© 2000 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 27, 2,
2000
© 2000 Oxford University Press
Preface
Affiliation of authors: Eppley Institute, University of Nebraska Medical Center, Omaha.
Correspondence to: Ercole Cavalieri, D.Sc., Eppley Institute for Research in Cancer and Allied Diseases, 986805 Nebraska Medical Center, Omaha, NE 68198-6805 (e-mail: ecavalie{at}unmc.edu).
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INTRODUCTION |
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 Top Introduction |
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In Greek mythology, the great Athenian hero Theseus volunteered to go into the Labyrinth to slay the Minotaur, the monster that was satisfied only by devouring Athenian youths. This noble accomplishment could never have been achieved unless Ariadne had fallen in love with the handsome Theseus and followed him into the Labyrinth, leaving behind her a thread that marked their path through the tortuous passageways and blind alleys. The thread served not only to ultimately reach the Minotaur but also to find the way out of the Labyrinth once the Minotaur was slain. This mythologic story contains elements that illustrate the war against cancer and the subtle approaches needed to conquer it.
We can identify the Labyrinth as the series of complex and intertwined events leading to cancer, the Minotaur. The thread represents the fundamental physicochemical properties of the cancer-initiating molecules that allow us to unravel the primary events in this disease process, thus exiting the Labyrinth victorious.
The first landmark finding was obtained by the brilliant intuitions of James and Elizabeth Miller in the late 1960s who recognized first, that chemical carcinogens bind covalently to cellular macromolecules, and second, that the ultimate electrophilic species of chemical carcinogens react with nucleophilic groups of DNA, RNA, and protein. The importance of this finding was the identification of the reactive electrophilic species as the unifying factor among the different structures of chemical carcinogens. Subsequently, attention was focused on the carcinogen-induced alterations of DNA because of the critical, heritable function of this macromolecule. Reaction of chemical carcinogens with DNA led to the discovery of two types of adducts, the stable adducts that remain in DNA unless removed by repair and the depurinating adducts that are lost from DNA by destabilization of the glycosyl bond between deoxyribose and adenine or guanine. Experimental evidence indicates that depurinating adducts play the major role in generating the critical mutations leading to initiation of cancer. In turn, the depurinating adducts obtained from electrophilic metabolites of estrogens, namely, catechol estrogen-3,4-quinones, may be endogenous initiators of several types of human cancer, including breast and prostate cancers.
Interest in the role of endogenous estrogens as tumor initiators led to the organization of a symposium on "Estrogens as Endogenous Carcinogens in the Breast and Prostate." The symposium, held March 16 and 17, 1998, explored our understanding of estrogen metabolism and genotoxicity and current knowledge in estrogen receptor-mediated processes as critical events in the initiation and promotion of cancer. Rather than merely reporting the proceedings of the symposium, this monograph represents an overview of various aspects of estrogen carcinogenesis, organized into comprehensive chapters by the symposium presenters.
As editors of this monograph, we wish to thank the Division of Cancer Biology, National Cancer Institute, in particular, Dr. David G. Longfellow and Ms. Karen R. Grotzinger, for the outstanding support given to the symposium and monograph. We also thank the members of the National Cancer Institute-supported focus group on estrogen carcinogenesis known as The Cancer Cube for their hard work and cooperation in preparing this monograph. Finally, we gratefully acknowledge the contributions of Mr. Harry W. Bullerdiek and Ms. Aimee R. Welch-Miller for coordinating all parts of the monograph preparation.
Omaha, Nebraska
August 17, 1999
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