate
`enzyme(s) in the cell, the amount and relative
`Phosphorylation Tumor cells
`5-Fluorouracil
`affinity of the naturally occurring enzyme sub-
`Cytosine arabinoside Phosphorylation Tumor cells
`strates, and the rate of degradation of the acti-
`6-Thioguanine
`Phosphorylation Tumorcells
`vated drug bycatabolic enzymes. For most an-
`6-Mercaptopurine
`Phosphorylation Tumorcells
`timetabolites, membrane transport
`is
`rapid
`Alkylating Agents
`relative to enzymatic activation andis therefore
`Tumor cells
`Aquation
`Cisplatin
`not rate limiting. Once insidethecell, antimetab-
`
`Cyclophosphamide—Enzymatic Liver
`olites must compete with the natural enzyme
`cleavage
`substrates for binding and activation, although -
`pharmacologic concentrations of administered
`drugs (often in the range of 1 .M to 1 mM)fre-
`quently are far greater than the concentrations of
`their physiologic counterparts (1 nM to 1 ».M),
`resulting in a competitive advantage for the
`drug. Finally, the activated drug is then a sub-
`strate for catabolic enzymesin the cell that tend
`to degrade the drug back to the parent com-
`poundor to an inactive metabolite. The concen-
`tration of active cytotoxic species in the cell is the
`result of all these processes. An excellent exam-
`ple is the pyrimidine nucleoside analogue, cy-
`tosine arabinoside (ara-C). Ara-C enters cells by
`a processof facilitated diffusion and is then me-
`tabolized in three successive phosphorylationre-
`actionsto the active triphosphate derivative,ara-
`CTP (Fig. 3.3). The first activating enzyme,
`deoxycytidine kinase, is found in lowest concen-
`
`that attacks nucleophilic sites on DNA(7). The
`activation of cyclophosphamide is mediated by
`‘hepatic microsomal enzymeswith the release of
`active alkylating species into the systemic cir-
`culation(8).
`Intracellular activation by tumorcells is a
`critical determinant of effect for virtually all
`antimetabolites. Cytosine arabinoside, 5-fluoro-
`uracil, and the purine antimetabolites (6-mercap-
`topurine and 6-thioguanine) all require phos-
`phorylation to active nucleotide forms before
`they are able to exert a cytotoxic effect. Al-
`though methotrexate is an effective enzyme
`inhibitor in its native form, conversion of the
`drug to polyglutamate metabolites intracellu-
`larly significantly increases its potency and fa-
`
`11 of 23
`11 of 23
`
`

`

`30 Section One / Principles of Chemotherapy: Scientific Foundation ofChemotherapy
`
`ara-C » ara-U
`
`1. Transport
`
`ara-C —e ara-U
`CdR
`tt
`t
`
`dCMP ata-CMP —=ara-UMP
`HY
`tt
`dCDP
`ara-CDP
`HoH
`dCTP vs ara-CTP
`
`
`
`phosphorylation
`
`2. Accumulation
`
`+
`
`dATP
`dGTP
`dTTP
`
`} === DNAincorporation
`
`Figure 3.3. Uptake and metabolism of cytosine arabinoside. Competition occurs between ara-C andthe naturally
`occurring nucleotides at every enzymatic step. The rate-limiting step for drug activation is conversion of ara-C to
`ara-CMPby deoxycytidine kinase.
`
`tration in cells and is believed to be the rate-
`limiting step in drug activation. Throughout
`the activation process, ara-C competes with
`endogenous substrates for enzyme binding. In
`the case of deoxycytidine kinase, the affinity for
`ara-C (K,, = 20 1M) is lower than that for the
`natural substrate, deoxycytidine ( K,, = 7.8 .M)
`(11). However, the enzymeis strongly inhibited
`by dCTP but weakly inhibited by ara-CTP,al-
`lowing accumulation of ara-CTP to higher con-
`centrations (12). Opposing the activation ofara-
`C are two deaminases, cytidine deaminase and
`dCMP deaminase, which convert ara-C and ara-
`CMP,respectively, to inactive uracil derivatives.
`The balance of these processes is crucial in de-
`termining the cytotoxicity of ara~C. Loss or di-
`minished affinity of an activating enzyme may
`be responsible for drug resistance, as may en-
`hanced activity of a catabolic enzyme.
`
`Drug Interaction with
`Intracellular Targets
`
`While anticancer drugs have traditionally
`been classified on the basis of their mechanism
`of action or their origins,
`they can also be
`grouped onthebasis of the target of drug action.
`There are essentially five potential targets of
`drugaction: nucleic acids, enzymes, membranes,
`microtubules, and hormone/growth factor re-
`
`ceptors. When nucleic acids are the targets, it is
`generally DNArather than RNA’binding that is
`presumedto cause cell death. There are several
`mechanisms by which drugs can bind DNA,the
`best understood being alkylation of nucleophilic
`sites within the double helix. Most alkylating
`agents have two moieties capable of developing
`a charged carbon that binds covalently to nega-
`tively charged sites on DNA such as the O6 or
`N7 positions of guanine. Cross-linking of the
`two strands of DNA bythe bifunctional alkyl-
`ating agent prevents the use of that DNA as a
`template for further DNA synthesis (13, 14).
