Hypoxia-targeted over-expression of carboxylesterase as a means of increasing tumour sensitivity to irinotecan (CPT-11).
Cowen, Rachel L
Williams, Kaye J
Telfer, Brian A
Flint, Pamela J
Southgate, Thomas D
Saunders, Mark P
AffiliationPaterson Institute for Cancer Research, Christie Hospital NHS Trust, and School of Pharmacy and Pharmaceutical Sciences, University of Manchester, UK.
MetadataShow full item record
AbstractThe induced expression of carboxylesterase (CE) enzymes, which convert the prodrug irinotecan (CPT-11) into its active cytotoxic metabolite SN-38, constitutes a promising strategy for cancer gene therapy. By incorporating hypoxia-responsive elements (HREs) in conjunction with the transgene, expression can be targeted specifically to hypoxic tissues (such as solid tumours), expressing the hypoxia-inducible factor 1 (HIF-1). We have constructed a recombinant adenoviral vector, AdHRE-rCE, encoding the cDNA for the highly efficient rabbit liver CE (rCE), under the control of a HRE derived from the human phosphoglycerate kinase 1 (PGK-1) gene in conjunction with a minimal SV40 promoter. In vitro, HT1080 fibrosarcoma and SW480 colon carcinoma cells demonstrated an approximately 10-fold hypoxia-dependent induction in CE expression following pre-infection with AdHRE-rCE, which led to a15-30-fold increased sensitivity to CPT-11. Furthermore, in vivo, SW480 tumour xenografts infected with AdHRE-rCE demonstrated a 2-fold decrease in tumour doubling time, when combined with 7 days of CPT-11 treatment, in comparison to mock-infected controls, with rCE expression shown to be limited to hypoxic regions only. As the cytotoxicity of CPT-11 is reduced under hypoxic conditions, over-expression of a highly efficient CE such as rCE under hypoxia control within these hypoxic cells could reverse this effect and, therefore, form the basis for future clinical treatment strategies.
CitationHypoxia-targeted over-expression of carboxylesterase as a means of increasing tumour sensitivity to irinotecan (CPT-11). 2007, 9 (4):244-52 J Gene Med
JournalThe Journal of Gene Medicine
- In vivo human carboxylesterase cDNA gene transfer to activate the prodrug CPT-11 for local treatment of solid tumors.
- Authors: Kojima A, Hackett NR, Ohwada A, Crystal RG
- Issue date: 1998 Apr 15
- An improved human carboxylesterase for enzyme/prodrug therapy with CPT-11.
- Authors: Wierdl M, Tsurkan L, Hyatt JL, Edwards CC, Hatfield MJ, Morton CL, Houghton PJ, Danks MK, Redinbo MR, Potter PM
- Issue date: 2008 Mar
- Adenoviral vector-mediated expression of a gene encoding secreted, EpCAM-targeted carboxylesterase-2 sensitises colon cancer spheroids to CPT-11.
- Authors: Oosterhoff D, Overmeer RM, de Graaf M, van der Meulen IH, Giaccone G, van Beusechem VW, Haisma HJ, Pinedo HM, Gerritsen WR
- Issue date: 2005 Mar 14
- Gene-directed enzyme prodrug therapy for osteosarcoma: sensitization to CPT-11 in vitro and in vivo by adenoviral delivery of a gene encoding secreted carboxylesterase-2.
- Authors: Oosterhoff D, Witlox MA, van Beusechem VW, Haisma HJ, Schaap GR, Bras J, Kruyt FA, Molenaar B, Boven E, Wuisman PI, Pinedo HM, Gerritsen WR
- Issue date: 2003 Aug
- Neural stem cell-mediated delivery of irinotecan-activating carboxylesterases to glioma: implications for clinical use.
- Authors: Metz MZ, Gutova M, Lacey SF, Abramyants Y, Vo T, Gilchrist M, Tirughana R, Ghoda LY, Barish ME, Brown CE, Najbauer J, Potter PM, Portnow J, Synold TW, Aboody KS
- Issue date: 2013 Dec