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.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Agarwal, D.P., Eckey, R., Rudnay A.-C., Volkens, T., and Goedde, H.W., 1989, “High-Km”aldehyde dehydrogenase isozymes in human tissues: constitutive and tumor associated forms. In: Progress in Clin. Biol. Res., vol. 290: Enzymology and Molecular Biology of Carbonyl Metabolism 2, pp. 119–131. Editors: H. Weiner and T.G. Flynn. Alan R Liss, Inc., New York.
Agarwal, D.P., and Goedde, H.W., 1990, Alcohol Metabolism, Alcohol Intolerance, and Alcoholism. Biochemical and Pharmacogenetic Approaches. Springer-Verlag, Berlin, Heidelberg, New York.
Borch, R.F., Hoye, T.R., and Swanson, T.A., 1984, In situ preparation and fate of cis-4-hydroxycyclophos-phamide and aldophosphamide: 1H and 31P NMR evidence for equilibration of cis-and trans-4-hy-droxycyclophosphamide with aldophosphamide and its hydrate in aqueous solution. J. Med. Chem., 27, 490–494.
Dockham, P.A., Lee, M.-O., and Sladek, N.E., 1992, Identification of human liver aldehyde dehydrogenases that catalyze the oxidation of aldophosphamide and retinaldehyde. Biochem. Pharmacol., 43, 2453–2469.
Eckey, R., Timmann, R., Hempel, J., Agarwal, D.P., and Goedde, H.W., 1991, Biochemical, immunological and molecular characterization of a “high Km” aldehyde dehydrogenase. In: Advances in experimental medicine and biology, vol. 284: Enzymology and molecular biology of carbonyl metabolism 3, pp. 43–52. Editors: H. Weiner, B. Wermuth and D.W. Crabb. Plenum Press, New York.
Hill, D.L., Laster, W,R, Jr., Kirk, M.C., ElDareer, S., and Struck, R.F., 1973, Metabolism of phosphamide (2-(2-chloroethylamino)3(2-chloroethyl)-tetrahydro 2H-l,3,2,-oxazaphosphorine 2-oxide) and production of a toxic phosphamide metabolite. Cancer Res., 33, 1016–1022.
Hilton, J., 1984, Role of aldehyde dehydrogenase in cyclophosphamideresistant L-1210 leukemia. Cancer Res. 44, 5156–5160.
Kastan, M.B., Schlaffer, E., Russo, J.E., Colvin, O.M., Civin, C.I. and Hilton, J., 1990, Direct demonstration of elevated aldehyde dehydrogenase in human hematopoietic progenitor cells. Blood, 75, 1947–1950.
Lin, K.-H., and Lindahl, R., 1987, Role of aldehyde dehydrogenase activity in cyclophosphamide metabolism in rat hepatoma cell lines. Biochem. Pharmacol., 36, 3305–3307.
Lindahl, R., 1992, Aldehyde dehydrogenases and their role in carcinogenesis. Critical Reviews in Biochemistry and Molecular Biology, 27, 283–334.
Lindahl R., and Hempel, H., 1991, Aldehyde dehydrogenases: what can be learned from a baker’s dozen sequences? In: Advances in experimental medicine and biology, vol. 284: Enzymology and molecular biology of carbonyl metabolism 3, pp. 1–8. Editors: H. Weiner, B. Wermuth and D.W. Crabb. Plenum Press, New York.
Lowry, O.H., Rosebrough, N.J., Farr, A.L., and Randall, R.J., 1951, Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193, 265–275.
Manthey, C.L., Landkamer, G.J., and Sladek, N.E., 1990, Identification of the mouse aldehyde dehydrogenases important in aldophosphamide detoxification. Cancer Res., 50, 4991–5002.
Marcart, M., and Gerbaut, L., 1982, An improvement of the Coomassie blue dye binding method allowing an equal sensitivity to various proteins: application to cerebrospinal fluid. Clin. Chim. Acta, 122, 93–101.
Meier-Tackmann, D., Eckey, R., Wolff, C., von Eitzen, U., Agarwal, D.P., and Goedde, H.W., 1993, Tumor-associated aldehyde dehydrogenase (ALDH3): expression in different human tumor cell lines with and without treatment with 3-methylcholanthrene. In: Advances in Experimental Medicine and Biology, vol. 328: Enzymology and Molecular Biology of Carbonyl Metabolism 4, pp. 115–122. Editors: H. Weiner, D.W. Crabb and T.G. Flynn. Plenum Press, N.Y.
Moreb, J., Zucali, J.R., Zhang, Y., Colvin, M.O., and Gross, M.A., 1992, Role of aldehyde dehydrogenase in the protection of hematopoietic progenitor cells from 4-hydroperoxy cyclophosphamide by interleukin lß and tumor necrosis factor. Cancer Res., 52, 1770–1774.
Niemeyer, U., Engel, J., Hilgard, P., Peukert, M., Pohl, J., and Sindermann, H., 1989, Mafosfamide — a derivative of 4 hydroxycyclophosphamide. Progress Clin. Biochem. Med. 9, 35–60.
Sladek, N.E., 1988, Metabolism of oxazaphosphorines. Pharmacol. Ther. 37, 301–355.
Sladek, N.E., Manthey, C.L., Maki, P.A., Zhang, Z., and Landkammer, G.J., 1989, Xenobiotic oxidation catalyzed by aldehyde dehydrogenases. Drug Metabolism Review 20, 697–720.
Sreerama, L., and Sladek, N.E., 1993, Identification and characterization of a novel class 3 aldehyde dehydrogenase overexpressed in a human breast adenocarcinoma cell line exhibiting oxazaphosphorine-specific acquired resistance. Biochem. Pharmacol., 45, 2487–2505.
Sreerama, L., and Sladek, N.E., 1994, Identification of a methylcholanthrene-induced aldehyde dehydrogenase in a human breast adenocarcinoma cell line exhibiting oxazaphosphorinesepecific acquired resistance. Cancer Research 54, 2176–2185.
von Eitzen, U., Meier-Tackmann, D., Agarwal, D.P., and Goedde, H.W., 1994, Detoxification of cyclophosphamide by human aldehyde dehydrogenase isozymes. Cancer Lett, 76, 45–49.
Yoshida, A., Davé, V., Han, H., and Scanlon, K.J., 1993, Enhanced transcription of the cytosolic ALDH gene in cyclosphosphamide resistant human carcinoma cells. In: Advances in Experimental Medicine and Biology, vol. 328: Enzymology and molecular biology of carbonyl metabolism 4, pp. 63–72. Editors: H. Weiner, B. Wermuth and D.W. Crabb, Plenum Press, New York.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1995 Springer Science+Business Media New York
About this chapter
Cite this chapter
Agarwal, D.P., Eitzen, U.V., Meier-Tackmann, D., Goedde, H.W. (1995). Metabolism of Cyclophosphamide by Aldehyde Dehydrogenases. In: Weiner, H., Holmes, R.S., Wermuth, B. (eds) Enzymology and Molecular Biology of Carbonyl Metabolism 5. Advances in Experimental Medicine and Biology, vol 372. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1965-2_15
Download citation
DOI: https://doi.org/10.1007/978-1-4615-1965-2_15
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-5808-4
Online ISBN: 978-1-4615-1965-2
eBook Packages: Springer Book Archive