Metabolism of cyclophosphamide by aldehyde dehydrogenases.

Abstract

Cyclophosphamide (Endoxan) and other oxazaphosphorines such as 4-hydroperoxy-cyclophosphamide, ifosfamide, and mafosfamide are widely used as antineoplastic drugs (Sladek, 1988; Lindahl, 1992). The cytotoxic effect is caused by alkylation reaction of these drugs with DNA and proteins inhibiting the cell proliferation. These chemotherapeutic agents are also extensively applied as immunosuppressants during bone marrow transplantation, and in autoimmune diseases. Cyclophosphamide is pharmacologically inactive, and needs to be biotransformed to its cytotoxic metabolite phosphoramide mustard via an intermediate metabolite 4-hydroxycyclophosphamide (Borch et al., 1984; Hill et al., 1973). The latter compound exists in equilibrium with aldophosphamide which can get converted to a non-cytotoxic compound carboxy-phosphamide through irreversible oxidation of the aldehyde group catalyzed by one or more forms of aldehyde dehydrogenases (Hilton et al., 1984; Sladek et al., 1989; Kastan et al, 1990; Dockham et al., 1992; Moreb et al., 1992). This enzymatic pathway leads to the detoxification of cyclophosphamide affecting its therapeutic efficiency. Therefore, induction or overexpression of one or more of the relevant ALDH forms in target cells might primarily account for the cyclophosphamide-specific acquired resistance exhibited by many neoplastic cells.KeywordsAldehyde DehydrogenaseALDH ActivityHuman Ovarian Carcinoma Cell LineHuman Breast Adenocarcinoma Cell LineAldehyde Dehydrogenase ActivityThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.