RELEVANCE OF INTERSTRAND DNA CROSS-LINKING INDUCED BY ANTHRACYCLINES FOR THEIR BIOLOGICAL-ACTIVITY

The relevance of interstrand DNA crosslinking induced by anthracyclines for their cytotoxic action was studied in several biological systems with cells differing in sensitivity towards these compounds. It was done by establishing the correlation between DNA crosslinking and cytotoxic activity of anthracyclines. The study showed that there is a strong positive correlation between cytotoxic activity of anthracyclines and their DNA crosslinking potency in HeLa S-3 cells for a group of six Daunomycin derivatives (r = 0.97) as well as for all the studied 13 anthracyclines of divergent chemical structure (r = 0.95). Similar relationships between cytotoxic activity and DNA crosslinking ability was found for Adriamycin(R) and Daunomycin in three other cellular systems: (i) in LoVo and about 20-fold Adriamycin-resistant LoVo/DX human colon adenocarcinoma cells, (ii) CHO-K1 and its Adriamycin-hypersensitive mutant CHO-ADRS Chinese hamster ovary cells and (iii) HeLa S-3 cells sensitized about 3-fold to cytotoxic action of Adriamycin and Daunomycin by lowering intracellular glutathione content, to about 10% of normal level, by buthionine sulfoximine treatment. The presented results show that DNA crosslinking induced by anthracyclines may be responsible for the cytotoxic activity of these compounds.