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Upcoming Studies on Lung Cancer and PCBs
Study #1
ANDERSON LM. METABOLIC AND PHARMACOLOGICAL DETERMINANTS
IN PERINATAL CARCINOGENESIS. Crisp Data Base National Institutes Of Health.
Author Address: NCI, NIH
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the number of tobacco-initiated lung tumors in newborn mice
were increased by PCBs 2.5-fold at 28 weeks, and fourfold at 28 and 52
weeks.
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PCBs promote lung tumors by triggering the early appearance
of tumors which would otherwise occur in old age.
Themes pursued included (1) transplacental risks of human
exposure chemicals, (2) genetic determinants of perinatal cancer risk,
(3) postnatal promotion of perinatally initiated tumors; and (4) promotion
of mammary tumors by bioretained chlorinated aromatic hydrocarbons. cis-
Dichlorodiammineplatinum, an anticancer agent sometimes used in pregnant
women for the treatment of malignant ovarian and uterine tumors, was tested
for transplacental tumor-initiating effects in SENCAR mice. Exposure to
7.5 mg/kg on gestation day 17 resulted in a significant increase in thymic
lymphomas (16% vs 0% in controls), lung tumors (9% vs 1%), and promotable
skin tumors (49% vs 10%). These results provide evidence that this drug
can initiate neoplastic lesions in multiple tissues transplacentally. With
regard to genetic determinants, DNA adducts of the metabolism-dependent
carcinogen, 3-methylcholanthrene (MC) were assayed by 32P-postlabeling
in mouse fetal tissues. Both parental and fetal genotypes at the Ah locus,
which controls induction of cytochrome P450 1A1, influenced level of adduction,
with greatest adducts in inducible fetuses carried in noninducible mothers,
and least where both were noninducible. Postnatal promotion of tumors
was studied after initiation of liver and lung tumors with N-nitrosodimethylamine
(NDMA) on day 4 of life, followed by treatment on day 8 with the polychlorinated
biphenyls (PCBs) mixture, Aroclor 1254. Incidences of NDMA-initiated lung
tumors were enhanced by PCBs 2.5-fold at 28 weeks, and multiplicities fourfold
at 28 and 52 weeks. Liver tumors occurred in significant numbers at
52 weeks only after NDMA/PCBs. At 72 weeks both tumor types had similar
incidences in both NDMA-only and NDMA/PCB groups. The results confirm
that PCBs promote lung as well as liver tumors by triggering the early
appearance of latent, neonatally initiated tumors otherwise presenting
in old age. (Anderson, NIH database)
Study #2
LINNOILA RI. CELLULAR DIFFERENTIATION IN NORMAL AND NEOPLASTIC
RESPIRATORY EPITHELIUM Author Address: NCI,NIH Crisp Data Base National
Institutes Of Health
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Clara cell specific protein (CC10) also known as a PCB (a
potent carcinogen)-binding protein may be related to lung cancers
Our aim is to characterize the cellular differentiation associated
with premalignant changes in respiratory epithelium. This has been studied
at the level of: A. Neuroendocrine differentiation. We have demonstrated
that 15% of non- small cell lung carcinomas (NSCLC) express multiple neuroendocrine
(NE) features. Our results indicate that these tumors are sensitive to
chemotherapy. The role of NE differentiation in non-neoplastic epithelium
is investigated. B. Peripheral airway cell differentiation. We found 30%
of the 400 NSCLC tumors examined to be positive for at least one of the
peripheral airway cell (PAC) markers SP-A and CC10. They also formed a
clinically distinct subset. Characterization of NSCLC cell lines expressing
PAC markers is in progress. In order to define premalignant lesions, we
are studying the response of PACs in non-neoplastic lung to pulmonary carcinogens,
including tobacco specific nitrosamines. C. Clara cell specific protein
(CC10) also known as a PCB (a potent carcinogen)-binding protein. We
have demonstrated that non-ciliated secretory cells, which are progenitor
cells for the epithelium and NSCLC, express high levels of CC10, while
only 10% of NSCLC are positive for CC10. Our preliminary results showed
that in the presence of smoking related atypia the patterns of CC10 mRNA
expression in non-neoplastic human lung were affected both in larger airways
and alveoli, while changes in smaller airways were minimal. Changes involved
both intensity and cellular distribution of mRNA. Further studies are in
progress. D. Oncogene expression. We have found overexpression of c-myc
in a high number of NSCLC as well as in the progenitor cells in human lung
by in situ hybridization. In a cohort of 120 NSCLC patients, overexpression
of p53 tumor suppressor gene was correlated with shorter survival in a
subset of patients. Molecular analysis of the potentially prognostic mutations,
and the mutations in premalignant changes in the surrounding non-neoplastic
lung is in progress. The significance of the project is that the results
will provide a rational basis for innovative approaches for early detection
and intervention in human lung cancer.
