Cancer Chemoprevention: Promising Cancer Chemopreventive Agents

682 Pages·2004·23.94 MB·English

by  Thomas W. Kensler PhD

CANCER CHEMOPREVENTION
CANCER DRUG DISCOVERY AND DEVELOPMENT
A.
BEVERLY TEICHER, SERIES EDITOR
Cancer Chemoprevention, Volume 1: Promising Cancer Chemopreventive Agents, edited by Gary J. Kelloff,
Ernest T. Hawk, and Caroline C. Sigman, 2004
Proteasome Inhibitors in Cancer Therapy, edited by Julian Adams, 2004
Nucleic Acid Therapeutics in Cancer, edited by Alan M. Gewirtz, 2004
DNA Repair in Cancer Therapy, edited by Lawrence C. Panasci and Moulay A. Alaoui-Jamali, 2004
Hematopoietic Growth Factors in Oncology: Basic Science and Clinical Therapeutics,
edited by George Morstyn, MaryAnn Foote, and Graham J. Lieschke, 2004
Handbook of Anticancer Pharmacokinetics and Pharmacodynamics, edited by William D. Figg and
Howard L. McLeod, 2004
Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, Second Edition,
edited by Beverly A. Teicher and Paul A. Andrews, 2004
Handbook of Cancer Vaccines, edited by Michael A. Morse, Timothy M. Clay, and Kim H. Lyerly, 2004
Drug Delivery Systems in Cancer Therapy, edited by Dennis M. Brown, 2003
Oncogene-Directed Therapies, edited by Janusz Rak, 2003
Cell Cycle Inhibitors in Cancer Therapy: Current Strategies, edited by Antonio Giordano and Kenneth
J. Soprano, 2003
Chemoradiation in Cancer Therapy, edited by Hak Choy, 2003
Fluoropyrimidines in Cancer Therapy, edited by Youcef M. Rustum, 2003
Targets for Cancer Chemotherapy: Transcription Factors and Other Nuclear Proteins, edited by
Nicholas B. La Thangue and Lan R. Bandara, 2002
Tumor Targeting in Cancer Therapy, edited by Michel Page, 2002
Hormone Therapy in Breast and Prostate Cancer, edited by V Craig Jordan and Barrington J. A. Furr,
2002
Tumor Models in Cancer Research, edited by Beverly A. Teicher, 2002
Tumor Suppressor Genes in Human Cancer, edited by David E. Fisher, 2001
Matrix Metalloproteinase Inhibitors in Cancer Therapy, edited by Neil J. Clendeninn and Krzysztof
Appelt, 2001
Farnesyltransferase Inhibitors in Cancer, edited by Saia M. Sebti and Andrew D. Hamilton, 2001
Platinum-Based Drugs in Cancer Therapy, edited by Lloyd R. Kelland and Nicholas P. Farrell, 2000
Apoptosis and Cancer Chemotherapy, edited by John A. Hickman and Caroline Dive, 1999
Signaling Networks and Cell Cycle Control: The Molecular Basis of Cancer and Other
Diseases, edited by J. Silvio Gutkind, 1999
Antifolate Drugs in Cancer Therapy, edited by Ann L. Jackman, 1999
Antiangiogenic Agents in Cancer Therapy, edited by Beverly A. Teicher, 1999
Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, edited by
Beverly A. Teicher, 1997
Cancer Therapeutics: Experimental and Clinical Agents, edited by Beverly A. Teicher, 1997
CANcER
CHEMOPREVENTION
1.·
VoLUME PROMISING CANcER CHEMOPREVENTIVE AGENTS
Edited by
J.
GARY KELLOFF' MD
T.
ERNEST HAWK, MD, MPH
National Institutes ofH ealth
Rockville, MD
c.
CAROLINE SIGMAN, PhD
CCS Associates
Mountain View, CA
*
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Library of Congress Cataloging-in-Publication Data
ISBN 978-1-61737-342-8 ISBN 978-1-59259-767-3 (eBook)
DOI 10.1007/978-1-59259-767-3
Cancer chemoprevention I edited by Gary J. Kelloff, Ernest T. Hawk, Caroline C. Sigman.
p. ; em. -- (Cancer drug discovery and development)
Includes bibliographical references and index.
