title: [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.
authors.affiliation: Katedra i Zakład Farmakodynamiki i Farmakologii Molekularnej Uniwersytet Mikołaja Kopernika w Toruniu Collegium Medicum im. Ludwika Rydygiera w Bydgoszczy.
authors.forename: Anna
authors.initials: A
authors.lastname: Sloderbach
authors.affiliation: Katedra i Zakład Farmakodynamiki i Farmakologii Molekularnej Uniwersytet Mikołaja Kopernika w Toruniu Collegium Medicum im. Ludwika Rydygiera w Bydgoszczy.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Górska
authors.affiliation: Katedra i Zakład Farmakodynamiki i Farmakologii Molekularnej Uniwersytet Mikołaja Kopernika w Toruniu Collegium Medicum im. Ludwika Rydygiera w Bydgoszczy.
authors.forename: Marta
authors.initials: M
authors.lastname: Sikorska
authors.affiliation: Katedra i Zakład Technologii Chemicznej Środków Leczniczych Uniwersytet Mikołaja Kopernika w Toruniu Collegium Medicum im. Ludwika Rydygiera w Bydgoszczy.
authors.forename: Konrad
authors.initials: K
authors.lastname: Misiura
authors.affiliation: Katedra i Zakład Farmakodynamiki i Farmakologii Molekularnej Uniwersytet Mikołaja Kopernika w Toruniu Collegium Medicum im. Ludwika Rydygiera w Bydgoszczy.
authors.forename: Bogusław
authors.initials: B
authors.lastname: Hładoń
mesh_terms: D000079:Acetaldehyde / Q000031:analogs & derivatives / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D001711:Biotransformation; D003520:Cyclophosphamide / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D007069:Ifosfamide / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; C004656:chloroacetaldehyde; D000444:Aldehyde Dehydrogenase; D005982:Glutathione Transferase; D005978:Glutathione; D000079:Acetaldehyde; D007069:Ifosfamide