`A second mechanism of drug binding to nu-
`cleic acids is intercalation, the insertion of a
`planar ring structure between two adjacent
`nucleotide bases of DNA. This mechanism is
`characteristic of many antitumorantibiotics. The
`antibiotic molecule is noncovalently, although
`firmly, bound to DNA and distorts the shapeof
`the double helix, resulting in inhibition of RNA
`or DNAsynthesis (15, 16). Recent data suggest
`that many classical intercalating agents such as
`doxorubicin may in fact be inhibitors of the en-
`zyme topoisomerase II and may produce DNA
`strand breaks due to inhibition of the reanneal-
`ing function of this enzyme(17, 18).
`A third mechanism of nucleic acid damageis
`illustrated by the anticancer drug bleomycin.
`The amino-terminal tripeptide of the bleomycin
`
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`

`molecule appears to intercalate between gua-
`nine-cytosine base pairs of DNA. The opposite
`end of the bleomycin peptide serves as a ferrous
`oxidase and is able to catalyze the reduction of
`molecular oxygen to superoxide or hydroxyl
`radicals that produce DNAbreakage (19, 20).
`Enzymes represent the second generalcate-
`gory of targets for chemotherapeutic agents. An-
`timetabolites function as inhibitors of key en-
`zymesin the purine or pyrimidine biosynthetic
`pathways or as inhibitors of DNA polymerase.
`Since most of these enzymes are active during
`DNAsynthesis, antimetabolites tend to be cyto-
`toxic only when presentin sufficient concentra-
`tion during the vulnerable S phase of thecell cy-
`cle. In general,
`the effectiveness of enzyme
`inhibitors also depends on the amountandaffin-
`ity of the target enzyme and on the extent of
`competition by natural substrates for enzyme
`binding. In the case of methotrexate, for exam-
`ple, complete saturation of all dihydrofolate re-
`ductase binding sites is required before the en-
`zymeis effectively inhibited. As methotrexate
`inhibits the function of this enzyme, dihydrofo-
`late, the natural substrate, accumulates behind
`the metabolic block and is able to effectively
`compete with methotrexate for further enzyme
`binding (21). Thus, large amounts of methotrex-
`ate, well in excess of the enzyme-binding capac-
`ity, are required to effectively inhibit dihydro-
`folate reductase activity.
`If
`the enzyme is
`increased in amount, as.in many resistantcells,
`it may not be possible to effectively deliver cy-
`totoxic levels of methotrexate to the intracellular
`binding sites.
`The microtubular spindle structure provides
`a third target for chemotherapeutic agents. The
`vinca alkaloids (vincristine, vinblastine, vinorel-
`bine) exert their cytotoxic effects by binding to
`specific sites on tubulin, causing inhibition of as-
`sembly of tubulin into microtubules and ulti-
`mately leading to dissolutionof the mitotic spin-
`dle structure (22). Although their principal
`function is the formation of the mitotic spindle
`during cell division, microtubulesare also in-
`volved in many vital interphase functions, in-
`cluding the maintenance of shape, motility, sig-
`nal transmission,andintracellular transport (23).
`The taxanes (paclitaxel, docetaxel), an important
`newclass of anticancer agents, exert their cyto-
`toxic effects by promoting polymerization oftu-
`bulin. Paclitaxel was the first in this group of
`novel plant alkaloids (24, 25). The microtubules
`formed in the presenceof paclitaxel are extraor-
`dinarily stable and dysfunctional, thereby caus-
`
`Chapter 3 / Principles of Pharmacology 31
`
`ing the death of the cell by disrupting the normal
`microtubule dynamics required for cell division
`and vital interphase processes. Paclitaxel has
`provenactivity in ovarian and breast cancer and
`has recently shown promisein the treatment of
`other tumortypes (26).
`The searchforspecific inhibitors of tumor and
`growthfactor receptors has beenof great interest
`since the demonstration that antiestrogens can
`be effective in the treatment of breast cancers
`that contain the estrogen receptor. Recent studies
`have also demonstrated an importantrole for the
`antiandrogen, flutamide,
`in the treatment of
`prostate cancer (27). As more information be-
`comes available concerning the growth regula-
`tory properties of peptide oncogene products
`and their cellular receptors, these molecules are
`likely to become increasingly importantas tar-
`gets of novel chemotherapeutic agents (28).
`
`Cellular Repair of Drug-Induced Injury
`
`Cells that have been damaged by cytotoxic
`drugs frequently exhibit a variety of repair
`mechanisms. Indeed, the cytotoxic effects of a
`drug often represent the balance between injury
`and repair, and amplified repair mechanisms
`may account for cellular resistance to certain
`drugs. The cytotoxicity of alkylating agents re-
`flects the balance between cross-link formation
`and removal by cellular repair processes. Many
`cells contain specific enzymes able to removeal-
`kyl moieties from DNA, thereby repairing drug
`damage. A specific example is the protein O°%-
`alkyl-guanine transferase that repairs DNA in-
`jury produced by chloroethyl-nitrosoureas.Cells
`containing large amounts of this protein tend to
`be relatively resistant to these chemotherapeutic
`agents (29).
