Environmental and Molecular Mutagenesis - Legacy Tobacco ...

has been reported as strongly $enotoxic in other systems . Both compounds were
extremely potent DNA-damaging agents, inducin8 > +29 NG at 30 and 10
nanograms/mI, respectively . Tetraplatin was strongly positive : + 6.47 to + 58 .26 NG at 3-
30 ug/ml . Cisplatin also induced UDS with similar cytotoxicity to tetraplatin . Menogaril
and m-AMSA were tested up to toxic or near toxic doses and were both negative . Based
on these observations, anticancer drugs differ dramatically in their ability to induce
unscheduled DNA synthesis .
236
CORRELATION OF RESULTS FROM THREE GENETIC TOXICOLOGY TESTS WITH RESULTS
FROM ONCOGENICITY ASSAYS . M . C . Harnois*, T . Sofuni, and M . Ishidate,
Jr ., National Institute of Hygienic Sciences, Setagaya-ku, Tokyo
(Japan), *Fellow, Japan Foundation for Promotion of Cancer Research .
Literature data (1965-85) from the in vitro clastogenicity (IVC)
test (951 chemicals) were compared with databases on the S~ .~tSr.p~himurium
point mutation (STPM) test (316 chemicals),the bone marrow micronu~eus
(BMM) test (105 chemicals) and oncogenicity (0) tests (177 chemicals) .
Of the IVC+, 41% were STPM- and 55% were BMM- . Of the few IVCsubstances,
5/18 were STPM+ and 2/10 BMM+ . There were no 0- chemicals
when all three mutagenicity tests were + . Chemicals negative in all
three tests were either 0- (pyrene, methionine) or had an unresolved
oncogenic status by the criteria used (diazepam, phenanthrene) .
Chemicals IVC+ and 0+ but STPM- in our data were benzene,
hexamethylphosphoramide, mitomycin C, urethane (BMM+) and actinomycin
D, diethylstilboestrol, griseofulvin, lead acetate (BMM) .
Dibutylnitrosamine and ethylene thiourea were BMM- and IVC- but STPM+
and 0+ . The data indicate that no one test was adequate to demonstrate
genotoxic effect or predict oncogenic effectl the chromosome assays
and STPM test were complementary in both instances . (Ref . M . Ishidate,
Jr . et al . : Mutation Res ., 195, 151-213, 1988)
237
GENOTORICITY OF 2-AMINO-N6-NYDROEYADENINE (AMA) T6 LS178Y/TK+/- -3 .7 .2C OUSE
LYtlPHOMA CELLS . K . Narrington-Brockl P . Glover2 P . Poorman-Allen2 C . Doerr~, R .
Krehl2, D . Clive2 J . Nozier3 and M .N . Moore4 . lEnvironmontal Health Research and
Testing, Inc ., RTP, NC 27709 USA ; 2Wellcome Research Laboratories RTP, NC 27709 USA ;
3Florida Institute of Technology, Melbourne, FL 32901 USA ; 4U .S . Environmental
Protection Agency, RTP, NC 27711 USA .
Studies in a two-component heterokaryon of Neurofpora Srassa have shown AMA to be a
potent inducer of adenine-3 point mutations ; none of the induced mutants were found
to be multilocus deletions (Overton et al ., Environ . Mutagen ., 5•501-502, 1983) . An
international collaborative study has been initiated by do Serres to understand the
types of mutations induced by AHA in higher eukaryotic organisms . Using L5178Y/TK+/-
-3 .7 .2C mouse lymphoma cells we have found AAA to be a potent inducer of TK-/-
mutants (70 ng/ml induced approximately 1600 mutants/106 survivors ; survival - 19X) .
The majority of the colonies were large colonies ; however, a significant number of
small colonies was also induced . AMA induced a moderate (as compared to ethyl
methanesulfonate) response at the heort locus (40 ng/ml induced approximately 200
mutants/106 survivors) . The induced mutant frequency at the ouabain-resistance
marker was slightly lower (70 ng/ml induced approximately 135 mutants/106 survivors) .
Consistent with the induction of small-colony TK mutants, AAA was found to be
clastogenic . From these studies it appears that in addition to point mutations, AMA
may be capable of inducing chromosomal events in mammalian cells that are not
possible in the two component heterokaryon of Neurospora . Banded karyotype and
molecular analysis will be used to evaluate the type of genetic events induced by
AHA . (This abstract does not necessarily reflect U .S . EPA policy .)
238
ROLE OF ONCOGENES AND TUMOR SUPPRESSOR GENES IN HUMAN LUNG CARCINOGENESIS . Curtis C .
Harris, Laboratory of Hunan Carcinogenesis, National Cancer Institute, Bethesda, MD
20892 .
Five families of proto-oncogenes, ras, raf, fur, un and c have so far been
associated with human lung cancer . Human ~nch~ al ~thelicells in vitro are
being used to investigate the functional role of these specific oncogenes growth
regulatory genes in carcinogenesis and tumor progression . Using the protoplast
fusion method for high frequency gene transfection, the v-Ha-ras oncogene initiates a
cascade of events in the normal human bronchial cells leading'To their apparent
immortality, decreased responsiveness to inducers of squamous differentiation,
aneuploidy, and tumorigenicity with metastasis in athymic nude mice . Transfection of
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1989 EMS Abstracts 83
Notes