Adenoviral vector-mediated expression of a gene encoding secreted, EpCAM-targeted carboxylesterase-2 sensitises colon cancer spheroids to CPT-11

D. Oosterhoff, R. M. Overmeer, M. De Graaf, I. H. Van Der Meulen, G. Giaccone, V. W. Van Beusechem, H. J. Haisma, H. M. Pinedo, W. R. Gerritsen

Research output: Contribution to journalArticle

Abstract

CPT-11 (irinotecan or 7-ethyl-10[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) is an anticancer agent in use for the treatment of colon cancer. In order to be fully active, CPT-11 needs to be converted into SN-38 (7-ethyl-10-hydroxycamptothecin) by the enzyme carboxylesterase (CE). In humans, only a minority of CPT-11 is converted to SN-38. To increase the antitumour effect of CPT-11 by gene-directed enzyme prodrug therapy, we constructed a replication-deficient adenoviral vector Ad.C28-sCE2 containing a fusion gene encoding a secreted form of human liver CE2 targeted to the surface antigen epithelial cell adhesion molecule (EpCAM) that is highly expressed on most colon carcinoma cells. By targeting CE2 to EpCAM, the enzyme should accumulate specifically in tumours and leakage into the circulation should be minimised, Ad.C28-sCE2-transduced colon carcinoma cells expressed and secreted active CE that bound specifically to EpCAM-expressing cells. In sections of three-dimensional colon carcinoma spheroids transduced with Ad.C28-sCE2, it was shown that C28-sCE2 was capable of binding untransduced cells. Most importantly, treatment of these spheroids with nontoxic concentrations of CPT-11 resulted in growth inhibition comparable to treatment with SN-38. Therefore, Ad.C28-sCE2 holds promise in gene therapy approaches for the treatment of colon carcinoma.

Original languageEnglish (US)
Pages (from-to)882-887
Number of pages6
JournalBritish Journal of Cancer
Volume92
Issue number5
DOIs
StatePublished - Mar 14 2005
Externally publishedYes

Fingerprint

irinotecan
Carboxylesterase
Colonic Neoplasms
Gene Expression
Colon
Carcinoma
Epithelial Cell Adhesion Molecule
Enzyme Therapy

Keywords

  • Adenovirus
  • Carboxylesterase
  • CPT-11
  • EpCAM
  • Spheroid

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Oosterhoff, D., Overmeer, R. M., De Graaf, M., Van Der Meulen, I. H., Giaccone, G., Van Beusechem, V. W., ... Gerritsen, W. R. (2005). Adenoviral vector-mediated expression of a gene encoding secreted, EpCAM-targeted carboxylesterase-2 sensitises colon cancer spheroids to CPT-11. British Journal of Cancer, 92(5), 882-887. https://doi.org/10.1038/sj.bjc.6602362

Adenoviral vector-mediated expression of a gene encoding secreted, EpCAM-targeted carboxylesterase-2 sensitises colon cancer spheroids to CPT-11. / Oosterhoff, D.; Overmeer, R. M.; De Graaf, M.; Van Der Meulen, I. H.; Giaccone, G.; Van Beusechem, V. W.; Haisma, H. J.; Pinedo, H. M.; Gerritsen, W. R.

In: British Journal of Cancer, Vol. 92, No. 5, 14.03.2005, p. 882-887.

Research output: Contribution to journalArticle

Oosterhoff, D, Overmeer, RM, De Graaf, M, Van Der Meulen, IH, Giaccone, G, Van Beusechem, VW, Haisma, HJ, Pinedo, HM & Gerritsen, WR 2005, 'Adenoviral vector-mediated expression of a gene encoding secreted, EpCAM-targeted carboxylesterase-2 sensitises colon cancer spheroids to CPT-11', British Journal of Cancer, vol. 92, no. 5, pp. 882-887. https://doi.org/10.1038/sj.bjc.6602362
Oosterhoff, D. ; Overmeer, R. M. ; De Graaf, M. ; Van Der Meulen, I. H. ; Giaccone, G. ; Van Beusechem, V. W. ; Haisma, H. J. ; Pinedo, H. M. ; Gerritsen, W. R. / Adenoviral vector-mediated expression of a gene encoding secreted, EpCAM-targeted carboxylesterase-2 sensitises colon cancer spheroids to CPT-11. In: British Journal of Cancer. 2005 ; Vol. 92, No. 5. pp. 882-887.
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abstract = "CPT-11 (irinotecan or 7-ethyl-10[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) is an anticancer agent in use for the treatment of colon cancer. In order to be fully active, CPT-11 needs to be converted into SN-38 (7-ethyl-10-hydroxycamptothecin) by the enzyme carboxylesterase (CE). In humans, only a minority of CPT-11 is converted to SN-38. To increase the antitumour effect of CPT-11 by gene-directed enzyme prodrug therapy, we constructed a replication-deficient adenoviral vector Ad.C28-sCE2 containing a fusion gene encoding a secreted form of human liver CE2 targeted to the surface antigen epithelial cell adhesion molecule (EpCAM) that is highly expressed on most colon carcinoma cells. By targeting CE2 to EpCAM, the enzyme should accumulate specifically in tumours and leakage into the circulation should be minimised, Ad.C28-sCE2-transduced colon carcinoma cells expressed and secreted active CE that bound specifically to EpCAM-expressing cells. In sections of three-dimensional colon carcinoma spheroids transduced with Ad.C28-sCE2, it was shown that C28-sCE2 was capable of binding untransduced cells. Most importantly, treatment of these spheroids with nontoxic concentrations of CPT-11 resulted in growth inhibition comparable to treatment with SN-38. Therefore, Ad.C28-sCE2 holds promise in gene therapy approaches for the treatment of colon carcinoma.",
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