Possible role of acrolein in oxazaphosphorine-induced enhancement of immunological reactivity

Summary The aim of the present study was to analyze further the immunopotentiating effects of low doses of oxazaphosphorines. We examined 4-hydroperoxycyclophosphamide (4-HC) and mafosfamide, which degrade spontaneously in water without requiring liver enzymes to become active. Both drugs, at concentrations ranging from 0.01 µM to 1 µM, enhanced mitogenic responses of human lymphocytes. Higher concentrations were toxic. Acrolein, which is one of the degradation products of oxazaphosphorines, had similar effects. Immunopotentiation was not monocyte-dependent. Attempts to inactivate released acrolein with human serum reduced toxicity but the immunostimulating property of the drugs remained Similar effects were noted when lymphocytes were exposed to acrolein dissolved in serum. 2-Mercaptoethanesulfonate (mesna), which is highly reactive with acrolein, reduced the toxicity of solutions of both oxazaphosphorines and acrolein. Immunopotentiation was not clearly demonstrable since mesna itself enhanced the responses. Pretreatment of lymphocytes with 4-HC or mafosfamide did not reduce the capacity of concanavalin A to induce suppressor cells. It is speculated that acrolein may play a role in oxazaphosphorine-induced enhancements of immune responses.