In vivo and in vitro investigations on biological effects of aromatic bis-(2-chloroethyl)amino-bisphosphonic acids, new agents proposed for chemotherapy of bone tumors: cytostatic activity in rat osteosarcoma; toxicity and genotoxicity in liver and bone marrow; mutagenicity in S. typhimurium.
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.
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects*; D001859:Bone Neoplasms / Q000188:drug therapy*; D004249:DNA Damage; D005260:Female; D005784:Gene Amplification; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects*; D008297:Male; D009153:Mutagens; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology / Q000633:toxicity*; D012516:Osteosarcoma / Q000188:drug therapy*; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects
D000970:Antineoplastic Agents; D009153:Mutagens; D009588:Nitrogen Mustard Compounds; C049704:4-(4-(bis(2-chloroethyl)amino)phenyl)-1-hydroxybutane-1,1-bisphosphonic acid; C057357:((3-(bis(2-chloroethyl)amino)-4-methylphenyl)hydroxymethane)bisphosphonic acid