Abstract
BackgroundColorectal cancer is often a deadly disease and cannot be cured at metastatic stage. Oncolytic adenoviruses have been considered as a new therapeutic option for treatment of refractory disseminated cancers, including colorectal cancer. The safety data has been excellent but tumor transduction and antitumor efficacy especially in systemic administration needs to be improved.MethodsHere, the utility of αvβ integrin targeting moiety Arg-Gly-Asp (RGD) in the Lys-Lys-Thr-Lys (KKTK) domain of the fiber shaft or in the HI-loop of adenovirus serotype 5 for increased tumor targeting and antitumor efficacy was evaluated. To this end, novel spleen-to-liver metastatic colorectal cancer mouse model was used and the antitumor efficacy was evaluated with magnetic resonance imaging (MRI).ResultsBoth modifications (RGD in the HI-loop or in the fiber shaft) increased gene transfer efficacy in colorectal cancer cell lines and improved tumor-to-normal ratio in systemic administration of the vector.ConclusionsAntitumor potency was not compromised with RGD modified viruses suggesting increased safety profile and tumor specificity.
Highlights
Colorectal cancer is often a deadly disease and cannot be cured at metastatic stage
Intravenous administration of unmodified adenovirus 5 vectors to mice leads mainly to infection of liver cells. This is mostly due to natural engulfment of adenoviral particles by hepatic macrophages [13] and several blood factors have been suggested to be involved by bridging the viral capsid proteins to heparan sulphate proteoglycans (HSPG) and some other receptor molecules on the surface of hepatocytes [14,15,16,17,18,19,20]
Coxsackie- and adenovirus receptor (CAR) binding ablation by changing amino acid residues of the fiber binding motif has been suggested to avoid vector ending into the liver hepatocytes but this modification has been shown to be an inadequate to change the biodistribution of the virus [21]
Summary
Colorectal cancer is often a deadly disease and cannot be cured at metastatic stage. Oncolytic adenoviruses have been considered as a new therapeutic option for treatment of refractory disseminated cancers, including colorectal cancer. Metastatic disseminated disease can be cured only rarely and even though early detection and prevention strategies play a key role in improving colorectal cancer statistics, new therapeutic. Intravenous administration of unmodified adenovirus 5 vectors to mice leads mainly to infection of liver cells. This is mostly due to natural engulfment of adenoviral particles by hepatic macrophages (mainly Kupffer cells) [13] and several blood factors have been suggested to be involved by bridging the viral capsid proteins to heparan sulphate proteoglycans (HSPG) and some other receptor molecules on the surface of hepatocytes [14,15,16,17,18,19,20]. In the absence of CAR, Lys-Lys-Thr-Lys (KKTK) domain in the fiber shaft has been suggested to play a major role in viral internalization via low affinity binding with HSPG [27,28,29] and a mutation in this domain has been shown to decrease viral tropism towards hepatocytes [27,29]
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