Burger's Medicinal Chemistry and Drug Discovery, Chemotherapeutic Agents (Volume 5)

1127 Pages·2003·39.83 MB·English

by  Donald J. Abraham

BURGER'S MEDICINAL
CHEMISTRY AND
DRUG DISCOVERY
Sixth Edition
Volume 5: Chemotherapeutic Agents
Edited by
J.
Donald Abraham
Department of Medicinal Chemistry
School of Pharmacy
Virginia Commonwealth University
Richmond, Virginia
WILEY-
INTERSCIENCE
A John Wiley and Sons, Inc., Publication
CONTENTS
1 MOLECULAR BIOLOGY OF 3 ANTITUMOR NATURAL
CANCER, 1 PRODUCTS, 107
Jesse D. Martinez Lester A. Mitscher
Michele Taylor Parker Apurba Dutta
Kimberly E. Fultz Department of Medicinal Chemistry
Natalia A. Ignatenko Kansas University
Lawrence, Kansas
Eugene W. Gerner
Departments of Radiation Oncology1
Cancer Biology Section 4 RADIOSENSITIZERS AND
Molecular and Cellular Biology RADIOPROTECTll% AGENTS, 151
Biochemistry and Molecular
Edward A. Bump
Biophysics
DRAXIMAGE Inc.
Cancer Biology Graduate Program
Kirkland, Quebec, Canada
The University of Arizona
Stephen J. Hoffman
Tuscon, Arizona
Allos Therapeutics, Inc.
Westminster, Colorado
2 SYNTHETIC DNA-TARGETED
William 0. Foye
CHEMOTHERAPEUTIC AGENTS
Massachusetts College of Pharmacy
AND RELATED TUMOR-
and Health Sciences
ACTIVATED PRODRUGS, 51
Boston, Massachusetts
William A. Denny
Auckland Cancer Society Research
5 SYNTHETIC ANTIANGIOGENIC
Centre AGENTS, 215
Faculty of Medical and Health
Orest W. Blaschuk
Sciences
Mc Gill University, Royal Victoria
The University of Auckland
Hospital
Auckland, New Zealand
Montreal, Quebec, Canada
J. Matthew Symonds
Adherex Technologies Inc.
Ottawa, Ontario, Canada
xiii
Contents
6 FUTURE STRATEGIES IN 11 RATIONALE OF DESIGN OF
IMMUNOTHERAPY, 223 ANTI-HIV DRUGS, 457
Douglas F. Lake Ahmed S. Mehanna
Sara 0. Dionne Massachusetts College of Pharmacy
University of Arizona Cancer Center and Health Sciences
Tucson, Arizona Department of Pharmaceutical
Sciences
School of Pharmacy
7 SELECTIVE TOXICITY, 249
Boston, Massachusetts
John H. Block
College of Pharmacy 12 ORGAN TRANSPLANT DRUGS,
Oregon State University 485
Corvallis, Oregon
Bijoy Kundu
Medicinal Chemistry Division
8 DRUG RESISTANCE IN CANCER Central Drug Research Institute
CHEMOTHERAPY, 281 Lucknow, India
Amelia M. Wall
13 SYNTHETIC ANTIBACTERIAL
Division of Clinical Pharmacology
AGENTS, 537
and Therapeutics
Nitya Anand
Children's Hospital of Philadelphia
B-62, Nirala Nagar,
Cancer Pharmacology Institute
Lucknow, India
University of Pennsylvania
Philadelphia, Pennsylvania
William A. Remers
University of Arizona
College of Pharmacy
9 ANTIVIRAL AGENTS, DNA, 293
Tucson, Arizona
Tim Middleton
Todd Rockway 14 P-LACTAM ANTIBIOTICS, 607
Abbott Laboratories
Daniele Andreotti
Abbott Park, Illinois
Stefano Biondi
Enza Di Modugno
10 ANTIVIRAL AGENTS, RNA GlaxoSmithKline Research Center
VIRUSES (OTHER THAN HIV), Verona, Italy
AND ORTHOPOXVIRUSES, 359
15 TETRACYCLINE,
Christopher Tseng
AMINOGLYCOSIDE, MACROLIDE,
Catherine Laughlin
AND MISCELLANEOUS
NIAID
ANTIBIOTICS, 737
National Institutes of Health
Gerard D. Wright
Bethesda, Maryland
Antimicrobial Research Centre
Department of Biochemistry
McMaster University
Hamilton, Ontario, Canada
Daniel T. W. Chu
Chiron Corporation
Emeryville, California
Contents
16 ANTIMYCOBACTERIAL 19 ANTIPROTOZOAL AGENTS,
AGENTS, 807 1033
Piero Sensi David S. Fries
University of Milan TJ Long School of Pharmacy
Milan, Italy University of the Pacific
Stockton, California
Giuliana Gialdroni Grassi
University of Pavia Alan H. Fairlamb
Pavia, Italy Division of Biological Chemistry
and Molecular Microbiology
The Wellcome Trust Biocentre
17 ANTIFUNGAL AGENTS, 881
