Classical oxazaphosphorines – metabolism and therapeutic properties – new implications

Abstract

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.

Osteopontin and fatty acid binding protein in ifosfamide-treated rats

“…Ifosfamide [3-(2-chloroethyl)-2-[(2-chloroethyl)-amino] tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide] is a cytostatic that belongs to the family of the oxazaphosphorine alkylating agents [1]. Besides ifosfamide (IF), the group also contains cyclophosphamide (CP), trofosfamide and mafosfamide [2].…”

“…Ifosfamide was discovered in the 1960s and introduced into common clinical practice in the 1970s [3]. It exerts antineoplastic activity and it is also administrated in the treatment of osteosarcoma, neuroma, multiple myeloma and leukemias [2]. IF is a prodrug and to acquire antineoplastic activity, it must be metabolized to cytotoxic agents.…”

“…One pathway, with the involvement of CYP3A4, CYP2B6 and CYP2C9 (with less participation of CYP2C8 and CYP2C19), leads to the formation of isophosphoramide mustard and acrolein. The second pathway, catalyzed by CYP3A4, CYP3A5 and CYP2B6, leads to the formation of chloroacetaldehyde (CAA) [1,2]. Those metabolites are responsible for the cytotoxic effects of IF result from their ability of attaching to the nucleophilic N-7 position of one of the nitrogenous base of DNA, guanine (the other alkylation sites include N-1 and N-3 position of adenine, N-3 position of cytosine and O-6 of guanine).…”

“…Those metabolites are responsible for the cytotoxic effects of IF result from their ability of attaching to the nucleophilic N-7 position of one of the nitrogenous base of DNA, guanine (the other alkylation sites include N-1 and N-3 position of adenine, N-3 position of cytosine and O-6 of guanine). Depending on the position of the alkylated nitrogenous DNA base, intra- and interstrand DNA cross-links are formed and the final consequence of this cross-link formation is the activation of apoptotic mechanisms, leading to cell death [2,4].…”

“…The administration of oxazaphosphorines is associated with many adverse drug reactions due to the fact that the same active metabolites produce toxic effects. Similarly to the other cytostatics, common side effects observed during oxazaphosphorine’s pharmacotherapy include: alopecia, myelosuppression (manifested by anemia, neutropenia and thrombocytopenia), nausea, vomiting and hypersensitivity reactions [2,4]. The more specific toxicities related to both IF and CP involve hemorrhagic cystitis, neurotoxicity and nephrotoxicity [1].…”