The purpose of this project is to evaluate anti-tumor compounds, for their mutagenic potential in a higher organism in vivo and to relate these findings to their molecular structure and mechanism of action. Mutagenicity will be measured in terms of the incidence of mutations in somatic tissue and through the production or sex- linked recessive lethals and chromosome breaks and loss in the germ cells o, Drosophila melanogaster. The compounds to be tested are capable of intercalating with DNA, these are: (1, fagaronine and other benzophenanthridine alkaloids; (2) ellipticine; (3) other fused derivatives of quinolium and isoquinolium salts, such as: indoisoquinoline analogs of fagaronine and nitidine; the positional isomer of fagaronine and mesylated derivatives; 3- nitrobenzothiozolo(3,2-a)quinolium and 7-ethylbenzimidiazolo(3,2- a)quinolium; (4) anthracycline daunomycin and adriamycin. The comparative studies we propose will allow us to determine the molecular features that reduce the mutagenicity of some of these compounds in vivo. The simultaneous study of mutagenicity in somatic and germ cells of the same individual and the possibility of studying several genetic end-points will allow us to make a better assessment of the possible carcinogenicity of the compound. It is also our goal to validate the zeste somatic mutation assay of Drosophila for some of the anthracycline antibiotics. This test could be of great value for testing the genotoxicity of these numerous compounds which are still the object of intensive research. The knowledge gained from these studies will complement structure-activity and mutagenicity studies being performed in other laboratories with other systems and could be used for the development of more effective, non-mutagenic anticancer drugs. Through this project we will train students in genotoxicity testing using Drosophila. As a result, they will have a better understanding of genetics, mutagenesis and carcinogenesis; they will develop skills in designing experiments, collection of data, scientific writing and seminar presentations.
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