Copper chelator enhancement of bleomycin cytotoxicity

Abstract

Bleomycin's effects on DNA strand scission are inhibited by low concentration of some metal ions (including copper), greatly stimulated by ferrous (Fe+2) ions, and increased and probably mediated by the production of superoxide radicals (O2-), hydroxyl radicals (OH), and hydrogen peroxide (H2O2). However, the role of these mechanisms in overall bleomycin cytotoxicity is not known. For this reason, we have treated the Chinese hamster cell line (V79) cells with a copper chelator, diethyldithiocarbamate (DDC) and bleomycin in vitro DDC is known to inhibit superoxide dismutase (SOD), an enzyme responsible for the scavenging of O2-. The cytotoxicity is determined by the standard clonogenic survival method, which shows that DDC treated cells are more susceptible to bleomycin either as a function of bleomycin dose or as a function of bleomycin treatment time. These results support the notion that reducing Cu2+ levels and/or increasing O2- concentrations can modify the cytotoxicity of bleomycin.

Sodium ditiocarb as adjuvant immunotherapy for high risk breast cancer: A randomized study

“…Besides its immune effects DDC can interact with cytotoxic drugs. In vitro, DDC has shown a potentiation of bleomycin [18] and it displays a protective effect against nephrotoxicity of cis-platinum [19]. In vitro DDC exhibited a glutathione peroxydase activity [3] which is involved in cellular mechanism of resistance to anthracyclines and alkylating agents.…”

Effects of diethyldithiocarbamate and endogenous polyamine content on cellular responses to hydrogen peroxide cytotoxicity

“…DDC has been observed to induce either sensitization or protection toward the cytotoxic effects of a number of physical and chemical stresses [1][2][3][4][5][6][7]. Sensitization has been attributed, in part, to DDC's ability to chelate copper and thus inhibit copper-dependent anti-oxidant enzymes, such as superoxide dismutase [1,16].…”

“…Paradoxically, both sensitizing and protective effects have been observed in a variety of experimental systems. Enhancement of radiation [1], hyperthermia [1,2] and bleomycin [3] toxicity during DDC exposure has been well documented in mammalian cell cultures. On the other hand, protective effects of DDC have been repeatedly observed during whole-body irradiation in mice [4][5][6][7] with potential selective radioprotection of bone marrow [5].…”

Cytotoxicity of diethyldithiocarbamate in human versus rodent cell lines

“…Because of its high affinity chelation of certain metallic ions (e.g. Zn, Cu, Ni) and inactivation of certain metalloenzymes [3], DDTC is also being actively investigated as an adjunctive oncologic therapy to reduce the normal tissue toxicities of cisplatin chemotherapy [5,6] or to enhance the efficacy of cyclophosphamide [7,8], bleomycin [9], and ionizing irradiation [10].…”