Hypoxia-targeted over-expression of carboxylesterase as a means of increasing tumour sensitivity to irinotecan (CPT-11).

2.50
Hdl Handle:
http://hdl.handle.net/10541/72844
Title:
Hypoxia-targeted over-expression of carboxylesterase as a means of increasing tumour sensitivity to irinotecan (CPT-11).
Authors:
Matzow, Torkjel; Cowen, Rachel L; Williams, Kaye J; Telfer, Brian A; Flint, Pamela J; Southgate, Thomas D; Saunders, Mark P
Abstract:
The 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.
Affiliation:
Paterson Institute for Cancer Research, Christie Hospital NHS Trust, and School of Pharmacy and Pharmaceutical Sciences, University of Manchester, UK.
Citation:
Hypoxia-targeted over-expression of carboxylesterase as a means of increasing tumour sensitivity to irinotecan (CPT-11). 2007, 9 (4):244-52 J Gene Med
Journal:
The Journal of Gene Medicine
Issue Date:
Apr-2007
URI:
http://hdl.handle.net/10541/72844
DOI:
10.1002/jgm.1016
PubMed ID:
17397102
Type:
Article
Language:
en
ISSN:
1099-498X
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorMatzow, Torkjel-
dc.contributor.authorCowen, Rachel L-
dc.contributor.authorWilliams, Kaye J-
dc.contributor.authorTelfer, Brian A-
dc.contributor.authorFlint, Pamela J-
dc.contributor.authorSouthgate, Thomas D-
dc.contributor.authorSaunders, Mark P-
dc.date.accessioned2009-07-07T16:34:54Z-
dc.date.available2009-07-07T16:34:54Z-
dc.date.issued2007-04-
dc.identifier.citationHypoxia-targeted over-expression of carboxylesterase as a means of increasing tumour sensitivity to irinotecan (CPT-11). 2007, 9 (4):244-52 J Gene Meden
dc.identifier.issn1099-498X-
dc.identifier.pmid17397102-
dc.identifier.doi10.1002/jgm.1016-
dc.identifier.urihttp://hdl.handle.net/10541/72844-
dc.description.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.en
dc.language.isoenen
dc.subjectCanceren
dc.subject.meshAdenoviridae-
dc.subject.meshAnimals-
dc.subject.meshAntineoplastic Agents, Phytogenic-
dc.subject.meshCamptothecin-
dc.subject.meshCarboxylesterase-
dc.subject.meshCell Hypoxia-
dc.subject.meshCell Line-
dc.subject.meshEnzyme Inhibitors-
dc.subject.meshGene Expression Regulation, Neoplastic-
dc.subject.meshGenetic Vectors-
dc.subject.meshHumans-
dc.subject.meshNeoplasms-
dc.subject.meshRabbits-
dc.subject.meshTransplantation, Heterologous-
dc.titleHypoxia-targeted over-expression of carboxylesterase as a means of increasing tumour sensitivity to irinotecan (CPT-11).en
dc.typeArticleen
dc.contributor.departmentPaterson Institute for Cancer Research, Christie Hospital NHS Trust, and School of Pharmacy and Pharmaceutical Sciences, University of Manchester, UK.en
dc.identifier.journalThe Journal of Gene Medicineen

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