University of Dundee
William J. Watkins
Dundee, United Kingdom
Thomas E. Renau
Essential Therapeutics
Mountain View, California 20 ANTHELMINTICS, 1089
Robert K. Griffith
18 ANTIMALARIAL AGENTS, 919 West Virginia University
School of Pharmacy
Dee Ann Casteel
Morgantown, West Virginia
Department of Chemistry
Bucknell University
INDEX, 1097
Lew isburg, Pennsylvania
BURGER'S
MEDICINAL CHEMISTRY
AND
DRUG DISCOVERY
CHAPTER ONE
Molecular Biology of Cancer
JESSED . M
ARTINEZ
M T P
ICHELE AYLOR ARKER
K E. F
IMBERLY ULTZ
NATALAIA. I
GNATENKO
E W. G
UGENE ERNER
Departments of Radiation Oncology/Cancer Biology Section
Molecular and Cellular Biology
Biochemistry and Molecular Biophysics
Cancer Biology Graduate Program
The University of Arizona
Tuscon, Arizona
Contents
1 Introduction, 2
2 Tumorigenesis, 2
2.1 Normal-Precancer-Cancer Sequence, 2
2.2 Carcinogenesis, 3
2.3 Genetic Variability and Other Modifiers of
Tumorigenesis, 5
2.3.1 Genetic Variability Affecting Cancer, 5
2.3.2 Genetic Variability in
c-myc-Dependent Expression of
Ornithine Decarboxylase, 7
2.4 Epigenetic Changes, 7
3 Molecular Basis of Cancer Phenotypes, 10
3.1 Immortality, 10
3.2 Decreased Dependence on Growth Factors to
Support Proliferation, 11
3.3 Loss of Anchorage-Dependent Growth and
Altered Cell Adhesion, 12
3.4 Cell Cycle and Loss of Cell Cycle Control, 14
3.5 Apoptosis and Reduced Sensitivity to
Apoptosis, 16
3.6 Increased Genetic Instability, 19
3.7 Angiogenesis, 20
4 Cancer-Related Genes, 21
4.1 Oncogenes, 21
4.1.1 Growth Factors and Growth Factor
Receptors, 21
4.1.2 G Proteins, 23
4.1.3 SerineIThreonine Kinases, 24
Burger's Medicinal Chemistry and Drug Discovery 4.1.4 Nonreceptor Tyrosine Kinases, 24
Sixth Edition, Volume 5: Chemotherapeutic Agents 4.1.5 Transcription Factors as Oncogenes,
Edited by Donald J. Abraham 25
ISBN 0-471-37031-2 02 003 John Wiley &Sons, Inc. 4.1.6 Cytoplasmic Proteins, 26
Molecular Biology of Cancer
4.2 Tumor Suppressor Genes, 26 5.3.4 Limitations of Microarray
4.2.1 Retinoblastoma, 27 Technologies, 37
4.2.2 p53, 27 5.4 Modifying Cell Adhesion, 37
4.2.3A denomatous Polyposis Coli, 29 5.4.1 MMP Inhibitors, 37
4.2.4 Phosphatase and Tensin Homologue, 5.4.2 Anticoagulants, 38
30 5.4.3 Inhibitors of Angiogenesis, 38
4.2.5 Transforming Growth Factor-& 30 5.5 Prospects for Gene Therapy of Cancer, 39
4.2.6 Heritable Cancer Syndromes, 32 5.5.1 Gene Delivery Systems, 39
5 Interventions, 32 5.5.1.1 Viral Vectors, 40
5.1 Prevention Strategies, 32 5.5.1.2N on-Viral Gene Delivery
5.2 Targets, 33 Systems, 42
5.2.1 Biochemical Targets, 33 5.6 Gene Therapy Approaches, 43
5.2.2 Cycloorrygenase-2 and Cancer, 33 5.6.1 Immunomodulation, 43
5.2.3O ther Targets, 35 5.6.2 Suicidal Gene Approach, 44
5.3 Therapy, 35 5.6.3 Targeting Loss of Tumor Suppressor
5.3.1 Importance of Studying Gene Function and Oncogene
Expression, 35 Overexpression, 44
5.3.2 cDNA Microarray Technology, 35 5.6.4 Angiogenesis Control, 45
5.3.3D iscoveries from cDNA Microarray 5.6.5 Matrix Metalloproteinase, 45
Data, 37 6 Acknowledgments, 46
1 INTRODUCTION optosis, are now known to contribute to cer-
tain types of cancer. Cancer is distinctive from
Cancer is a major human health problem other tumor-forming processes because of its
worldwide and is the second leading cause of ability to invade surrounding tissues. This
death in the United States (1).O ver the past chapter will address mechanisms regulating
30 years, significant progress has been the important cancer phenotypes of altered
achieved in understanding the molecular basis cell proliferation, apoptosis, and invasiveness.