Study #3
WARSHAWSKY D. METABOLIC ACTIVATION OF N-HETEROCYCLIC AROMATICS.
Crisp Data Base National Institutes Of Health. Author Address: UNIV OF
CINCINNATI COLL OF MED, 3223 EDEN AVE, CINCINNATI, OH 45267-0056
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PCB enzyme induction will be used to test the metabolic activation
of two lung carcinogens
N-heterocyclic aromatics are environmentally important pollutants,
however, little is known of their mechanism of action or biological effects.
The objective is to investigate the metabolic activation of 7H-dibenz(c,g)carbazole
(DBC) which is a potent carcinogen in mouse lung, liver, and skin,
with respect to dibenz(a,j)acridine (DBA) a moderate to weak carcinogen
in mouse lung and skin. Since the structural difference between
the well characterized polycyclic aromatic hydrocarbons and the N-heterocyclic
analogs is the existence of a nitrogen atom in the aromatic ring system
of the latter, it is hypothesized that any differences in metabolism, metabolic
activation, DNA binding, or carcinogenic potency is due not only to the
presence of a nitrogen atom but to the aromaticity of the heteroatom containing
ring. The specific aims involve the characterization of the metabolic activation
and DNA binding of DBC and DBA in mouse skin and liver as follows: 1) determine
the modulation of metabolism of DBC and DBA incubated with liver preparations
using a variety of inducing agents, 2) determine the modulation of DNA
binding of DBC and DBA with induced liver preparations, 3) determine the
modulation of metabolism of DBC and DBA with induced skin preparations,
4) characterize the covalent binding of selected metabolites of DBC and
DBA to DNA in vitro with liver preparations, 5) characterize the covalent
binding of DBC and DBA to DNA in skin and liver in vivo and 6) undertake
chronic dose response carcinogenicity studies for DBC and DBA relative
to benzo(a)pyrene and mixtures thereof. Phenobarbital, Aroclor 1254,
DBC, DBA and 3-methylcholanthrene will be used for enzyme induction
and subcellular liver and skin fractions will be prepared. Metabolism of
DBC and DBA will be analyzed by HPLC and alumina column chromatography.
In vitro DNA binding and DNA adducts (as standards) will be analyzed by
radiometry, HPLC, and analytical techniques. In vivo studies will involve
the development of finger prints of DNA adducts using (32)P-postlabeling
techniques and dephosphorylation of the adducts for comparison with in
vitro adducts. Lastly, analysis of the biological responses of mixtures
will determine whether additive, synergistic or inhibitory effects are
involved. This approach will provide valuable information concerning the
disposition of an important class of carcinogens and will lead to a better
understanding of the mechanism(s) of action of N-heterocyclic aromatic
carcinogenesis.
Study #4
HEJTMANCIK M. EVALUATION OF DIOXIN TOXIC EQUIVALENCY FACTORS.
Crisp Data Base National Institutes Of Health
This project has been designed to test the following hypotheses:
The USEPA interim TEFs for dioxins, dibenzofurans and PCBs can predict
the relative carcinogenic potency of single congeners in female Sprague-Dawley
rats. The USEPA interim TEFs for dioxins, dibenzofurans, and planar PCBS
can predict the relative carcinogenic potency of an environmentally relevant
mixture of these chemicals in the female Sprague-Dawley rat. The carcinogenicity
of a dioxin is not altered by the presence of a nondioxin like PCB. The
relative potencies for biochemical endpoints, such as CYP1A1 induction,
in the two-year studies are equivalent to the relative potency for carcinogenesis
when estimated based on administered dose. The relative carcinogenic potencies
of the individual congeners, based on target tissue dose, are the same
as the relative potencies based on CYP1A1 induction using the same target
tissues. The relative carcinogenic/biochemical potencies based on administered
dose are the same as those based on tissue dose. The relative potencies
based on serum or whole blood concentrations are equivalent to administered
dose and target tissue dose. Two-year studies are to be performed with
five individual compounds (TCDD, PeCDF, PCB126, PCB118 and PCB153) and
two mixtures (Mix 1: TCDD, PeCDF, PCB126; and Mix 2: PCB126 and PCB153).
Interim evaluations to be performed at 13, 30 and 52 weeks will include:
Thyroid hormones; liver CYP1A1, CYP1A2 and CYP1B1, UDP-GT, porphyrins and
retinol; lung CYP1A1 and CYP1B1; tissue concentration of test chemical(s)
in liver, lung, blood and adipose tissue; certain organ weights,
cell proliferation of liver, and limited histopathologic evaluation. Complete
histopathologic evaluation and tissue concentration of test chemical(s)
will be performed at terminal sacrifice.
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