Hua Wang1, Zhijian Cai2, Fei Yang2, Juan Luo3, Makoto Satoh4, Yoichi Arai5, Dechuan Li6. 1. Department of Urology, Zhejiang Cancer Hospital, Hangzhou, China. Electronic address: hwangua@aliyun.com. 2. Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, China. 3. Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, China. 4. Department of Urology, Sen-en General Hospital, Tagajo, Miyagi, Japan. 5. Department of Urology, Tohoku University Graduate School of Medicine, Sendai, Japan. 6. Department of Urology, Zhejiang Cancer Hospital, Hangzhou, China.
Abstract
OBJECTIVE: To evaluate the therapeutic efficacy of AxdAdB-3 with Arg-Gly-Asp (RGD)-fiber modification (AxdAdB3-F/RGD), which enables integrin-dependent infection in bladder cancers. METHODS: Flow cytometric analysis was applied to evaluated adenovirus-mediated gene transduction into various cells. The cytopathic effects of AxdAdB3-F/RGD were evaluated in bladder cancer cell lines and a normal bladder mucosa-derived cell line (HCV29) with AxCAZ3-F/RGD (control) or AxdAdB-3. The efficacy of bladder instillation therapy with AxdAdB3-F/RGD for orthotopic bladder cancer was investigated in nude mice. RESULTS: Expression of coxsackievirus adenovirus receptor (CAR) and integrins (αvβ3 and αvβ5) vary in different bladder cancer cell lines. The susceptibility of various cell lines to adenovirus was associated with the expression of CAR. AxdAdB-3 was more cytopathic in CAR-positive bladder cancer cells than in CAR-negative cells, whereas AxdAdB3-F/RGD caused effective oncolysis in both CAR-positive and CAR-negative bladder cancer cells. AxdAdB3-F/RGD was not cytotoxic to HCV29 cells. Direct instillation of AxdAdB3-F/RGD into the bladder of the orthotopic model, established by CAR-deficient human bladder cancer cells, inhibited tumor growth and led to significantly elongated survival. CONCLUSION: E1A and E1B double-restricted oncolytic adenovirus with RGD fiber modification has enhanced infectivity and oncolytic effects to CAR-deficient bladder cancers, suggesting the therapeutic potential of AxdAdB3-F/RGD for bladder cancers.
OBJECTIVE: To evaluate the therapeutic efficacy of AxdAdB-3 with Arg-Gly-Asp (RGD)-fiber modification (AxdAdB3-F/RGD), which enables integrin-dependent infection in bladder cancers. METHODS: Flow cytometric analysis was applied to evaluated adenovirus-mediated gene transduction into various cells. The cytopathic effects of AxdAdB3-F/RGD were evaluated in bladder cancer cell lines and a normal bladder mucosa-derived cell line (HCV29) with AxCAZ3-F/RGD (control) or AxdAdB-3. The efficacy of bladder instillation therapy with AxdAdB3-F/RGD for orthotopic bladder cancer was investigated in nude mice. RESULTS: Expression of coxsackievirus adenovirus receptor (CAR) and integrins (αvβ3 and αvβ5) vary in different bladder cancer cell lines. The susceptibility of various cell lines to adenovirus was associated with the expression of CAR. AxdAdB-3 was more cytopathic in CAR-positive bladder cancer cells than in CAR-negative cells, whereas AxdAdB3-F/RGD caused effective oncolysis in both CAR-positive and CAR-negative bladder cancer cells. AxdAdB3-F/RGD was not cytotoxic to HCV29 cells. Direct instillation of AxdAdB3-F/RGD into the bladder of the orthotopic model, established by CAR-deficient human bladder cancer cells, inhibited tumor growth and led to significantly elongated survival. CONCLUSION: E1A and E1B double-restricted oncolytic adenovirus with RGD fiber modification has enhanced infectivity and oncolytic effects to CAR-deficient bladder cancers, suggesting the therapeutic potential of AxdAdB3-F/RGD for bladder cancers.
Authors: Kim E M van Kessel; Tahlita C M Zuiverloon; Arnout R Alberts; Joost L Boormans; Ellen C Zwarthoff Journal: Nat Rev Urol Date: 2015-09-22 Impact factor: 14.432
Authors: Selas T F Bots; Vera Kemp; Steve J Cramer; Diana J M van den Wollenberg; Marten Hornsveld; Martine L M Lamfers; Gabri van der Pluijm; Rob C Hoeben Journal: Hum Gene Ther Date: 2022-03 Impact factor: 5.695