Overexpression or Polycyclic Aromatic Hydrocarbon-Mediated Induction of an Apparently Novel Class 3 Aldehyde Dehydrogenase in Human Breast Adenocarcinoma Cells and its Relationship to Oxazaphosphorine-Specific Acquired Resistance

TLDR: The pharmacological upshot is that a relative oxazaphosphorine-insensitivity is conferred on those cells in which constitutive or induced expression of the relevant enzyme(s) occurs.

Abstract: Oxazaphosphorines such as cyclophosphamide are widely used in the treatment of certain neoplasms (Sladek, 1988). Because they are, perse, without cytotoxic activity, their metabolism, Figure 1, has been the subject of intensive investigation. In the course of these investigations, it was established that certain aldehyde dehydrogenases catalyze the irreversible detoxification of the oxazaphosphorines when they catalyze the oxidation of aldophosphamide to carboxyphosphamide. Class 1 aldehyde dehydrogenases, e.g., mouse AHD-2 and human ALDH-1, are particularly important in this regard (Manthey et al., 1990; Dockham et al., 1992). Other “aldehyde” dehydrogenases, e.g., human ALDH-2 and succinic semialdehyde dehydrogenase, also catalyze the reaction albeit less well as judged by Km values (Dockham et al., 1992). Still others, e.g., human ALDH-4, ALDH-5 and betaine aldehyde dehydrogenase, do not catalyze the reaction at all (Dockham et al., 1992). The pharmacological upshot is that a relative oxazaphosphorine-insensitivity is conferred on those cells in which constitutive or induced expression of the relevant enzyme(s) occurs.