Possible role of acrolein in 4-hydroperoxycyclophosphamide-induced cell damage in vitro

Unlike "conventional" oxazaphosphorines such as cyclophosphamide (CP) and ifosfamide, a relatively new drug termed 4-hydroperoxy-CP (4-HC) degrades spontaneously in water yielding phosphoramide mustard considered to be the activated cytotoxic metabolite. During this degradation a toxic, volatile factor termed acrolein is also formed. In order to examine the possible role of this compound in 4-HC-induced inhibition of tumor cell growth in vitro, 8 different established human tumor cell lines were cultured in the presence of 4-HC or equimolar concentrations of acrolein. It was observed that the cell lines differed widely with respect to sensitivity to these compounds. However, each individual cell line exhibited virtually identical sensitivities to both 4-HC and acrolein. The observation that 2-mercaptoethansulfonate (mesna), which is highly reactive with acrolein but not with phosphoramide mustard, could markedly reduce the cytotoxic activity of 4-HC indicates that acrolein may play an important role in 4-HC induced cell damage in vitro.