`Cells also contain a variety of free radical—
`scavenging systems that protect them from the
`effects of ionizing radiation and drugs such as
`bleomycin and anthracyclines, which generate
`oxygen free radicals intracellularly. Catalase, su-
`peroxide dismutase, and glutathione peroxidase,
`key enzymes in the detoxification of reactive ox-
`ygen species, may be deficient in some tissues
`(e.g., cardiac muscle (30)), leading to excessive
`drug toxicity, or increased in others, leading to
`relative drug resistance. Recent studies suggest
`that expansion of intracellular reduced gluta-
`thione pools may be an important mechanism of
`alkylating-agentresistance in animal and human
`tumors (31, 32).
`Finally, cells may be able to circumvent drug-
`
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`
`32 Section One / Principles of Chemotherapy:Scientific Foundation of Chemotherapy
`
`induced injury by increased productionof target
`enzymes. In experimental models, for example,
`exposure of cells to methotrexate or 5-fluoroura-
`cil can be shown to stimulate production of di-
`hydrofolate reductase (33) or thymidylate syn-
`thase (34), respectively. New enzymeproduction
`occurs within minutesto hours of drug exposure
`and is presumed to represent enhanced transla-
`tion of existing mRNA rather than transcription
`of additional message. Overexpression of DNA
`clearly does occur, however, and may be a fun-
`damental mechanism of cellular resistance to
`antimetabolites and natural products due to
`increased constitutive production of target en-
`zymes or P-glycoprotein (35).
`As mentioned above, a prerequisite to drug
`effect at the target tissue is adequate drug deliv-
`ery. Pharmacokinetics describes the concentra-
`tion-time history of a drug in the body and can
`be used to answer fundamental questions con-
`cerning the optimal route and schedule of drug
`administration.
`
`PRINCIPLES OF PHARMACOKINETICS
`
`Definitions
`
`Pharmacokinetics is the study of drug absorp-
`tion, distribution, metabolism, and excretion. A
`fundamental concept
`in pharmacokinetics is
`drug clearance, ie., elimination of drugs from
`the body, analogous to the concept ofcreatinine
`clearance.In clinical practice, clearance of a drug
`is rarely directly measured butis calculated as
`either
`
`Clearance = Dose/AUC
`or
`
`(eq. 3.1)
`
`Clearance = Infusion rate/C,,
`
`(eq. 3.2)
`
`The AUC (or area under the concentration-time
`curve) represents the total drug exposure inte-
`grated over time and is an important parameter
`for both pharmacokinetic and pharmacody-
`namic analyses. As indicated in eq. 3.1, the clear-
`ance is simply the ratio of the dose to the AUC,
`so that the higher the AUC(for a given dose) the
`lower the clearance.If a drug is administered by
`continuousinfusion and steady-state is achieved,
`the clearance can be estimated from a single
`measurement of plasma drug concentration as
`per eq. 3.2.
`Clearance can be considered conceptually to
`be a function of both distribution and elimina-
`tion. In the simplest pharmacokinetic model,
`
`Clearance = VK
`
`(eq. 3.3)
`
`where V is the volume of distribution, and K is
`the elimination constant. V is the volumeoffluid
`in which the doseis initially diluted; thus the
`higher the V, the lowerthe initial concentration.
`K is the elimination constant, whichis inversely
`proportional to the half-life, the period of time
`that must elapse to reach a 50% decrease in
`plasma concentration. Whenthehalf-life is short,
`Kis high, and plasma concentrations decline rap-
`idly. Thus, both a high V and a high K result in
`relatively low plasma concentrations and a hig
`clearance.
`‘
`
`Linear Pharmacokinetic Models
`
`Although pharmacokinetic analysis can be
`conducted without specifying any mathematical
`model (noncompartmental methods), it is help-
`ful to use such models as guides in therapeutic
`decision making. Drugs with linear pharmaco-
`kinetics have several important properties (Table
`3.2). The key feature of a linear pharmacokinetic
`modelis that
`
`dC _
`a KC
`
`(eq. 3.4)
`
`whereC is the concentration, K is the elimination
`constant, ¢ is the time, and dC/dt is the instanta-
`neous rate of change in concentration. This in-
`dicates that the instantaneousrate of change in
`drug concentration dependsonly on the current
`concentration. The half-life will remain constant,
`no matter how high the concentration.
`One implication of this principle is that the
`drug exposure (AUC)is not affected by changes
`in drug schedule. For example, the AUCafter a
`60 mg/m?bolus dose of doxorubicin equais the
`total AUCforthree daily (or weekly) bolus doses
`of 20 mg