Læknablaðið - 15.10.1983, Side 25

LÆKNABLAÐID
249
TABLE OF CONTENTS
I. INTRODUCTION
A. Historical Background
B. Current Concepts
II. INITIATION
A. Metabolism
1. Activation and Detoxification
2. Modulation of Metabolism
3. Organ and Species Differences
B. Interactions with Macromolecules
1. DNA Alterations and Repair
2. Modulation of DNA Damage
and Repair
C. Proliferative Status of Target Cells
III. PROMOTION
A. Efffects of Promoters
B. Potential Mechanisms of Action
IV. PROGRESSION
V. SUMMARY AND CONCLUSIONS
I. INTRODUCTION
During the last decade considerable progress
has been made in understanding the overall
mechanisms of carcinogenesis. The new re-
search findings offer a framework for re-
evaluation of the current concepts regarding
carcinogenesis that are required in order to
provide better models of the phenomenon
under study. Only by continuous re-evaluation
of our concepts and refinement of our experi-
mental models can we hope to establish the
mechanisms underlying carcinogenesis. In this
review attempts are made to reexamine the
mechanisms underlying tumor induction in
light of new findings of the last few years.
A. Historical Background
Studies in paleopathology have indicated that
few tumors occurred in prehistoric times (79)
and that tumor incidence increased with the
development of complex societies. The in-
volvement of social lifestyles in cancer occur-
rence was first observed by Ramazzino (1700)
who noted that nuns exhibited a higher
frequence of breast cancer than other women
(58). Subsequently, Hill (1761) associated use
of tobacco snuff with cancer of the nasal
passage (27) and Potts (1775) reported that
the occurrence of scrotal cancer in chimney
sweeps was associated with occupational ex-
posure to soot (57). In 1895, Rehn published
evidence that aromatic amines were asso-
ciated with bladder cancer (59), Unna (1894)
and Dubreuilh (1896) reported the association
of sunlight and skin cancer (18, 72), and Weis-
mann 1881) suggested an association between
the »germplasm« and cancer (76). During the
twentieth century, numerous chemical agents
have been found to induce cancer in experi-
mental animals. Recently, the role of environ-
mental factors (including life styles and habits)
in the enhancement or inhibition of tumor
formation has been given greater attention
(17, 45). With these findings, the scientific and
lay public became increasingly aware of the
phenomenon of carcinogenesis. Consequently,
in the last decade, more rapid progress has
been made in understanding the overall me-
chanisms of carcinogenesis than at any other
time in history.
B. Current Concepts
A number of important scientific issues con-
cerning carcinogenesis have developed over
the last few years. First, cancer can be induced
by either physical, chemical, or biological
agents. Second, an estimate of the potency of
these agents may never be exact and may vary
with life style, habit, age, sex, ethnic back-
ground, test species, diet, dose level, dose rate,
route of administration, vehicle or solvent
used, the presence or absence of other agents,
and the environmental conditions prior to,
during, or after exposure. Third, tumor devel-
opment is a multistage process involving both
genetic and epigenetic events, which may
include the participation of both chemicals
and viruses. Fourth, numerous physical, chemi-
cal, and biological agents may alter the
frequency of tumor induction by altering one
or more of the stages in carcinogenesis. Fifth,
the development of tumors, at least initially,
appears to require an alteration in the infor-
mation processing of cells and the subsequent
fixation and propagation of these changes.
Finally, only by understanding the stages of
tumorigenesis, the substances which modulate
them, and how these may differ between cells,
organs and species, will we ultimately be able
to predict unambiguously and quantitatively
the tumorigenic potential of a substance
and/or life style in man.
II. INITIATION
A. Metabolism
1. Activation and Detoxification. Chemical