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

J. Uchino, K. Takayama, A. Harada, T. Sone, T. Harada, D. T. Curiel, M. Kuroki, Y. Nakanishi

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)94-100
Number of pages7
JournalCancer Gene Therapy
Volume15
Issue number2
DOIs
Publication statusPublished - Feb 1 2008

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irinotecan
Carboxylesterase
Poisons
Neoplasms
Prodrugs
Enzymes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

Cite this

Tumor targeting carboxylesterase fused with anti-CEA scFv improve the anticancer effect with a less toxic dose of irinotecan. / Uchino, J.; Takayama, K.; Harada, A.; Sone, T.; Harada, T.; Curiel, D. T.; Kuroki, M.; Nakanishi, Y.

In: Cancer Gene Therapy, Vol. 15, No. 2, 01.02.2008, p. 94-100.

Research output: Contribution to journalArticle

Uchino, J, Takayama, K, Harada, A, Sone, T, Harada, T, Curiel, DT, Kuroki, M & Nakanishi, Y 2008, 'Tumor targeting carboxylesterase fused with anti-CEA scFv improve the anticancer effect with a less toxic dose of irinotecan', Cancer Gene Therapy, vol. 15, no. 2, pp. 94-100. https://doi.org/10.1038/sj.cgt.7701100
Uchino, J. ; Takayama, K. ; Harada, A. ; Sone, T. ; Harada, T. ; Curiel, D. T. ; Kuroki, M. ; Nakanishi, Y. / Tumor targeting carboxylesterase fused with anti-CEA scFv improve the anticancer effect with a less toxic dose of irinotecan. In: Cancer Gene Therapy. 2008 ; Vol. 15, No. 2. pp. 94-100.
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