A rapid mechanism-based screen to detect potential anti-cancer agents

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Abstract

Several mutant Chinese hamster ovary (CHO) cell lines have been adapted to the microtiter tetrazollum assay in order to obtain useful mechanistic information relevant to the cytotoxic activity of marine natural products. The sensitivity of a DNA double-strand break repair deficient CHO line, xrs-6, was compared with that of a DNA repair competent CHO line, BR1, to several known drugs. The deficiency of the xrs-6 cells makes them overly sensitive to compounds [e.g. topoisomerase II (topo II) inhibitors] that produce DNA double-strand breaks. Described here is the valldation of this unique cellular screen to detect such compounds. Those drugs thought to produce their effects by the inhibition of topo if, produced the largest differential cytotoxicity agalnst the mutant CHO pair. Other agents that are known to either produce single-strand breaks, cross-links or to inhibit the synthesis of DNA did not possess appreciably enhanced cytotoxicity to the xrs-6 line. The usefulness of the screen was shown by its ability to detect topo II inhibitory activity in several new marine natural products. This activity was confirmed by an in vitro enzyme inhibition assay. In contrast, the screen predicted a lack of topo II inhibitory activity in some other structurally related marine natural products and this lack of activity was confirmed by an in vitro enzyme inhibition assay.

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