Interaction of dacarbazine and imexon, In Vitro and In Vivo, in human A375 melanoma cells

Aim: We evaluated mechanisms of interaction between the alkyating agent dacarbazine (DTIC) and the prooxidant, imexon, in the human A375 melanoma cell line. Materials and Methods: The effect of DTIC and imexon, alone and in combination, was evaluated for growth inhibition (MTT), radiolabeled drug uptake, cellular thiol content (HPLC), and DNA strand breaks (Comet assay). Pharmacokinetic and antitumor effects were evaluated in mice. Results: Growth inhibition in vitro was additive with the two drugs. There was no effect on drug uptake or on the number of DNA strand breaks. There was a >75% reduction in cellular glutathione and cysteine with imexon but not DTIC. Co-administration of the two drugs in mice caused an increase in the area under the curve of both drugs, but the combination was not effective in reducing human A375 melanoma tumors in vivo. Conclusion: Imexon and dacarbazine show additive effects in vitro but not in vivo in human A375 melanoma cells.