DNA-DAMAGE AND CYTOTOXICITY INDUCED IN MAMMALIAN-CELLS BY A TETRAMETHYLFUROQUINOLINONE DERIVATIVE

1,4,6,8-Tetramethyl-2H-furo[2,3-h]quinolin-2-one (FQ) is an angelicin isoster characterized by a strong photosensitizing activity. FQ shows a significant antiproliferative activity also in the dark, i.e., witho ut UVA activation. The cytotoxic activity of FQ in the dark was detect ed in Hero cells and in normal human lymphocytes; FQ showed notable an tiproliferative effects, barely lower in comparison with ellipticine, used as a reference. Similar results were obtained studying the FQ's c apacity for forming chromosome aberrations. For both FQ and ellipticin e, the chromosomal damage correlated closely with cell killing; when c ompared with ellipticine at the same levels of survival, FQ appeared t o be much less genotoxic. Using alkaline elution we have investigated the ability of FQ to damage DNA. The formation of equivalent amounts o f single-strand breaks (SSB) and DNA-protein cross-links (DPC) was obs erved; in addition, these lesions appeared to be located at the some s ites in DNA. Experiments carried out with neutral elution demonstrated the formation of double-strand breaks (DSB). All these data are consi stent with an inhibition of topoisomerase II; this hypothesis was conf irmed performing an enzymatic test in vitro using topoisomerase II fro m Drosophila melanogaster embryos. (C) 1997 Wiley-Liss, Inc.