1. Cancer--Chemopreventwn.
[DNLM: 1. Anticarcinogenic Agents--therapeutic use. 2. Neoplasms--prevention & control. 3. Chemoprevention--methods. QZ 267 C2144 2004] I. Kelloff,
Gary. II. Hawk, Ernest T. III. Sigman, Caroline C. IV. Series.
RC268.15.C3612 2004
616.99'4061--dc22
2004000342
PREFACE
The past three decades have seen significant cinogenesis. Since that time, remarkable progress has been
advances in cancer treatment and early detection. Particu made in developing chemoprevention strategies, started
larly noteworthy are decreased mortality from childhood by Sporn's (e.g., 6) and Wattenberg's (e.g., 7,8) research
leukemia, and increased screening for breast, colon, and on mechanisms of chemopreventive drugs and assays for
prostate cancer, resulting in the detection of smaller, less evaluating these drugs in animal models, and Hong's early
advanced lesions with concomitant improved treatment clinical studies on prevention of head and neck carcino
and, in some cases, improved outcomes. Nonetheless, dur genesis (9,10). In the early 1980s, the US National Cancer
ing this same period overall cancer incidence has Institute (NCI), recognizing the promise of chemo
increased; morbidity associated with surgery, radiation, prevention, established a chemoprevention drug develop
and chemotherapy is still considerable; and disappoint ment program that has grown to incorporate and support
ingly, overall cancer survival has remained relatively flat mechanistic research on potential chemopreventive
(1,2). However, there has been an enormous gain in our agents, in vitro and animal efficacy screening, efficacy
understanding of carcinogenesis and cancer progression, modeling of human cancers, development of cancer
owing in large part to the technology allowing exploration biomarkers as potential surrogate endpoints, preclinical
of signal transduction pathways, identification of cancer toxicology and pharmacology, clinical safety and phar
associated genes, imaging of tissue architecture, and macology, and clinical efficacy studies. In the mid-1990s,
molecular and cellular function. NCI and FDA scientists worked together to develop guid
This knowledge has focused cancer therapeutics ance for developing and obtaining marketing approval for
on drugs that take advantage of cellular control mecha chemoprevention drugs (II). The chemopreventive agent
nisms to selectively eradicate cancer cells. Several of these development program has been complemented by world
new drugs are now on the market-notably, the mono wide research efforts in screening and early diagnosis,
clonal antibody trazumutab (Herceptin®) and imatinib epidemiology of cancer prevention, mechanisms of car
mesylate (Gleevec®). Trazumutab blocks ligand binding cinogenesis, and agent discovery. The 1990s saw the first
to human epidermal growth factorreceptor-2 (HER2; also fruits of chemopreventive agent development-FDA
called ErbB2, Neu) (3). HER2/Neu has tyrosine kinase approvals for tamoxifen in prevention of breast cancer
(TK) activity that activates signal transduction involved in ( I2) and celecoxib in treatment of colorectal precancers
cell growth and development, and is associated with can (13).
cer progression and resistance to chemotherapy. The general strategy for developing chemo
Trazumutab is approved for use in treatment of metastatic preventive agents, as described in the NCI/FDA guidance
breast cancer that overexpresses HER-2/Neu. Imatinib (II, see also I4-I8 ), is to first characterize the efficacy of
mesylate is an oral small molecule inhibitor that targets the candidate drugs using in vitro transformation modulation,
bcr-abl TK that results from the Philadelphia (Ph) chro chemoprevention-related mechanistic assays, and animal
mosome, which is found in 95% of chronic myeloid leu tumor models of carcinogenesis. As for most other drug
kemias (C ML) (4 ). The drug is approved for treatment of indications, the most promising efficacious agents then
CML. Imatinib mesylate also inhibits platelet-derived undergo preclinical toxicity, pharmacokinetics, and phar
growth factor receptor and c-Kit TKs, and has been macodynamics evaluation. Clinical development is
approved to treat unresectable or metastatic c-kit-positive planned and implemented for those agents that meet crite
gastrointestinal stromal tumors (5 ). ria for acceptable toxicity as well as efficacy. Often, addi
Most importantly, knowledge of carcinogenesis tional efficacy and toxicity testing is done to test alternative
has provided new and promising opportunities to prevent routes of agent delivery, dosage regimens, new target tis
cancer-that is, to treat precancer or inhibit carcinogen sues, and combinations of agents for increased efficacy
esis (a process often involving 20-30 years in human epi and decreased toxicity, and to evaluate toxicities seen in
thelial cancers) rather than waiting to treat the cancer. early clinical studies.
