Environmental and Molecular Mutagenesis - Legacy Tobacco ...

166 1989 EMS Abstracts _ • r -_ . . _. 481
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http://legacy.library.ucsf.edu/tid/clb93d00/pdf
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^ ~ PREDICTINC' lRtTAGENICITY AND MUTAGENIC NECHANISNS USING STRUCTURAL CONCEPTS AND
ARTIFICIAL INTELLI E~NCE . H .S . Rosenkranz and G . Klopman, Departments of Environmental
Health Soienoes,_ad1=hemistry, Case Western Reserve Univ ., Cleveland, Ohio 44106 .
Heretofore structure activity relationships (SAR) have been confined to highly
oongenerie data bases (i .e ., specific chemical classes) . Thus the study of individual
molecules or small groups of molecules has not generally been possible due to the
paucity of data . The CASE (Computer Automated Structure Evaluation) method developed
by us is an expert system which is completely automatic and self-learning . We have
demonstrated that it is further unique in that it can use non-congeneric data bases
and still be highly predictive of mutagenioity . In the present study a subset of the
Gene-Tox Sa/rnonella mutagenicity data base consisting of 808 chemicals was analyzed by
CASE and the generated structural determinants were used to study the basis of the
mutagenicity of a series of agents . Thus, it was shown that for phenylazoaniline
dyes retention of the azo moiety is essential for mutagenicity . For 1-amino-2naphthol-derived
azo dyes, on the other hand, reductive cleavage of the azo bond is
required for activity . The basis of the inactivation of azo dyes and polyeyolie
aromatic hydrocarbons by sulfonation was also elucidated and it was demonstrated that
only certain sites are targets for inaotivation by sulfonation .
It will be demonstrated that CASE can be used to design molecules retaining their
beneficial properties but of greatly reduced mutagenioity .
MODULATION OF GENOTOXIC EFFECTS IN HUMANS . M.P. Rosin and A .M Gilbert,
Carcinogenesis Unit. School of Kinesiology, Simon Fraser University . Burnaby, B.C. and British
Columbia Cancer Research Centre . Vancouver, B.C ., Canada
482
Human populations are constantly exposed to a multiplicity of environmental agents, the
interactions of which can have a profound effect on cancer risk. This paper describes studies
validating the micronucleus test on exfoliated cells (MEC test) as a technique for studying the
interplay of carcinogens, cocarcinogens, genetics and dietln a biological response with relevance
to cancer, chromosome breakage in target epithelial sites. The initial studies described in this
paper involved carcinogen-exposed populations in which combinations of poor diet, alcohol, and
tobacco chewing were shown to interact to increase MEC frequencies in the oral cavity . In these
populations, oral supplementation with beta-carotene and/or vitamin A resulted in a reduction in
MEC frequencies even when exposure to tobacco/alcohol remained unchanged . Recent studies
are aimed at incorporating genetic factors (defective DNA repair processes, spontaneous
chromosomal instability) into these models . The population currently being examined is
comprised of patients with ataxia-telangiectasia (A-T), a cancer-predisposing syndrome
characterized by a hypersensitivity of cultured cells to the action of free radical-producing
chemicals and spontaneous chromosomal Instability . Our initial observations indicate that MEC
frequencies are elevated in A-T patients and in some of the parents of such patients (at risk for
breast cancer) . These studies suggest that the MEC test may be one approach by which the
complex interactions of environmental and genetic factors can be delineated .
483
0°-METNYLGUANINE-DNA-HETHYLTRANSFERASE ACTIVITY IN SURGICAL SPECIMENS FROM HIGH GRADE
HUMAN MALIGNANT GLIOMAS .
0 . Rossi, G . Arena, G . Frosina, G . Fronza, A . Sobrero, S .L . Gentile, E . Bruzzone, N . Bal_
dini, C . Silvestro, and A . Abbondandolo, National Institute for Research on Cancer, Genova
(Italy), University of Genova (Italy), and Neurosurgical Clinic, S . Martino Hospital,
Genova (Italy)
Chloroethylnitrosoureas (CENUs) are used, usually in combination with radiotherapy,
in the clinical treatment of brain tumors . As pointed out by R .W . Kohn (1987), "It seeas
likely that only tumors consisting predominantly of transferase-deficient cells would be
potentially responsive to chloroethylnitrosoureas . Tumor tissues could be assayed for
guanine-06-alkyltransferase, and treatment with these drugs could be confined to patients
bearing transferase-deficinet tumors" . MT-deficiancy has been found to be relatively fre_
quent among cell lines derived from human brain tumors but has not been demonstrated so
far, to our knowledge, in tumor tissues . We have started a study to measure the MT aetiv_
ity in surgical specimens from high grade human malignant glio®as, with the dual aim to
(i), know whether lack of activity can be demonstrated in these tumors, and (ii), relate
the measured levels of MT to the histology of the tumors and to the response of patients
to chemotherapy with 1-(2-chloroethyl)-3-cyclohaxyl-l-nitrosourea (CCNU) . To date, 12
gliomas have been assayed . In 11 tumors, MT activities ranging from 30 to 150 fmoles/mg
protein have been measured . The only negative specimen derived from a patient who had re
ceived radiotherapy before surgery . At the present stage of the study&therefore, we
have no unequivocal evidence for the existence of MT-deficient gliomas .
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