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

Cancer Gene Therapy volume 15, pages 94–100 (2008)Cite this article

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.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

Ad:

adenovirus

ADEPT:

antibody-directed enzyme prodrug therapy

ALT:

alanine aminotransferase

CE:

carboxylesterase

CEA:

carcinoembryonic antigen

CMV:

cytomegalovirus

DLT:

dose limiting toxicity

FCS:

fetal calf serum

IgG:

immunoglobulin G

MOI:

multiplicity of infection

NSCLC:

non-small cell lung cancer

PCR:

polymerase chain reaction

scFv:

single chain variable fragment

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Acknowledgements

We thank Mr J Suzuki, from the Yakult Central Institute for Microbiological Research who provided the technical assistance throughout this study. The study was supported by grant-in-aid scientific research from the Ministry of Education, Culture, Sports, Science and Technology in Japan.

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Authors and Affiliations

  1. Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    J Uchino, K Takayama, A Harada, T Harada & Y Nakanishi

  2. Department of Toxicology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan

    T Sone

  3. Departments of Medicine, Division of Human Gene Therapy, Pathology and Surgery, and The Gene Therapy Center, The University of Alabama at Birmingham, Birmingham, AL, USA

    D T Curiel

  4. Department of Biochemistry, Fukuoka University School of Medicine, Fukuoka, Japan

    M Kuroki

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  1. J Uchino
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  2. K Takayama
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Correspondence to K Takayama.

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Uchino, J., Takayama, K., Harada, A. et al. Tumor targeting carboxylesterase fused with anti-CEA scFv improve the anticancer effect with a less toxic dose of irinotecan. Cancer Gene Ther 15, 94–100 (2008). https://doi.org/10.1038/sj.cgt.7701100

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