Sporn (6) coined the term chemoprevention to describe Clinical development of chemopreventive agents,
this discipline in oncology: use of drugs, biologics, or as for other pharmaceuticals, is carried out primarily in
nutrients that can be applied at any time in the process Phase I, II, and III trials. Phase I clinical trials are safety,
before invasive disease to inhibit, delay, or reverse car- pharmacokinetics, and pharmacodynamics studies. These
v
vi Preface
trials include single-dose studies in both fasting and Antimutagens (Chapters 1--4) block the activity
nonfasting normal subjects to characterize single dose of carcinogens by preventing carcinogen activation (e.g.,
pharmacokinetics and acute toxicity. Also, repeated daily modifiers of cytochrome P450s described in Chapters 2
dose studies assess multiple-dose pharmacokinetics and and 4) and promoting carcinogen detoxification (e.g.,
chronic toxicity using multiple-dose levels for a period of phase 2 enzyme enhancers described in Chapters 1 and 3).
1-3 months in normal subjects or up to 12 months in sub The interest in developing phase 2 enzyme enhancers,
jects at increased risk of cancer( s) for which the drug dem particularly glutathione-S-transferase (GST) inducers, is
onstrates efficacy in preclinical evaluation. Participation considerable because they are found in foods (e.g., crucif
of normal subjects for more than one month is considered erous vegetables, garlic), may be effective in restoring
based on available information (toxicity, clinical experi effects of genes masked by hypermethylation (e.g., GST
ence, etc.) for each drug on a case-by-case basis. In most genes), and have demonstrated preclinical
cases, the Phase I studies evaluate drug effects as well as chemopreventive activity in multiple cancer targets (e.g.,
serum (and sometimes agent tissue) levels of the agent. oltipraz).
Agent effects believed to be potentially associated with Antiinflammatories and their derivatives (Chap
chemopreventive activity are measured. For example, in ters 5-11), particularly NSAIDs (Chapters 5 and 6), may
studies of nonsteroidal antiinflammatories (NSAIDs),
be the best substantiated chemopreventive agents. A
serum and tissue levels of prostaglandins (e.g., PGE2) wealth of mechanistic, epidemiologic, animal efficacy,
would be measured. In studies with the irreversible orni
and clinical intervention (e.g., celecoxib, sulindac, and
thine decarboxylase (ODC) inhibitor eflornithine, tissue
aspirin) data support the chemopreventive potential of
levels of polyamines are measured.
antiinflammatories, as well as their activities against other
Phase II trials are initial efficacy studies. These
diseases of aging. Toxicity presents some problems for
randomized, double-blind, placebo-controlled trials
antiinflammatories. Gastrointestinal bleeding and ulcer
emphasize the evaluation of phenotyic and genotypic
ation are associated with chronic NSAID use, caused by
(molecular) biomarkers that are highly correlated to can
this interference with cyclooxygenase (COX) products
cer incidence and may serve as surrogate endpoints for
(the primary mechanism of action of NSAIDs is COX
cancer incidence reduction. Phase III studies are random
inhibition). As described in Chapters 5 and 6, several strat
ized, blinded, placebo-controlled clinical efficacy trials.
egies have been explored to limit this toxicity, including
These studies are typically large and have the objectives of
use of agents specific for inhibition of COX-2, the induc
demonstrating a significant reduction in incidence or de
ible, inflammation-associated form of COX, thus sparing
lay in occurrence of cancer, validating surrogate endpoints,
normal cell function mediated by COX- 1. Other strategies
further assessing drug toxicity, and further characterizing
include topical instead of systemic delivery of drug as
the relationship of dose and/or pharmacokinetics to effi
described for corticosteroids in Chapter 9.
cacy and toxicity.
