Tumor targeting carboxylesterase fused with anti-CEA scFv improve the anticancer effect with a less toxic dose of irinotecan

Cancer Gene Ther. 2008 Feb;15(2):94-100. doi: 10.1038/sj.cgt.7701100. Epub 2007 Dec 21.


Irinotecan (CPT-11) is a key drug for the treatment of various cancers. CPT-11 can be considered to be a prodrug, since it needs to be activated into the toxic drug SN-38 by the enzyme carboxylesterase. However, CPT-11 may induce severe diarrhea and bone marrow suppression as adverse effects, thus leading to treatment interruption. The tumor-specific activation of CPT-11 is a possible strategy to avoid the severe toxicities by reducing the serum concentration of CPT-11. In this study, we constructed human liver carboxylesterase-2 fused with anticarcinoembryonic antigen (CEA) scFv as a targeting molecule. The recombinant enzyme anchors onto the tumor cell surface CEA, and thus metabolize CPT-11 extracellularly. In addition a secreted tumor-targeted form of carboxylesterase should help prevent the leakage of the enzyme from the site of the tumor into the circulation. This fusion protein showed CPT-11 activation to SN-38 and specific binding to CEA-expressing cells. In combination with CPT-11, the recombinant carboxylesterase protein exerted antiproliferative effects on human cancer cells. This recombinant enzyme is, therefore, a promising new tool in enzyme prodrug therapy for the treatment of carcinoma with CPT-11.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Antineoplastic Agents, Phytogenic / toxicity
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacokinetics
  • Camptothecin / pharmacology
  • Camptothecin / toxicity
  • Carboxylesterase / antagonists & inhibitors
  • Carboxylesterase / genetics*
  • Carboxylesterase / metabolism
  • Carcinoembryonic Antigen / genetics*
  • Carcinoembryonic Antigen / immunology
  • Carcinoembryonic Antigen / metabolism
  • Dose-Response Relationship, Immunologic
  • Gene Targeting
  • HeLa Cells
  • Humans
  • Immunoglobulin Variable Region / genetics*
  • Immunoglobulin Variable Region / physiology
  • Irinotecan
  • Recombinant Fusion Proteins / genetics


  • Antineoplastic Agents, Phytogenic
  • Carcinoembryonic Antigen
  • Immunoglobulin Variable Region
  • Recombinant Fusion Proteins
  • Irinotecan
  • CES2 protein, human
  • Carboxylesterase
  • Camptothecin