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Enzymology and Molecular Biology of Carbonyl Metabolism 6 pp 133–146Cite as

Inhibition of Human Class 3 Aldehyde Dehydrogenase, and Sensitization of Tumor Cells that Express Significant Amounts of this Enzyme to Oxazaphosphorines, by the Naturally Occurring Compound Gossypol

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 414))

Abstract

Cytosolic class 3 aldehyde dehydrogenase (ALDH-3) is a demonstrated determinant of cellular sensitivity to the cytotoxic action of certain widely used antineoplastic prodrugs collectively referred to as oxazaphosphorines, e.g., cyclophosphamide, ifosfamide, 4-hydroperoxycyclophosphamide, 4-hydroperoxyifosfamide and mafosfamide (cellular sensitivity to these drugs decreases as cellular levels of ALDH-3 increase) (Sladek, 1993; Sreerama and Sladek, 1993a,b, 1994; Bunting et al., 1994; Rekha et al., 1994; Sladek et al., 1995; Sreerama et al., 1995; Bunting and Townsend, 1996). Thus, tumor cells, otherwise sensitive to the oxazaphosphorines, became resistant to these drugs when electroporated with purified ALDH-3 protein or transfected with the cDNA coding for ALDH-3 (Bunting et al., 1994; Sreerama and Sladek, 1995; Bunting and Townsend, 1996), and, of therapeutic significance, relatively elevated levels of this enzyme can account for intrinsic, transient acquired, and stable acquired, resistance to the oxazaphosphorines on the part of malignant cells (Sreerama and Sladek, 1993a,b, 1994; Rekha et al., 1994; Sreerama et al., 1995). Resistance to the oxazaphosphorines mediated by ALDH-3 is ostensibly due to the enzyme-catalyzed oxidative detoxification of aldophosphamide, the pivotal metabolite of these prodrugs (Sreerama and Sladek, 1993a, 1994; Rekha et al., 1994; Sreerama et al., 1995; Bunting and Townsend, 1996).

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Authors and Affiliations

  1. Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, 55455, USA

    Ganaganur K. Rekha & Norman E. Sladek

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  1. Ganaganur K. Rekha
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  2. Norman E. Sladek
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Editors and Affiliations

  1. Purdue University, West Lafayette, Indiana, USA

    Henry Weiner

  2. University of South Dakota School of Medicine, Vermillion, South Dakota, USA

    Ronald Lindahl

  3. Indiana University School of Medicine, Indianapolis, Indiana, USA

    David W. Crabb

  4. Queen’s University, Kingston, Ontario, Canada

    T. Geoffrey Flynn

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Rekha, G.K., Sladek, N.E. (1996). Inhibition of Human Class 3 Aldehyde Dehydrogenase, and Sensitization of Tumor Cells that Express Significant Amounts of this Enzyme to Oxazaphosphorines, by the Naturally Occurring Compound Gossypol. In: Weiner, H., Lindahl, R., Crabb, D.W., Flynn, T.G. (eds) Enzymology and Molecular Biology of Carbonyl Metabolism 6. Advances in Experimental Medicine and Biology, vol 414. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5871-2_16

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  • DOI: https://doi.org/10.1007/978-1-4615-5871-2_16

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