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Upcoming Studies on Lung Cancer and PCBs
Study #1
ANDERSON LM. SENSITIVITY FACTORS IN SPECIAL CARCINOGENESIS
MODELS Crisp Data Base National Institutes Of Health. Author Address: NCI,
NIH
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PCBs and dioxins are tumor promoters
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PCBs and dioxins may interact with genetic susceptibilities
in the K-ras gene, resulting in lung cancer
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dioxin caused a significant increase in K-ras p21 in lung
cell membranes in some but not all mouse strains
Cancer is often the outcome of interaction between external
exposures or lifestyle factors, and genetic susceptibilities. These processes
can be studied through epidemiology, and through modeling in animals. Nasopharyngeal
cancer is common only in certain geographically-delimited populations,
with lifestyle factors, especially diet, implicated in causation, and genetics
and infections as secondary factors. Causative chemicals in the diet may
include N-nitrosamines, especially N- nitrosodimethylamine, which is activated
in cells by cytochrome P450 2E1 (CYP2E1). We have found a striking correlation
between incidence of nasopharyngeal cancer in Chinese and an allelic form
of the CYP2E1 gene, c2c2, that may be highly expressed. However, this association
was limited to nonsmokers. Among smokers, incidence of the disease was
less, and was positively associated with the other allelic form of CYP2E1,
c1c1. Thus a complex interplay of several exposure factors with genetic
constitution determined cancer outcome. To begin to understand the role
of the CYP2E1 gene in more detail, we have examined part of the structure
of this gene in two species of monkey, patas and cynomolgus. The polymorphic
promoter region of the gene in the patas monkeys is very similar to that
of the c2c2 humans, whereas that of the cynomolgus monkeys, while still
highly homologous, is much longer and has a different base sequence in
the diagnostic RFLP site. The patas and human both have evolved on the
savannah of Africa, whereas the cynomolgus is an arboreal species. The
patas monkey has potential as a model for the susceptible c2c2 humans.
We have used modeling in mice to begin to approach the question of promotion
of lung tumors, suspected to occur during the long latency of human
lung cancers, and a possible target for intervention strategies. Since
the K-ras gene is often mutated in both murine and human lung adenocarcinomas,
we have started to examine the levels and cell membrane localization of
K-ras p21 in mouse lung as a function of genetics and of exposure to the
tumor promoters, 2,3,7,8,-tetrachloro-dibenzo-p- dioxin (TCDD) and polychlorinated
biphenyls. We discovered, for the first time, marked differences among
various genetic mouse strains. Whereas the total K-ras p21 was similar
in all strains, amounts in membrane were significantly greater in C57BL/6
and BALB/c mice, compared with other strains. Treatment with TCDD caused
a significant increase in the p21 in lung cell membranes in some but not
all mouse strains. The relevance of these changes in genetic susceptibility
to tumor promotion is under study.
Study #2
SHIELDS PG. DEVELOPMENT OF METHODS FOR HUMAN MOLECULAR
DOSIMETRY. Crisp Data Base National Institutes Of Health. Author Address:
NCI, NIH
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study of DNA-adducts may serve to pinpoint genetic susceptibility
to cancer
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PCBs are measurable in human lung and are being studied to
assess enzyme induction in the lung
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enzyme presence can predict the presence of important DNA-adducts
associated with cancer
The phases of development, validation and application of
biomarkers for cancer risk requires intensive study for each phase in order
to build a reliable foundation for cancer risk assessments. This
laboratory has focused upon the development of DNA-adduct detection assays
that will serve to validate screening assays. These methods also will allow
for the study of adducts as phenotypes of cancer susceptibility. Towards
that end, chemically specific methods have been developed for the detection
of 7-methyl-dGp, 7-ethyl-dGp and polycyclic aromatic hydrocar- bon-dGp
adducts. Separately, improved methods and validation of N- acetyltransferase
(NAT) and glutathione-S-transferase M1 (GSTM1) genetic polymorphisms have
been developed. These studies have led to the discovery that GSTM1 null
genotypes predict the presence of PAH-dGp adducts in human lung
in vivo. Cytochrome P450 2E1 and 2D6 predict the presence of 7-methyl-dGp
adducts. Determination of the different adduct levels in the same tissues
demonstrate the differences in metabolic tendencies for adduct formation.
Separately, an analysis of different parts of human lung indicate that
interindividual differences in adduct formation is a greater predictor
of adduct levels compared to the location in the lung and possible associated
factors such as airflow. An interlaboratory study has shown that polychlorinated
biphenyl (PCB) congeners are measurable in human lung and this procedure
will be used to assess the effects of PCBs on cytochrome P450 induction.
This work also has demonstrated the superiority of RFLP method detection
for NAT genotypes and that these genotypes correlate with 4-aminobiphenyl
hemoglobin adducts. Finally, polychlorinated biphenyl congeners have
been reliably detected in human lung tissue and these methods will be used
to assess correlations with enzyme induction in vivo.
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The
Animal Studies 32 - 32
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