Two new aromatic bis-(2-chloroethyl)-amino derivatives (
BCMP and BAD) which are linked to osteotropic
bisphosphonates were investigated for their therapeutical efficacy in rat
osteosarcoma. Furthermore their genotoxic potential in vitro was determined in S. typhimurium and in mammalian cells. Finally, parameters for toxicity and genotoxicity were determined in liver and bone marrow cells following in vivo treatment. It was shown that BAD was of higher therapeutic effectiveness than
BCMP. Both compounds induced approximately a two fold increase of his+ revertants in S. typhimurium TA1535 following metabolic activation by subcellular liver fractions. Both compounds also induced amplification of SV40
DNA in SV40 transformed cells (CO631). This endpoint may be of importance for acquired resistancy of cells during
therapy.
DNA-single strand breaks were induced by
BCMP but not by BAD in liver cells and CO631 cell line. Following in vivo treatment
BCMP was of higher genotoxic activity in liver cells than BAD. In comparison, genotoxicity of both compounds was much lower in bone marrow cells than in liver cells.
BCMP was again more potent than BAD in inducing
DNA single strand breaks, whereas BAD was more toxic. The higher therapeutic efficacy of BAD together with its lower genotoxic properties makes this compound superior to
BCMP as a candidate for applied
chemotherapy in humans.