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The Human Breast Cancer Cell DNA Synthesome Can Serve as a Novel In Vitro Model System for Studying the Mechanisms of Action of Anticancer Drugs

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This report describes preliminary results from our studies at the use of breast cancer DNA Synthesome as an In Vitro Model system to evaluate the mechanism of action of anticancer drugs. In this work the pharmacological profile of new eight hydrazone derivatives structurally designed as ribonucleotide reductase inhibitors are discussed. Also a series of new seven 1 ,4-naphtoquinones derivatives structurally related to the natural product lapachol and designed to act as topoisomerase inhibitors were investigated as well. The antiproliferative activity and the ability to inhibit DNA synthesis through preventing 3H-thymidine incorporation were determined using MCF-7 breast cancer cell lines and some derivatives showed significant results. Our study showed also that the hydrazone new drugs were unable to inhibit the cellular DNA synthetic apparatus in the in vitro DNA replication assay using the human breast cancer DNA synthesome multi-protein complex what is consistent with their being RR inhibitors since the deoxyribonucleotide biosynthesis enzymes are not a part of the DNA synthesome. At least four compounds of the 1 ,4-naphtoquinone series showed remarkable results and seem to be promising drugs for the study of the appliance of the breast cancer DNA synthesome as a model system to evaluate anticancer drugs.

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Annual summary rept. 1 Jul 1998-30 Jun 2001



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