Steroid hormones and their nuclear receptors are
Cancer Chemoprevention Volume 1 is a compre
targets for chemoprevention because they exert tissue
hensive survey of promising cancer chemopreventive
specific proliferative effects on cells by modulating tran
agents, grouped by pharmacological and/or mechanistic
scription. Although some of these effects are associated
classes. The agent classes presented vary widely in terms
with carcinogenesis and other toxicities, many can be
of stage of development as chemopreventives, ranging
beneficial (e.g., bone-protecting effects of estrogens). Two
from such extensively studied groups as NSAIDs and
strategies have been explored for chemoprevention in
antiestrogens to drugs with recently identified potential
hormone-responsive tissues-reducing levels of hor
based on mechanistic activity (e.g., protein kinase inhibi
mones (by inhibiting steroid aromatase and Sa-reductase)
tors, histone deacetylase inhibitors, and anti-angiogenesis
agents), as well as agents yet to be evaluated in and selectively blocking hormone receptors (Chapters 12-
chemoprevention settings (e.g., proteasome and chaper 16). Antiestrogens have shown high promise as
one protein inhibitors). Attention is devoted to food chemopreventive agents (e.g., tamoxifen), and mechanis
derived agents (such as tea, curcumin, soy isoflavones), tic studies have suggested that tissue and receptor-specific
vitamins, and minerals because of their high promise for activities can be exploited to develop third and fourth gen
prevention in healthy populations. For each agent class, eration selective estrogen receptor modulators (SERMs)
the discussion addresses considerations for chemo that maximize beneficial activities (Chapters 12 and 16).
preventive drug discovery and development outlined Although current androgen receptor antagonists have side
above as they apply to the class in general and to specific effects that limit their use in treating asymptomatic men,
agents within the class. Methods for evaluating chemo selective androgen receptor antagonists (SARA) may have
preventive activity and strategies for chemoprevention in activities in androgen-sensitive tissues similar to SERM
major cancers are described in detail in the second volume activities in estrogen-sensitive tissues (the theoretical ba
of Cancer Chemoprevention. sis for SARA is described in Chapter 14 ). Other members
Preface vii
of the steroid superfamily-vitamin D, retinoids, and and epidemiological cancer settings (Chapters 29-39).
dehydroepiandrostenedione (DHEA)-have shown However, the development of chemopreventive agents
potent chemopreventive activity, but also have some dose from these sources is complicated. In some cases, identi
related safety issues. As for the steroid hormones and re fication and use of a key component in the complex dietary
ceptors, much research has been devoted to strategies that mixture (e.g., epigallocatechin gallate in tea) has proven to
avert toxic side effects. For example, Chapters 17 and 19 be a useful sentinel. In most cases, it has only been pos
describe the design of vitamin D and DHEA analogs with sible to demonstrate chemopreventive activity of vitamins
reduced toxicity that retain chemopreventive activity. in deficiency states, making it difficult to evaluate vitamin
Many side effects of retinoids (e.g., night blindness and agents in a clinical setting. These issues are discussed in
dermatitis) result from vitamin A depletion. Chapter 18 Chapters 31-37. Activity with tea (Chapter 30) and other
describes the design of retinoids that interact selectively dietary polyphenols presents the issues and strategies for
with retinoid receptor isoforms associated with carcino identifying chemopreventive activity of complex dietary
genesis and its inhibition (and may have less effect on mixtures.
