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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

The Importance of Tumor Glucuronidase in the Activation of Irinotecan in a Mouse Xenograft Model

Helen M. Dodds, Peter J. Tobin, Clinton F. Stewart, Pam Cheshire, Suzan Hanna, Peter Houghton and Laurent P. Rivory
Journal of Pharmacology and Experimental Therapeutics November 2002, 303 (2) 649-655; DOI: https://doi.org/10.1124/jpet.102.039040
Helen M. Dodds
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Peter J. Tobin
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Clinton F. Stewart
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Pam Cheshire
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Suzan Hanna
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Peter Houghton
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Laurent P. Rivory
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Abstract

The anticancer drug irinotecan (CPT-11) is activated to the potent topoisomerase I inhibitor, SN-38 (7-ethyl-10-hydroxycamptothecin), by esterases. SN-38 is in turn conjugated to the inactive SN-38 glucuronide (SN-38G). The reverse reaction is mediated by β-glucuronidases. Hence, production of SN-38 may occur through either pathway. In this study we conducted in vitro studies to examine these two reactions in neuroblastoma xenograft tumors (NB1691) and compared the rates of SN-38 production with those observed in the liver and plasma of the host SCID (severe-combined immunodeficient) mice. The rate of formation of SN-38 from CPT-11 by esterases slowed considerably during a 60-min incubation, consistent with the known deacylation-limited nature of this reaction. For xenograft tumor tissue, Km andVmax values of 1.6 μM and 4.4 pmol/min/mg of protein, respectively, were observed. By comparison, these parameters were estimated to be 6.9 μM and 9.4 pmol/min/mg for mouse liver and 2.1 μM and 40.0 pmol/min/mg for mouse plasma, respectively. The formation of SN-38 from SN-38G was very pronounced in both liver and xenograft tumor tissue, in which it was nonsaturable (0.125–50 μM) and time-independent (0–60 min). The derived values ofVmax/Km were 0.65 μl/min/mg for the tumor and 2.12 μl/min/mg for the liver preparations. Microdialysate experiments revealed the concentrations of SN-38G and CPT-11 in tumor to be comparable. At equal substrate concentrations, production of SN-38 from SN-38G in tumor extracts was comparable with that from CPT-11. Therefore, reactivation of SN-38 in the tumor by β-glucuronidases may represent an important route of tumor drug activation for CPT-11.

Footnotes

  • DOI: 10.1124/jpet.102.039040

  • Abbreviations:
    CPT-11
    irinotecan (7-ethyl-10-[4-(1-piperidino)1-piperidino]carbonyloxycamptothecin)
    SN-38
    7-ethyl-10-hydroxycamptothecin
    SN-38G
    SN-38 glucuronide
    APC
    7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin
    CPT
    camptothecin
    TBAP
    tetrabutylammonium phosphate
    SCID
    severe combined immunodeficient
    HPLC
    high-performance liquid chromatography
    AUC
    area under the concentration-time curve
    • Received May 16, 2002.
    • Accepted July 8, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 303 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 2
1 Nov 2002
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

The Importance of Tumor Glucuronidase in the Activation of Irinotecan in a Mouse Xenograft Model

Helen M. Dodds, Peter J. Tobin, Clinton F. Stewart, Pam Cheshire, Suzan Hanna, Peter Houghton and Laurent P. Rivory
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 649-655; DOI: https://doi.org/10.1124/jpet.102.039040

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

The Importance of Tumor Glucuronidase in the Activation of Irinotecan in a Mouse Xenograft Model

Helen M. Dodds, Peter J. Tobin, Clinton F. Stewart, Pam Cheshire, Suzan Hanna, Peter Houghton and Laurent P. Rivory
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 649-655; DOI: https://doi.org/10.1124/jpet.102.039040
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