Abstract
Current clinical success rates of adenoviral vector (Adv)-based gene therapy of squamous cell carcinoma (SCC) of the head and neck remain unsatisfactory. A major problem with this approach is thought to be related to low Adv transduction efficiency due to weak expression of the adenovirus receptor, coxsackie-adenovirus receptor (CAR), in SCC. To improve the limited infectivity of Adv in oral SCC, we constructed mutated Adv incorporating the integrin-binding motif, RGD, in the HI loop of the fiber knob. The mutated Adv infected target cells through integrins commonly expressed in oral SCC. LacZ marker gene expression after infection with this mutated Adv (Adv-F/RGD) in oral SCC cell lines that showed reduced expression of CAR was approximately 5-10 times higher than that obtained with the parental Adv containing wild-type fiber knob (Adv-F/wt). In an in vitro study, transduction of oral cancer cell lines with Adv-F/RGD expressing human IL-2 (AxCAhIL2-F/RGD) resulted in greater production of cytokine than AxCAhIL2-F/wt infection. In an in vivo therapeutic xenograft model of oral SCC in nude mice, AxCAhIL2-F/RGD demonstrated antitumor effects superior to those of AxCAhIL2-F/wt. These data suggest that exploitation of genetically altered adenovirus vectors with integrin-binding motifs may offer significant improvements in oral SCC gene therapy.
Highlights
Squamous cell carcinoma of the head and neck (HNSCC) afflicts an estimated 500,000 patients annually worldwide.[1]
We evaluated whether oral SCC cells infected with Ad - F/ RGD carrying the human IL -2 therapeutic gene (AxCAhIL2 -F /RGD ) produced a higher level of IL -2 than those infected with a vector containing control wild -type fiber ( AxCAhIL2- F/ wt )
We have demonstrated that employment of Adv -F /RGD, carrying an RGD peptide motif in the fiber, can result in enhanced expression of an IL- 2 transgene and improve in vivo antitumor effects against oral SCC expressing low levels of CAR
Summary
Squamous cell carcinoma of the head and neck (HNSCC) afflicts an estimated 500,000 patients annually worldwide.[1]. While it is accepted that of the available systems, adenoviral vectors ( Advs ), possess superior levels of in vivo gene transfer capability, their present level of efficiency may be suboptimal for HNSCC gene therapy.[5] In several clinical trials involving in vivo gene delivery, a relative resistance of target tissues to adenoviral infection has been reported.[13]. Use of a higher dose leads to more problems with possible adverse effects, such as allergic immune reactions, or reactions to toxic Adv components such as hexon and penton Another approach is to create genetically modified Adv, which converts tropism from CAR to other molecules. We investigated whether Adv - F/ RGD can improve transduction efficiency into oral SCC cells expressing low levels of CAR and whether Adv - F/ RGD carrying the human IL -2 gene can exert antitumor effects in an oral SCC xenograft model
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
