ANTHRACYCLINES - REVIEW OF GENOTOXICITY AND CARCINOGENICITY STUDIES

The genotoxicity and carcinogenicity data from in vitro and in vivo st udies conducted during preclinical safety assessment of doxorubicin (D OXO), epirubicin (EPI) and idarubicin (IDA), are reviewed. The genotox icity assays included a) gene mutation in Salmonella typhimurium with 5 tester strains; b) gene mutation in the V79 mammalian (lung) cell li ne; c) chromosome aberrations in human lymphocytes cultured in vitro; and d) chromosome aberrations in mouse bone marrow cells after intrave nous (i.v.) administration in vivo. The long-term toxicity studies in the rat included a) single dose administration (3 mg/kg DOXO, 3.6 EPI and 0.75 IDA) to female rats of two different age groups, i.e. younger (7 weeks old at dosing) and older (13 weeks old), followed by one-yea r observation; and b) multiple dose administration to male and female rats (7 weeks old at dosing), consisting of i.v. administration of 0.2 5, 0.5 and 1 mg/kg DOXO or EPI and 0.06, 0.125 and 0.25 mg/kg IDA, onc e every 3 weeks for 10 cycles, followed by 18 months of observation. T he genotoxicity studies revealed activity in gene mutation assays in b acterial and mammalian cells, and in chromosome aberration assays in h uman lymphocytes in vitro and in mouse bone marrow in vivo. In the two long-term studies in the rat, only mammary tumors were present. This finding was expected and, according to the literature, can be consider ed as species specific and not directly compound-related. The lack of tumor induction at the usual target organs for DNA reactive compounds, which are almost the same as those considered as target organs in ant hracycline-exposed animals, indicates that the type and the extent of DNA damage precludes stimulation for proliferation and induction of ne oplasia. Although an epigenetic mechanism can be hypothesized, support for such a mechanism is lacking.