Mutagenesis, Vol. 14, No. 2, 243-248,
March 1999
© 1999 UK Environmental Mutagen Society/Oxford University Press
A combined biochemical and cytogenetic study of thioridazine-induced damage to nucleic acids
1 Laboratory of Biochemistry, Faculty of Chemistry, Aristotle University of Thessaloniki 54006 and 2 Laboratory of Medical Biology and Genetics, The Medical School, Demokritus University of Thrace, PO Box 93, Alexandroupolis 68100, Greece
In this work the biochemical effects of thioridazine, a commonly used phenothiazine, have been studied upon native double- and single-stranded DNA and also upon a supercoiled plasmid. The results indicate that thioridazine causes damage and scissions to these nucleic acids but only at concentrations much higher than the one used in our cytogenetic experiments and that the damage seems to depend on the concentrations used. Furthermore, we studied the action of thioridazine alone or in combination with caffeine and/or melphalan upon human lymphocytes in vitro. Thioridazine and caffeine (a well-known inhibitor of cellular repair mechanisms) were shown to act synergistically to potentiate the cytogenetic effect of melphalan on human lymphocytes. It is suggested that thioridazine alone or in combination with caffeine may exert its synergistic effect on melphalan cytotoxicity to cultured human lymphocytes not only indirectly, i.e. as a strong calmodulin inhibitor by facilitating the intracellular retention of melphalan, but also directly by reaction with nucleic acids and by causing scissions in and damage to them. Therefore, thioridazine (as chlorpromazine) has some potential as an adjuvant chemotherapeutic agent for the treatment of human cancer.
3 To whom correspondence should be addressed. Tel: +30 551 39888; Fax: +30 551 39898; Email: lialiari{at}demokritos.cc.duth.gr