An improved human carboxylesterase for enzyme/prodrug therapy with CPT-11

M. Wierdl, L. Tsurkan, J. L. Hyatt, C. C. Edwards, M. J. Hatfield, C. L. Morton, P. J. Houghton, M. K. Danks, M. R. Redinbo, P. M. Potter

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

CPT-11 is a potent antitumor agent that is activated by carboxylesterases (CE) and intracellular expression of CEs that can activate the drug results in increased cytotoxicity to the drug. As activation of CPT-11 (irinotecan-7-ethyl- 10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) by human CEs is relatively inefficient, we have developed enzyme/prodrug therapy approaches based on the CE/CPT-11 combination using a rabbit liver CE (rCE). However, the in vivo application of this technology may be hampered by the development of an immune response to rCE. Therefore, we have developed a mutant human CE (hCE1m6), based on the human liver CE hCE1, that can activate CPT-11 approximately 70-fold more efficiently than the wild-type protein and can be expressed at high levels in mammalian cells. Indeed, adenoviral-mediated delivery of hCE1m6 with human tumor cells resulted in up to a 670-fold reduction in the IC50 value for CPT-11, as compared to cells transduced with vector control virus. Furthermore, xenograft studies with human tumors expressing hCE1m6 confirm the ability of this enzyme to activate CPT-11 in vivo and induce antitumor activity. We propose that this enzyme should likely be less immunogenic than rCE and would be suitable for the in vivo application of CE/CPT-11 enzyme/prodrug therapy.

Original languageEnglish (US)
Pages (from-to)183-192
Number of pages10
JournalCancer Gene Therapy
Volume15
Issue number3
DOIs
StatePublished - Mar 1 2008
Externally publishedYes

Keywords

  • CPT-11
  • Carboxylesterase
  • Enzyme/prodrug therapy
  • Xenograft

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

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    Wierdl, M., Tsurkan, L., Hyatt, J. L., Edwards, C. C., Hatfield, M. J., Morton, C. L., Houghton, P. J., Danks, M. K., Redinbo, M. R., & Potter, P. M. (2008). An improved human carboxylesterase for enzyme/prodrug therapy with CPT-11. Cancer Gene Therapy, 15(3), 183-192. https://doi.org/10.1038/sj.cgt.7701112