of cancer. The accumulation of this basic Recently, it has become possible to exploit
knowledge has established that cancer is a va- this basic information to develop mechanism-
riety of distinct diseases and that defective based strategies for cancer prevention and
genes cause these diseases. Further, gene de- treatment. The success of both public and pri-
fects are diverse in nature and can involve ei- vate efforts to sequence genomes, including
ther loss or gain of gene functions. A number human and other organisms, has contributed
of inherited syndromes associated with in- to this effort. Several examples of mechanism-
creased risk of cancer have been identified. based anti-cancer strategies will be discussed.
This chapter will review our current under- Finally, potential strategies for gene therapy
standing of the mechanisms of cancer develop- of cancer will also be addressed.
ment, or carcinogenesis, and the genetic basis
of cancer. The roles of gene defects in both
germline and somatic cells will be discussed as
they relate to genetic and sporadic forms of
2.1 Normal-Precancer-Cancer Sequence
cancer. Specific examples of oncogenes, or can-
cer-causing genes, and tumor suppressor Insight into tumor development first came
genes will be presented, along with descrip- from epidemiological studies that examined
tions of the relevant pathways that signal nor- the relationship between age and cancer inci-
mal and cancer phenotypes. dence that showed that cancer incidence in-
While cancer is clearly associated with an creases with roughly the fifth power of elapsed
increase in cell number, alterations in mecha- age (2). Hence, it was predicted that at least
nisms regulating new cell birth, or cell prolif- five rate-limiting steps must be overcome be-
eration, are only one facet of the mechanisms fore a clinically observable tumor could arise.
of cancer. Decreased rates of cell death, or ap- It is now known that these rate-limiting steps
2 Turnorigenesis
are genetic mutations that dysregulate the ac- humans as the paradigm. They suggest that
tivities of genes that control cell growth, reg- malignant colorectal tumors (carcinomas)
ulate sensitivity to programmed cell death, evolve from preexisting benign tumors (ade-
and maintain genetic stability. Hence, tumor- nomas) in a stepwise fashion with benign, less
igenesis is a multistep process. aggressive lesions giving rise to more lethal
Although the processes that occur during neoplasms. In their model, both genetic [e.g.,
tumorigenesis are only incompletely under- adenomatous polyposis coli (APC) mutations]
stood, it is clear that the successive accumula- and epigenetic changes (e.g., DNA methyl-
tion of mutations in key genes is the force that ation affecting gene expression) accumulate
drives tumorigenesis. Each successive muta- over time, and it is the progressive accumula-
tion is thought to provide the developing tu- tion of these changes that occur in a preferred,
mor cell with important growth advantages but not invariable, order that are associated
that allow cell clones to outgrow their more with the evolution of colonic neoplasms. Other
normal neighboring cells. Hence, tumor devel- important features of this model are that at
opment can be thought of as Darwinian evolu- least four to five mutations are required for
tion on a microscopic scale with each succes- the formation of a malignant tumor, in agree-
sive generation of tumor cell more adapted to ment with the epidemiological data, with
overcoming the social rules that regulate the fewer changes giving rise to intermediate be-
growth of normal cells. This is called clonal nign lesions, that tumors arise through the
evolution (3). mutational activation of oncogenes and inac-
Given that tumorigenesis is the result of tivation of tumor suppressor genes, and that it
mutations in a select set of genes, much effort is the sum total of the effect of these mutations
by cancer biologists has been focused on iden- on tumor cell physiology that is important
tifying these genes and understanding how rather than the order in which they occur.
they function to alter cell growth. Early efforts An important implication of the multistep
in this area were lead by virologists studying model of tumorigenesis is that lethal neo-
retrovirus-induced tumors in animal models. plasms are preceded by less aggressive inter-
These studies led to cloning of the first onco- mediate steps with predictable genetic alter-
genes and the realization that oncogenes, in- ations. This suggests that if the genetic defects
deed all cancer-related genes, are aberrant which occur early in the process can be identi-
forms of genes that have important functions fied, a strategy that interferes with their
in regulating normal cell growth (4). In subse- function might prevent development of more
quent studies, these newly identified onco- advanced tumors. Moreover, preventive screen-
genes were introduced into normal cells in an ing methods that can detect cells with the
effort to reproduce tumorigenesis in vitro. Im- early genetic mutations may help to identify
portantly, it was found that no single onco- these lesions in their earliest and most curable
-
gene could confer all of the physiological traits stages. Consequently, identification of the
of a transformed cell to a normal cell. Rather genes that are mutated in cancers and eluci-
this required that at least two oncogenes act- dation of their mechanism of action is impor-
ing cooperatively to give rise to cells with the tant not only to explain the characteristic phe-
fully transformed phenotype (5). This obser- notypes exhibited by tumor cells, but also to
vation provides important insights into tu- provide targets for development of therapeu-
morigenesis. First, the multistep nature of tu- tic agents.