vitamin A activities), as well as study designs that lessen Recently, interest has increased in evaluating
toxicity (e.g., retinoid drug holidays and combinations potential chemopreventive agents that may not work
with other chemopreventive agents). directly on precancer cells, but modify the activity of cel
As noted earlier, cellular control mechanisms are lular and tissue machinery (Chapters 40-43). Angiogen
of great interest for cancer therapy, and molecules on sig esis, which requires stimulation of endothelial tissue and
nal transduction pathways that mediate these mechanisms is required for growth of neoplastic tissue, has been a tar
are potentially good targets for cancer drugs. Because get of chemoprevention in particular (Chapter 40). Also,
many of these molecular targets are overexpressed, ampli proteasomes can be involved in cell proliferation by pro
fied, or mutated in precancers, signal transduction path moting activation of transcription factors (e.g., NfB) and
ways are also of interest as mechanisms for chemo their inhibition may have a role in chemoprevention (Chap
prevention. Chapters 20-28 outline the rationale and ter 41). Epigenetic modulation ofDN A is another new and
potential strategies for chemoprevention at some of these potentially very productive mechanism for chemo
targets: EGFR, ODC, ras, raj, cyclic GMP phosphodi prevention-e.g., by modulation of DNA methylation
esterase, Hsp90, and molecules involved in cell cycle (Chapter 42) and inhibition of histone deacety lases (Chap
control. Because signal transduction pathways are also ter 43). Proof of principle studies have shown chemo
critical to normal cell function, chemoprevention strate preventive efficacy of the DNA methylating agent,
gies involving these pathways are designed to minimize azacytidine, and the histone deacetylase inhibitor SAHA
effects on normal cells. For example, potential in animal studies.
chemopreventive agents inhibit targets expressed or As this volume demonstrates, much progress has
depleted only in rapidly proliferating cells or focus on been made in discovering and developing of agents that
targets at points on the pathways that allow normal cells to have shown or have promise to become chemopreventive
function via alternative routes. A few drugs have shown drugs. The pace of this progress is increasing because of
chemopreventive efficacy at these targets (e.g., EGFR and advances in many scientific disciplines that contribute to
ras inhibitors); however, side effects resulting from their our understanding, not least of which is delineation of
primary mechanisms of action and correlating with their genetic progression models that define the carcinogenesis
potency raise concerns about safety and tolerability for process from precancer to invasive disease in both humans
long-term use in asymptomatic people. For that reason, and preclinical models. These models provide the infor
food-derived agents that demonstrate pleiotropic inhibi mation and opportunity to discover and develop agents
tory effects on signal transduction are interesting potential targeted to the specific molecular abnormalities that de
chemopreventives because of their expected relatively low fine carcinogenesis. Data derived from diverse disciplines
toxicity. Soy isoflavones, which are also antiestrogens continue to prove that disruption of carcinogenesis is al
(Chapter 24) and monoterpenes (Chapter 25), are ways more successful when the intervention is early in the
examples of food-derived agents that have demonstrated neoplastic process, that is, when· genetic lesions are less
chemopreventive efficacy. numerous and dysregulation of key pathways is minimal.
Dietary antioxidants (e.g., tea polyphenols, fla Therefore, the promise that chemopreventive drug inter
vonoids) and modulators of fat metabolism (e.g., 4-3 fatty vention can reduce the human cancer burden is very great.
acids, conjugated linoleic acid), vitamins and their ana Limited success in achieving this goal thus far relates more
logs (e.g., carotenoids, vitamin C, folic acid), vitamin to the difficulty and need of obtaining data that candidate
antioxidants (e.g., lycopene, vitamin E) and minerals (e.g., drugs are safe on chronic administration than questions of
calcium and selenium) have demonstrated chemo relative efficacy. The dose relationship of antioxidants
preventive efficacy in animal and, in some cases, clinical becoming prooxidants depending on tissue microenviron-
viii Preface
ments, of antihormones becoming agonists based on tis 6. Sporn MB. Approaches to prevention of epithelial
sue-specific context, and of signal transduction inhibitors cancer during the preneoplastic period. Cancer Res
disturbing normal cell function while successfully inhib 1076;36:2699-2702.
iting carcinogenesis, are but a few examples of this phe 7. Wattenberg LW. Inhibition of chemical carcinogen
nomenon. The field of chemoprevention drug discovery esis. J Natl Cancer lost 1978;60:11-18.
