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Related Experiment Videos

Inactivation of aldophosphamide by human aldehyde dehydrogenase isozyme 3.

F Giorgianni1, P K Bridson, B P Sorrentino

  • 1Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 38105, Memphis, TN, USA.

Biochemical Pharmacology
|June 17, 2000
PubMed
Summary

Overexpressing human aldehyde dehydrogenase 3 (hALDH3) in leukemia cells did not confer resistance to cyclophosphamide chemotherapy. This is due to hALDH3

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Tumor resistance to oxazaphosphorines like cyclophosphamide is linked to aldehyde dehydrogenase (ALDH) overexpression.
  • ALDH enzymes can inactivate cyclophosphamide by oxidizing aldophosphamide to carboxyphosphamide.
  • Human ALDH isozyme 3 (hALDH3) gene transfer can induce oxazaphosphorine resistance in mammalian cells.

Purpose of the Study:

  • To investigate if retroviral introduction of hALDH3 into a human leukemia cell line confers resistance to oxazaphosphorines.
  • To evaluate the potential of hALDH3 overexpression for protecting against cyclophosphamide-induced myelosuppression.

Main Methods:

  • Retroviral transduction of a human leukemia cell line with the hALDH3 gene.
  • Assay of hALDH3 activity in transduced and untransduced cells.

Related Experiment Videos

  • Testing resistance to aldophosphamide-generating compounds (mafosfamide, 4-hydroperoxycyclophosphamide).
  • Kinetic analysis of recombinant hALDH3 and hALDH1 with aldophosphamide and NAD.

    • Main Results:

    • Transduced cells showed increased hALDH3 activity (0.016 IU/mg protein) compared to controls (2x10^-5 IU/mg).
    • No detectable resistance to aldophosphamide-generating compounds was observed in polyclonal transduced cells.
    • hALDH3 exhibited significantly lower catalytic efficiency for aldophosphamide oxidation than hALDH1.
    • Kinetic studies suggested different reaction mechanisms for hALDH1 and hALDH3.

    Conclusions:

    • Retroviral hALDH3 overexpression in leukemia cells does not confer resistance to oxazaphosphorines.
    • The limited protection is partly attributed to the low catalytic activity of hALDH3 against aldophosphamide.
    • hALDH3's enzymatic properties differ from hALDH1, impacting its efficacy in drug resistance modulation.