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, Laurent P. Rivory

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


The anticancer drug irinotecan (CPT-11) is activated to the potent topoisomerase I inhibitor, SN-38 (7-ethyl-10-hydroxy-camptothecin), 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 and Vmax 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 of Vmax/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.

Original languageEnglish (US)
Pages (from-to)649-655
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - Nov 1 2002
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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