Cyclophosphamide (CPA) and
ifosfamide (IFO) belong to oxazaphosphorine drugs and for a few decades have been widely used for treatment of solid tumours and haematological
malignancies. Both drugs are administered in pharmacologically inactive form and require metabolic activation by
cytochrome P-450 (CYP). Metabolic transformations taking place under the action of specific CYP
isoenzymes lead to the formation of therapeutically essential metabolites and some toxic compounds affecting quality of
therapy. The first stage of these conversions is connected with hydroxylation reactions occurring on the C-4
carbon atom within a ring and C-1 atoms of 2-chloroethyl chains. As a result of C-4 hydroxylation 4-hydroxy derivatives (4-OH-CPA and 4-OH-IFO) are formed and remain in tautomeric equilibrium with aldo compounds which in
cancer cells spontaneously release cytotoxic
phosphoramide mustards and urotoxic
acrolein. At the same time hydroxychloroethyl compounds formed during hydroxylation of side-chains are unstable and collapse with the release of inter alia nephro- and neurotoxic
chloroacetaldehyde (CAA). Due to formation of toxic metabolites it is essential to use some preventive agents such as
mesna and recently examined
agmatine. Since CPA and IFO are widely used anticancer drugs, their efficacy is limited not only by their toxicity but also due to occurring resistance. This resistance seems to be a result of changes of expression and activity of
enzymes such as CYP and
aldehyde dehydrogenase (ALDH) and increase of intracellular levels of
glutathione (GSH) and
glutathione S-transferase (GST). At present a few methods of overcoming this resistance are being examined including the use of metabolism modulators,
antisense oligonucleotides selectively inhibiting gene expression, and introducing genes of some CYP
isoenzymes to a
cancer tissue.