DNA damage induced by 4,6,8,9-tetramethyl-2H-furo[2,3-h]quinoline-2-one, anew furocoumarin analog: Biological consequences

4,6,8,9-Tetramethyl-2H-furo[2,3-h]quinolin-2-one (HFQ) and its isomer FQ (1 ,4,6,8-tetramethyl-2H-furo[2,3-h]quinolin-2-one) showed very strong antipro liferative activity in mammalian cells, about two times greater than 8-meth oxypsoralen (8-MOP). Both compounds induced DNA-protein cross-links (DPC) b ut not interstrand cross-links. The FQ generated DPC in a biphotonic proces s, yielding a new kind of diadduct, whereas HFQ induced DPC by a monophoton ic one, probably without its physical participation in the covalent bridge, These lesions gave different toxic responses, Sensitization of FQ led to e xtensive DNA fragmentation and to a number of chromosomal aberrations. Conv ersely, HFQ seemed to be completely inactive and 8-MOP gave intermediate re sults. A strict relationship between DPC formation and induction of chromos omal aberrations was observed. The HFQ did not induce light skin erythemas, whereas FQ was more phototoxic than 8-MOP, thus suggesting that FQ lesions , DPC in particular, may be implicated in skin phototoxicity, Ehrlich ascit es cells, a transplantable mouse tumor, inactivated by furoquinolinone sens itization and injected into healthy mice, protected them from a successive challenge by viable tumor cells. This response appeared to be based on an i mmune mechanism. Comparable amounts of base substitution revertants were sc ored when testing furoquinolinones and 8-MOP in bacteria but no DPC were de tected, This suggests that classic mutagenesis tests on bacteria are insuff icient to give adequate information on furocoumarin genotoxicity, Given its features, HFQ can be regarded as an interesting new agent for psoralen plu s UVA photochemotherapy and photopheresis.