8. Wattenberg LW. Chemoprevention of cancer. Can
and development will move forward by access to and
cer Res 1985;45:1-8.
recruitment of numerous scientific disciplines that allow
9. Hong WK, EndicottJ, Itri LM, et al. 13-cis-Retinoic
incremental developments documenting efficacy/safety
acid in the treatment of oral leukoplakia. N Engl J
and net therapeutic benefit at each stage. Important com
Med 1986;315:1501-1505.
ponents of this process include definition of molecular
10. Hong WK, Lippman SM, Itri LM, et al. Prevention
targets, creation of in vitro and in vivo models to evaluate
of second primary tumors with isotretinoin in squa
inhibition of the targets, establishing assays for measuring
mous-cell carcinoma of the head and neck. N Engl J
drug effect biomarkers, establishing therapeutic dose and
Med 1990;323:795-801.
incremental safety, stratifying human subjects for cancer
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drugs, mechanisms of action, and relevant drug effect 1998;90(18): 1371-1388.
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describes exciting methodologies that will help accelerate fect of celecoxib, a cyclooxygenase-2 inhibitor, in
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CoNTENTS
Preface ........................................................................................................................................................................... v
Contributors ................................................................................................................................................................ xiii
PART I. ANTIMUTAGENS
1 Inducers of Enzymes That Protect Against Carcinogens and Oxidants:
Drug- and Food-Based Approaches with Dithiolethiones and Sulforaphane ............................................... 3
Thomas W. Kensler and Paul Talalay
2 Chemoprevention by Isothiocyanates ............................................................................................................... 21
StephenS. Hecht
3 Antigenotoxic and Cancer Preventive Mechanisms of N-Acetyl-1-Cysteine ................................................... 37
Silvio De Flora, Alberto Izzotti, Adriana Albini, Francesco D'Agostini, Maria Bagnasco,
and Roumen Balansky
4 Modifiers of Cytochrome(s) P450 .................................................................................................................... 69
John DiGiovanni and Heather E. Kleiner
PART II. ANTIINFLAMMATORIES
5 Antiinflammatories and Chemoprevention: NSAIDs and Other Inhibitors
of Arachidonic Acid Metabolism .................................................................................................................. 87
Gary B. Gordon, Gary J. Kellofj, and Caroline C. Sigman
6 Cyclooxygenase-2 Inhibitors and Colorectal Cancer Prevention .................................................................. 107
Raymond N. DuBois
7 Lipoxygenases as Targets for Cancer Prevention ........................................................................................... 115
Susan M. Fischer and Russell D. Klein
8 Inducible Nitric Oxide Synthase as a Target for Chemoprevention .............................................................. 133
Lorne J. Hofseth, Tomohiro Sawa, S. Perwez Hussain, and Curtis C. Harris
9 Chemoprevention of Cancer of the Respiratory Tract by Agents Delivered by Aerosol:
Applications to Glucocorticoids and 5-Fluorouracil ................................................................................. 153
Timothy S. Wiedmann and Lee W. Wattenberg
10 Chemoprevention of Cancer by Curcumin .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . .. 169
Bandaru S. Reddy and Chinthalapally V. Rao
11 Prostacyclin and Lung Cancer Chemoprevention . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . .. .. .. .. 177
Robert L. Keith, York E. Miller, Paul A. Bunn Jr., Patrick Nana-Sinkam, Raphael A. Nemenofj,
and Mark W. Geraci
PART III. NucLEAR RECEPTOR SuPERFAMILY
12 Nuclear Receptor Superfamily: Targets for Chemoprevention ...................................................................... 195
Julia A. Lawrence and Kapil Dhingra
A. Antiandrogens
13 Prostate Cancer Chemoprevention: Sa-Reductase Inhibitors ........................................................................ 211
Jennifer E. Drisko and Siu-Long Yao
14 Searching for SARA: The Role of Selective Androgen-Receptor Antagonists in Prostate Cancer .............. 219
MarkS. Chapman, William Y. Chang, Andres Negro-Vilar, and Jeffrey N. Miner
ix