Oncogene and Transgenics Correlates of Cancer Risk Assessments

350 Pages·1992·12.355 MB·English

by  Elizabeth L. Anderson (auth.), Constantine Zervos (eds.)

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PREFACE
The data, the information, and even the overarching knowledge necessary for
risk assessments of economically important environmental carcinogens come, for the
most part, from the applied biological disciplines, e.g., toxicology, epidemiology,
biostatistics, etc. The more fundamental biological disciplines, e.g., biochemistry, cell
biology, molecular biology, molecular genetics of cancer, etc., have enormous but
unrealized potential to improve current cancer risk assessment methods. The objective
of this advanced research workshop ARW was to advance the state of the art of cancer
risk assessment methods by identifying potential short and long term contributions to
such methods from the more fundamental disciplines. Attention was paid to short and
long term contributions from research advances in the biochemistry and physiology of
oncogenes (oncogenes research) and in the construction and utilization of transgenic
animals (transgenics research).
In the last 20 years, researchers in the fundamental biological disciplines, i.e.,
biochemists, geneticists, molecular and cell biologists, etc., have, inter alia, advanced
spectacularly our understanding of the nature of neoplastic diseases. Their phenomenal
progress is the combined result of both advances and refinements of the techniques
available to them and of new fundamental discoveries. Among the latter the most
significant are the discoveries of oncogenes and of the feasibility of creating transgenic
animals, i.e., of transferring well defined and expressible genes from the cells of one
species of organisms to the embryonic cells of another.
Oncogene research efforts have taken two major directions: (a) to identify,
isolate, and study the structure, properties, functions and interrelations of an increasing
number of members of the proto-oncogene families; and (b) to elucidated the role
proto-oncogenes play in the development and homeostasis of normal eukariotic cells and
in the initiation promotion and maintenance of the malignant state.
Thus far, research efforts in transgenics have been directed toward multiple
objectives mostly in diagnostics and therapeutics. The potential of transgenics in safety
testing is just beginning to be recognized.
The same 20 years of great progress in the fundamental biological disciplines
have also witnessed the expanded uses of cancer risk assessments (CRA) by individuals
and institutions concerned with public health and environmental protection. Risk
assessment methods are now an integral part of various strategies of cancer avoidance
and CRA documents for natural or man-made substances in the environment are yearly
produced and published in increasing numbers.
v
CRAt methods have been improved some since the assessments were first
introduced back in the early 70s. However, incorporation of new information and
knowledge has been slow. This observation rings particularly true for information and
knowledge from the fundamental disciplines of biology (biochemistry, molecular
biology, genetics, etc.)
The reasons are probably many. Most likely, they include the absence of an
acceptable overarching theory that credibly bridges the knowledge gap that separates
fundamental biology from CRA methods. It is also likely, however, that a major reason
is the absence of facile interdisciplinary communications between the practitioners in the
major areas.
There is a need to bring closer and to bridge fundamental biology and CRA
method research. This ARW brought together for in-depth discussions internationally
known researchers with experience in the molecular biology and molecular genetics of
cancer and CRA practitioners and theoreticians from the academe, government and
industry. It was a 5-day, work-intensive gathering of a small number of scientists and
experts. The invited participants prepared background papers in specified topics the
majority of which were distributed for study to all participants before the Workshop.
During the Workshop, speakers present their papers and lively discussion
followed. At the appropriate points round table discussions were held to propose,
discuss, and formulate recommendations.
The ARW featured the following specific themes.
A. A review of the current state of development of CRA methods. This review
focused on identifying and describing the knowledge gaps that force risk
assessors to make sweeping assumptions about the mechanisms of spontaneous
and environmentally induced neoplasia.
B. A review of the current state of development and the likely future research
directions of molecular biology and cancer genetics. This review focused
specifically on the following two areas:
1. The production and characteristics of transgenic animals and their
