THE ALKYLATING ANTITUMOR DRUG TALLIMUSTINE DOES NOT INDUCE DNA-REPAIR

Tallimustine, an alkylating benzoyl mustard derivative of distamycin A (FCE 24517), is novel anti-tumor agent. Both its cytotoxic activity a gainst human LoVO cells and nicking efficiency on isolated plasmid DNA were studied in relation to hyperthermic treatment and compared to th e effect of doxorubicin, a known non-alkylating anti-tumor agent. The results of this analysis indicate that the cytotoxic activity of talli mustine reflects its direct interaction with the DNA target. The abili ty of tallimustine to induce DNA repair in human primary normal fibrob lasts was monitored by determining both the stimulation of unscheduled DNA synthesis (UDS) and the ability to reactivate a plasmid containin g a reporter gene, treated in vitro with tallimustine, in comparison w ith the effect of UV-C irradiation. The results suggest that human cel ls able to repair UV-damage are unable to overcome DNA damage induced by tallimustine. Therefore, the hypothesis that the biological activit y of tallimustine is related to its alkylating properties is further s upported by the temperature studies and strengthened by the observed i nability of cells to repair tallimustine-induced DNA damage.