morigenesis can be rationalized as mutations
2.2 Carcinogenesis
in different genes with each event providing a
selective growth advantage. Second, oncogene Carcinogenesis is the process that leads to ge-
cooperativity is likely to be cause by the re- netic mutations induced by physical or chem-
quirement for dysregulation of cell growth at ical agents. Conceptually, this process can be
multiple levels. divided into three distinct stages: initiation,
Fearon and Vogelstein (6) have proposed a promotion, and progression (7). Initiation in-
linear progression model (Fig. 1.1) to describe volves an irreversible genetic change, usually
tumorigenesis using colon carcinogenesis in a mutation in a single gene. Promotion is gen-
Molecular Biology of Cancer
DNA
hypomethylation
Other genetic
Mutation of I Mutation of
alterations
APC 1.- K-ras Loss of DCC LOSS of p53 1
Normal
Hyper-
Carcinoma Metastasis
colon proliferation adEenarolym a !Intermedaiadtee noma adeLnaotem a
cell
Figure 1.1. Adenoma-carcinoma sequence. Fearon and Vogelstein (6) proposed this classic model
for the multistage progression of colorectal cancer. A mutation in the APC tumor suppressor gene is
generally considered to be the initiation event. This is followed by the sequential accumulation of
other epigenetic and genetic changes that eventually result in the progression from a normal cell to
a metastatic tumor.
erally associated with increased proliferation Promotion is a reversible process in which
of initiated cells, which increases the popula- chemical agents stimulate proliferation of ini-
tion of initiated cells. Progression is the accu- tiated cells. Typically, promoting agents are
mulation of more genetic mutations that lead nongenotoxic, that is they are unable to form
to the acquisition of the malignant or invasive DNA adducts or cause DNA damage but are
phenotype. able to stimulate cell proliferation. Hence, ex-
In the best-characterized model of chemical posure to tumor promoting agents results in
carcinogenesis, the mouse skin model, initia- rapid growth of the initiated cells and the
tion is an irreversible event that occurs when a eventual formation of non-invasive tumors. In
genotoxic chemical, or its reactive metabolite, the mouse skin tumorigenesis model, applica-
causes a DNA mutation in a critical growth tion of a single dose of an initiating agent does
controlling gene such as Ha-ras (8). Out- not usually result in tumor formation. How-
wardly, initiated cells seem normal. However, ever, when the initiation step is followed by
they remain susceptible to promotion and fur- repeated applications of a tumor promoting
ther neoplastic development indefinitely. agent, such as 12-0-tetradecanoyl-phorbol-
DNA mutations that occur in initiated cells 13-acetate (TPA),n umerous skin tumors arise
can confer growth advantages, which allow and eventually result in invasive carcinomas.
them to evolve andlor grow faster bypassing Consequently, tumor promoters are thought
normal cellular growth controls. The different to function by fostering clonal selection of cells
types of mutations that can occur include with a more malignant phenotype. Impor-
point mutations, deletions, insertions, chro- tantly, tumor formation is dependent on re-
mosomal translocations, and amplifications. peated exposure to the tumor promoter. Halt-
Three important steps involved in initiation ing application of the tumor promoter
are carcinogen metabolism, DNA repair, and prevents or reduces the frequency with which
cell proliferation. Many chemical agents must tumors form. The sequence of exposure is im-
be metabolically activated before they become portant because tumors do not develop in the
carcinogenic. Most carcinogens, or their active absence of an initiating agent even if the tu-
metabolites, are strong electrophiles and bind mor promoting agent is applied repeatedly.
to DNA to form adducts that must be removed Therefore, the genetic mutation caused by the
by DNA repair mechanisms (9). Hence, DNA initiating agent is essential for further neo-
repair is essential to reverse adduct formation plastic development under the influence of the
and to prevent DNA damage. Failure to repair promoting agent.
chemical adducts, followed by cell prolifera- Progression refers to the process of acquir-
tion, results in permanent alterations or mu- ing additional mutations that lead to malig-
tation(~i)n the genome that can lead to onco- nancy and metastasis. Many initiating agents
gene activation or inactivation of tumor can also lead to tumor progression, strong sup-
suppressor genes. port for the notion that further mutations are