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CONCEPTUAL FOUNDATIONS OF CHEMOPREVENTION: A CRITICAL ANALYSIS GERALD M. LOWER, JR.* and MARTY S. KANAREKi Human cancer continues to be a problem of significant importance that has, widi few exceptions, tended to evade both preventive and therapeutic approaches to control over the past 3 decades. Perhaps because many human cancers, particularly those involving epithelial tissues , are causally related to culture-mediated chemical exposures [1,2] (e.g., tobacco smoke, diet, occupation) and perhaps because of apparent difficulties in prevention through the modification of cultural behavior and the minimization of human exposures, considerable recent emphasis has been placed on approaches to the "chemoprevention" of these lesions [3-7]. In the comprehension of approaches to cancer control, it is usually useful to consider both what a thing is and what it is not. In general, chemoprevention has been portrayed as preclinical intervention directed at preventing the clinical emergence.of symptomatic disease, as opposed to direct intervention with exposures to causal agents or with frankly malignant lesions. In other words, chemoprevention is not classical prevention nor is it a posteriori therapeutic intervention in the traditional sense. Chemoprevention, then, presumes exposure to causal agents and represents intervention with biological mechanisms underlying the process of carcinogenesis prior to clinical manifestation. In developing a basis for an analysis of chemoprevention from common conceptual perspectives, it is necessary to refer briefly to the natural history ofthe human epithelial cancers. The natural history ofdisease in general [8] and the neoplastic diseases in particular [9] is divided conceptually into two portions, causal disease process leading to the initial Supported by contract NO1-CP-75905 from the National Cancer Institute and by die College of Agricultural and Life Sciences, University of Wisconsin—Madison. "Center for Human Systems, Institute for Environmental Studies, University ofWisconsin , WARF Building, 610 Walnut Street, Madison, Wisconsin 53706. tDepartment of Preventive Medicine, University ofWisconsin, 504 Walnut Street, Madison , Wisconsin 53706.© 1982 by The University of Chicago. All rights reserved. 0031-5982/83/2601-0288S01.00 Perspectives in Biology and Mediane, 26, 1 ¦ Autumn 1982 | 107 bodily responses and effectual disease process leading to die manifestation of symptomatic disease, clinical course, and final outcome. With the epitiielial cancers, comprising about 90 percent of human cancers, the initial responses (or initial causal events) are generally viewed as taking place at the molecular level in basal epithelial cells, are referred to as "initiation," and separate causality from effectual course [10]. In mechanistic terms, causal disease process in human cancer (e.g., tobacco-diet-occupation-related cancers) takes place in the human external environment with mechanisms of carcinogen formation (e.g., pyrolytic synthesis, natural biosynthesis, industrial synthesis) and mechanisms of environmental vector transport (e.g., tobacco smoke, diet, industrial contamination) (fig. 1). Then, with human exposure, causal disease process moves to the human internal environment and physiological/metabolic mechanisms of carcinogen biotransport, activation , and detoxication; all of which have the effect of determining the availability of ultimate carcinogenic (electrophilic) metabolites involved in the interaction with critical cellular macromolecules. Causal disease process, then, includes carcinogen formation, vector transport, physiologic/metabolic modulation, and interaction leading to initiation. CHEMICALLY- INDUCED HUMAN CANCER ? ·¦ INTERVENTION WITH ENVIRONMENTAL EMERGENCE __________OF CARCINOGENIC HAZARD_____________ ABANDONMENT OF CARCINOGEN MANUFACTURE ABANDONMENT OF HUMAN ACTIVITIES YIELDING CARCINOGENS AS A BY- PRODUCT INTERVENTION WITH ENVIRONMENTAL TRANSPORT _____________AND HUMAN EXPOSURE______________ ABANDONMENT OF CARCINOGEN USE ABANDONMENT OF HUMAN ACTIVITIES YIELDING EXPOSURE TO NATURALLY OCCURINGCARCINOGENS INTERVENTION WITH CARCINOGEN ACTIVATION INHIBITION OF ACTIVATION ENZYMES STIMULATION OF DETOXICATION ENZYMES INTERVENTION WITH REACTIVE ELECTROPHILES TITRATION OF ELECTROPHILES (SCAVENGING) WITH LOW- MOLECULAR WEIGHT NUCLEOPHILES INTERVENTION WITH GENOMIC DAMAGE ? STIMULATION OF REPAIR MECHANISMS INITIATION Fig. 1.—Approaches to preventive intervention o iz ui > UJ tt CL Ul CC a. o S ? ? ? 108 I Gerald M. Lower,Jr., and Marty S. Kanarek · Chemoprevention It is generally acknowledged that carcinogenesis of epithelial tissues is a multistep process in which the various stages of the process are represented by a series of discrete changes in the basal epithelial cell that cumulatively result in the preferred growth ofa malignant clone; hence, the long and dose-related latent period. In this multistep process, initiation (the first irreversible causal event) [10] is probably a genomic mutation involving the chemical modification of DNA, and all of the further...

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Additional Information

ISSN
1529-8795
Print ISSN
0031-5982
Pages
pp. 107-115
Launched on MUSE
2015-01-07
Open Access
No
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