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Research ArticleSymposium Article

Targeting Drug-Metabolizing Enzymes for Effective Chemoprevention and Chemotherapy

Hollie I. Swanson, Vincent C. O. Njar, Zhen Yu, David J. Castro, Frank J. Gonzalez, David E. Williams, Ying Huang, Ah-Ng T. Kong, Joshua C. Doloff, Jie Ma, David J. Waxman and Emily E. Scott
Drug Metabolism and Disposition April 2010, 38 (4) 539-544; DOI: https://doi.org/10.1124/dmd.109.031351
Hollie I. Swanson
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Vincent C. O. Njar
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Zhen Yu
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David J. Castro
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Frank J. Gonzalez
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David E. Williams
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Ying Huang
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Ah-Ng T. Kong
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Joshua C. Doloff
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Jie Ma
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David J. Waxman
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Emily E. Scott
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Abstract

The primary focus of chemoprevention research is the prevention of cancer using pharmacological, biological, and nutritional interventions. Chemotherapeutic approaches that have been used successfully for both the prevention and treatment of a number of human malignancies have arisen from the identification of specific agents and appropriate molecular targets. Although drug-metabolizing enzymes have historically been targeted in attempts to block the initial, genotoxic events associated with the carcinogenic process, emerging evidence supports the idea that manipulating drug-metabolizing enzymes may also be an effective strategy to be used for treating tumor progression, invasion, and, perhaps, metastasis. This report summarizes a symposium that presents some recent progress in this area. One area of emphasis is the development of a CYP17 inhibitor for treatment of prostate cancer that may also have androgen-independent anticancer activity at higher concentrations. A second focus is the use of a mouse model to investigate the effects of aryl hydrocarbon receptor and Cyp1b1 status and chemopreventative agents on transplacental cancer. A third area of focus is the phytochemical manipulation of not only cytochrome P450 (P450) enzymes but also phase II inflammatory and antioxidant enzymes via the nuclear factor-erythroid 2-related factor 2 pathway to block tumor progression. A final highlight is the use of prodrugs activated by P450 enzymes to halt tumor growth and considerations of dosing schedule and targeted delivery of the P450 transgene to tumor tissue. In addition to highlighting recent successes in these areas, limitations and areas that should be targeted for further investigation are discussed.

Footnotes

  • This work was supported in part by the National Institutes of Health National Cancer Institute [Grants CA11799101, CA02744028, CA90890, CA073674, CA094828, CA118947, CA49248] (to V.C.O.N., D.E.W., A.N.K., and D.J.W., respectively); the National Institutes of Health National Institute of Environmental Health Sciences [Grants ES00726316A1, ES07060, ES00210] (to V.C.O.N., D.E.W.); and The Linus Pauling Institute at Oregon State University (to D.E.W.).

  • This report is a summary of a session under the same name as follows: Njar VCO, Williams DE, Kong A-NT, and Waxman DJ (2009) Targeting drug metabolizing enzymes for effective chemopreventive approaches. Experimental Biology 2009; 2009 Apr 18–22; New Orleans, LA; The American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.109.031351.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    Nrf2
    nuclear factor-erythroid 2-related factor 2
    AR
    androgen receptor
    VN/124-1 (TOK-001)
    3β-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene
    ER
    endoplasmic reticulum
    PAH
    polycyclic aromatic hydrocarbon
    DBP
    dibenzo(a,l) pyrene
    AHR
    aryl hydrocarbon receptor
    EGCG
    (−)epigallocatechin gallate
    MAPK
    mitogen-activated protein kinase
    MMDX
    methoxymorpholinyl doxorubicin.

    • Received November 23, 2009.
    • Accepted January 20, 2010.
  • U.S. Government work not protected by U.S. copyright
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Drug Metabolism and Disposition: 38 (4)
Drug Metabolism and Disposition
Vol. 38, Issue 4
1 Apr 2010
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Research ArticleSymposium Article

Targeting Drug-Metabolizing Enzymes for Effective Chemoprevention and Chemotherapy

Hollie I. Swanson, Vincent C. O. Njar, Zhen Yu, David J. Castro, Frank J. Gonzalez, David E. Williams, Ying Huang, Ah-Ng T. Kong, Joshua C. Doloff, Jie Ma, David J. Waxman and Emily E. Scott
Drug Metabolism and Disposition April 1, 2010, 38 (4) 539-544; DOI: https://doi.org/10.1124/dmd.109.031351

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Research ArticleSymposium Article

Targeting Drug-Metabolizing Enzymes for Effective Chemoprevention and Chemotherapy

Hollie I. Swanson, Vincent C. O. Njar, Zhen Yu, David J. Castro, Frank J. Gonzalez, David E. Williams, Ying Huang, Ah-Ng T. Kong, Joshua C. Doloff, Jie Ma, David J. Waxman and Emily E. Scott
Drug Metabolism and Disposition April 1, 2010, 38 (4) 539-544; DOI: https://doi.org/10.1124/dmd.109.031351
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