Oncolytic adenovirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells
2011 (English)In: Gene Therapy, ISSN 0969-7128, E-ISSN 1476-5462, Vol. 18, no 11, 1052-1062 p.Article in journal (Refereed) Published
We have previously described the oncolytic adenovirus, Ad(CgA-E1A-miR122), herein denoted Ad5(CgA-E1A-miR122) that selectively replicates in and kills neuroendocrine cells, including freshly isolated midgut carcinoid cells from liver metastases. Ad5(CgA-E1A-miR122) is based on human adenovirus serotype 5 (Ad5) and infects target cells by binding to the coxsackie-adenovirus receptor (CAR) and integrins on the cell surface. Some neuroendocrine tumor (NET) and neuroblastoma cells express low levels of CAR and are therefore poorly transduced by Ad5. However, they often express high levels of somatostatin receptors (SSTRs). Therefore, we introduced cyclic peptides, which contain four amino acids (FWKT) and mimic the binding site for SSTRs in the virus fiber knob. We show that FWKT-modified Ad5 binds to SSTR2 on NET cells and transduces midgut carcinoid cells from liver metastases about 3-4 times better than non-modified Ad5 while it transduces normal hepatocytes at about 50% of Ad5. Moreover, FWKT-modified Ad5 overcomes neutralization in an ex vivo human blood loop model to greater extent than Ad5, indicating that fiber knob modification may prolong the systematic circulation time. We conclude that modification of adenovirus with the FWKT motif may be beneficial for NET therapy.
Place, publisher, year, edition, pages
2011. Vol. 18, no 11, 1052-1062 p.
oncolytic adenovirus, somatostatin, neuroendocrine tumors, carcinoid, neuroblastoma, proximity ligation
Cell and Molecular Biology Cancer and Oncology Microbiology in the medical area
Research subject Oncology; Molecular Medicine
IdentifiersURN: urn:nbn:se:uu:diva-146964DOI: 10.1038/gt.2011.54ISI: 000296889500004PubMedID: 21490682OAI: oai:DiVA.org:uu-146964DiVA: diva2:399465