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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Expression of Antisense RNA to Aldehyde Dehydrogenase Class-1 Sensitizes Tumor Cells to 4-Hydroperoxycyclophosphamide In Vitro

Jan S. Moreb, Chalesea Maccow, Mark Schweder and Jaima Hecomovich
Journal of Pharmacology and Experimental Therapeutics May 2000, 293 (2) 390-396;
Jan S. Moreb
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Chalesea Maccow
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Mark Schweder
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Jaima Hecomovich
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Abstract

Previous studies in this laboratory showed that the overexpression of human aldehyde dehydrogenase class-1 (ALDH-1) with a retroviral vector resulted in increased resistance to 4-hydroperoxycyclophosphamide (4-HC), an active metabolite of cyclophosphamide. The present study examined the effect of ALDH-1 antisense RNA expression on ALDH-1 activity and sensitivity to 4-HC toxicity. Three different ALDH-1 cDNAs were synthesized that are either missing the N terminus (N), C terminus (C), or both (NC) and subcloned into the BamHI cloning site of pLXSN retroviral vector in the antisense (AS) orientation (AS-N, AS-C, and AS-NC, respectively). It was demonstrated that the overexpression of each of the AS constructs in K562 leukemic cells and A549 lung cancer cells results in suppression of ALDH-1 mRNA and enzymatic activity. Furthermore, the AS-N and AS-NC were generally more effective than AS-C in reducing the ALDH-1 activity. Both K562 and A549 cells expressing the ALDH-1 AS became significantly more sensitive to 4-HC toxicity as demonstrated by clonogenic and liquid culture assays. The increase in 4-HC sensitivity was in correlation with the degree of suppression of ALDH-1 activity. Moreover, such increase in 4-HC sensitivity, especially with AS-N and AS-NC, was to a similar degree seen with the use of diethylaminobenzaldehyde, a specific inhibitor of ALDH-1. These results indicate that ALDH-1 expression and activity can be specifically and effectively suppressed by AS RNA and lead to increased sensitivity to 4-HC.

Footnotes

  • Send reprint requests to: Jan S. Moreb, M.D., Division of Hematology/Oncology, Department of Medicine, University of Florida College of Medicine, P.O. Box 100277, Gainesville, FL 32610-0277. E-mail: morebjs{at}medicine.ufl.edu

  • ↵1 This study was supported by Grant R29-CA59684 awarded by the National Cancer Institute (to J.S.M.).

  • Abbreviations:
    ALDH-1
    aldehyde dehydrogenase class-1
    4-HC
    4-hydroperoxycyclophosphamide
    AS
    antisense
    NSCLC
    nonsmall cell lung cancer
    FBS
    fetal bovine serum
    bp
    base pair
    WT
    wild type
    ECL
    enhanced chemiluminescence
    dCTP
    deoxy cytidine 5′-triphosphate
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    DEAB
    diethylaminobenzaldehyde
    CP
    cyclophosphamide
    CYP
    cytochrome P450
    • Received November 1, 1999.
    • Accepted January 7, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 2
1 May 2000
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Expression of Antisense RNA to Aldehyde Dehydrogenase Class-1 Sensitizes Tumor Cells to 4-Hydroperoxycyclophosphamide In Vitro

Jan S. Moreb, Chalesea Maccow, Mark Schweder and Jaima Hecomovich
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 390-396;

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Expression of Antisense RNA to Aldehyde Dehydrogenase Class-1 Sensitizes Tumor Cells to 4-Hydroperoxycyclophosphamide In Vitro

Jan S. Moreb, Chalesea Maccow, Mark Schweder and Jaima Hecomovich
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 390-396;
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