Cell killing and DNA damage induced in cultured mammalian cells by some tetrahydrobenzopsoralenquinones.
The mechanism of action of two tetrahydrobenzopsoralenquinones: 4-methyl-tetrahydrobenzopsoralenquinone (compound 3) and 4-hydroxymethyltetrahydrobenzopsoralenquinone (compound 4) was studied in mammalian cells. These agents differ structurally from earlier benzo and tetrahydrobenzopsoralen derivatives 4-hydroxymethylbenzopsoralen (compound 1) and 4-hydroxymethyltetrahydrobenzopsoralen (compound 2) by the replacement of the benzopyranone with a quinonepyranone. In this study, we evaluated the antiproliferative activity of such derivatives in normal human lymphocytes and CHO cells cultivated in vitro. Compound 4 showed a noticeable antiproliferative activity. Studying the induction of chromosomal aberrations and of SCEs, we demonstrated that compound 4 has a clastogenic effect on mammalian cells. By means of DNA filter elution and protein precipitation techniques we evaluated the DNA damage produced by the tested compounds. Some experiments performed in presence of a DNA synthesis inhibitor showed that ongoing DNA synthesis is involved in cell killing by derivative 4. All data obtained suggest that compound 4 can interfere with the activity of topoisomerase II. Catalytic studies carried out with purified topoisomerase II and bacteriophage DNA confirmed this hypothesis.
Department of Pharmaceutical Sciences of Padua University, Centro di Studio sulla Chimica del Farmaco e dei Prodotti Biologicamente Attivi del CNR, (associated to the National Institute for the Chemistry of Biological Systems), Padua, Italy.
C
C
Marzano
E
E
Severin
S
S
Falcomer
A
A
Chilin
F
F
Bordin
D000818:Animals; D016590:Aphidicolin / Q000494:pharmacology; D016227:Benzoquinones / Q000633:toxicity*; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D011564:Furocoumarins / Q000633:toxicity*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D012854:Sister Chromatid Exchange; D059005:Topoisomerase II Inhibitors
D016227:Benzoquinones; D011564:Furocoumarins; D059005:Topoisomerase II Inhibitors; D016590:Aphidicolin; D004247:DNA