Enhanced cytotoxicity of melphalan by prolonged exposure to nitroimidazoles: the role of endogenous thiols.

It was first demonstrated that prolonged exposure of hypoxic V-79 cells to misonidazole prior to irradiation produced an increased radiosensitization in 1977; it was postulated that the reduction of misonidazole resulted in intermediates capable of depleting cells of endogenous thiols, substances known to play a role in the hydrogen repair of target radicals produced by ionizing radiation. The present study shows that a prolonged exposure of V-79 cells to a variety of nitroimidazoles (misonidazole, Ro-05-9963, SR-2508, and MTR1-80) results in an enhanced cytotoxicity when these cells are subsequently exposed to melphalan. This process of enhanced melphalan toxicity occurred only when cells were pretreated with misonidazole under hypoxic conditions, suggesting that nitroreduction is necessary for chemosensitization as it is for increased radiosensitization. Different nitroimidazoles tested vary in the extent to which they sensitize cells to the subsequent action of melphalan. Repair from a misonidazole pretreatment is essentially complete by six hours. This study demonstrated that cysteamine could reduce the cytotoxicity of misonidazole and the enhancement of melphalan toxicity. This was an effect reversible with time and one implying similar mechanisms for the preincubation effect observed in vitro for radiation and chemotherapy agents.