potential utility in CRA; and
2. The role of oncogenes in the processes of spontaneous and induced
neoplasia.
C. Case studies to identify currently possible contributions to CRA methods from
current and immediately forthcoming knowledge about transgenics and
oncogenes. Recent cancer risk assessments for methylene chloride and benzene
were taken up as study cases.
D. Attempts to formulate recommendations for long term approaches to research
both in transgenics/oncogenes and in CRA methods. Recommendations were
sought likely to bring closer the work of the fundamental and applied research
groups and to increase the contributions of each group to the advances and the
utility of the other.
VI
A significant portion of the workshop time was taken up by discussions and by
efforts to formulate consensus recommendations for research pursuant to the workshop's
basic objective.
This volume is the product of the Workshop. In addition to the invited papers,
it includes a summary, findings, and recommendations for future work.
The editor of this volume wishes to thank the North Atlantic Treaty Organization
and the U.S. National Science Foundation for their support. He also gratefully
acknowledges the support of the Society for Risk Analysis and the International Life
Sciences Institute.
C. Zervos
Washington, D.C.
Vll
CONTENTS
CANCER RISK ASSESSMENTS: AN OVERVIEW . . . . . . . . . . . . . . . . . . . .. 1
Elizabeth L. Anderson
PHARMACODYNAMIC MODELS FOR CANCER RISK ASSESSMENT. . .. 21
Suresh H. Moolgavkar
PREDICTIVE VALUE FOR CANCER RISK ASSESSMENT OF
CELL- AND TISSUE-SPECIFIC FORMATION OF
CARCINOGEN-DNA ADDUCTS . . . . . . . . . . . . . . . . . . . . . . . . . .. 31
Ewalt Scherer
STUDIES ON THE ROLE OF PROTEIN KINASE C IN MULTISTAGE
CARCINOGENESIS AND THEIR RELEVANCE TO RISK
EXTRAPOLATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 43
Kevin R. O'Driscoll, Scott M. Kahn, Christoph M. Bomer,
Wei Jiang, and I. Bernard Weinstein
ONCOGENE ACTIVATION AND HUMAN CANCER .................. 61
Demetrios A. Spandidos and Margaret L.M. Anderson
GENETICS OF HEPATOCARCINOGENESIS IN MOUSE AND MAN ...... 67
Tommaso A. Dragani, Giacomo Manenti, Manuela Gariboldi,
F. Stefania Falvella, Marco A. Pierotti, and
Giuseppe Della Porta
PROTEIN KINASE C IN CARCINOGENESIS: COMPARATIVE
EXPRESSION OF ONCOGENES AND PROTEIN KINASE
C IN RHABDOMYOSARCOMA MODELS ................... 81
Monique Castagna, Jacqueline Robert Lezenes,
Xupei Huang, and Nicole Hanania
ONCOGENES AND HUMAN CANCERS . . . . . . . . . . . . . . . . . . . . . . . . . .. 91
J.S. Rhim, J.H. Yang, I.H. Lee, M.S. Lee, and J.B. Park
'IN VIVO' MODEL SYSTEMS TO STUDY ras ONCOGENE
INVOLVEMENT IN CARCINOGENESIS .................... 111
Ramon Mangues and Angel Pellicer
ix
K-ras ONCOGENE ACTIVATION IN NEOPLASIAS OF PATIENTS
WITH FAMILIAL ADENOMATOUS POLYPOSIS OR
KIDNEY TRANSPLANT ................................ 127
A. Ha1iassos and D.A. Spandidos
AN OVERVIEW OF TRANSGENIC MICE AS FUTURE MODELS
OF HUMAN DISEASES, IN DRUG DEVELOPMENT,
AND FOR GENOTOXICITY AND
CARCINOGENESIS STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . .. 133
J.C. Cordaro
REGULATING GENE EXPRESSION IN MAMMALIAN CELL
CULTURE AND TRANSGENIC MICE WITH YEAST
GAL4IUAS CONTROL ELEMENTS ....................... 155
David M. Omitz, Radek Skoda, Randall W. Moreadith,
and Philip Leder
GENES AND ONCOGENES OF THE ras SUPERFAMILY ............. 173
Armand Tavitian
ONCOGENIC TRANSGENIC MICE IN THE STUDY
OF CARCINOGENESIS ................................ 185
Chang-Ho Ahn and Won-Chu1 Choi
LEUKEMIA, LYMPHOMA, EMBRYONIC CARCINOMA AND
HEPATOMA INDUCED IN TRANSGENIC RABBITS
BY THE c-myc ONCOGENE FUSED WITH
IMMUNOGLOBULIN ENHANCERS ..................... " 199
Helga Spieker-Polet, Periannan Sethupathi, Herman Polet,
Pi-Chen Yam, and Katherine L. Knight
AN OVERVIEW OF THE OUTSTANDING ISSUES IN THE RISK
ASSESSMENT OF METHYLENE CHLORIDE . . . . . . . . . . . . . . .. 217
Rory B. Conolly, Kannan Krishnan, and Melvin E. Andersen
CANCER DOSE-RESPONSE MODELING AND
METHYLENE CHLORIDE .............................. 231
Gail Charnley
RISK ASSESSMENTS FOR BENZENE-INDUCED LEUKEMIA
- A REVIEW ..................................... " 241
Kenny S. Crump
COMPARATIVE METABOLISM AND GENOTOXICITY DATA
ON BENZENE: THEIR ROLE IN CANCER
RISK ASSESSMENT ................................. " 263
Sandro Grilli, Silvio Parodi, Maurizio Taningher,
and Annamaria Co1acci
x
DOSE-RESPONSE RELATIONSHIPS FOR BENZENE: HUMAN
AND EXPERIMENTAL CARCINOGENICITY DATA ........... 293
Silvio Parodi, Davide Malacarne, Sandro Grilli,
Annamaria Colacci, and Maurizio Taningher
A THRESHOLD FOR BENZENE LEUKEMOGENESIS . . . . . . . . . . . . . . .. 305
Bruce Molholt
SOME POINTS FOR DISCUSSION FROM THE
ONCOGENE WORKSHOP .............................. 313
Bruce Molholt
CONCLUDING REMARKS, FINDINGS AND
RECOMMENDATIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 319
C. Zervos
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 333
Xl