A prodrug activated by H2O2 and mitochondrial hydroxide: an improvement of cancer cells versus neutrophils selectivity

Many known chemotherapeutic anticancer agents exhibit neutropenia as a dose-limiting side effect. In this paper we suggest a prodrug concept solving this problem for camptothecin (HO-cpt). The prodrug is programmed according to Boolean “AND” logic. It requires for its activation the simultaneous presence of triggers T1 (H2O2) and T2 (pH 8 in mitochondria: Mit). The level of H2O2 in cancer cells is higher than that in normal cells. Thus, T1 discriminates cancer cells from the majority of normal cells excluding neutrophils, known to produce elevated levels of H2O2. T2 discriminates cancer cells from neutrophils, since the former cells have a higher number of Mit. We demonstrated that our prodrug exhibits antitumor activity both in vitro and in vivo, but is not toxic to normal cell and neutrophils in contrast to known single trigger prodrugs and the parent drug HO-cpt.