title: Efficacy of CD46-targeting chimeric Ad5/35 adenoviral gene therapy for colorectal cancers.
abstract: CD46 is a complement inhibitor membrane cofactor which also acts as a receptor for various microbes, including species B adenoviruses (Ads). While most Ad gene therapy vectors are derived from species C and infect cells through coxsackie-adenovirus receptor (CAR), CAR expression is downregulated in many cancer cells, resulting inefficient Ad-based therapeutics. Despite a limited knowledge on the expression status of many cancer cells, an increasing number of cancer gene therapy studies include fiber-modified Ad vectors redirected to the more ubiquitously expressed CD46. Since our finding from tumor microarray indicate that CD46 was overexpressed in cancers of the prostate and colon, fiber chimeric Ad5/35 vectors that have infection tropism for CD46 were employed to demonstrate its efficacy in colorectal cancers (CRC). CD46-overexpressed cells showed a significantly higher response to Ad5/35-GFP and to Ad5/35-tk/GCV. While CRC cells express variable levels of CD46, CD46 expression was positively correlated with Ad5/35-mediated GFP fluorescence and accordingly its cell killing. Injection of Ad5/35-tk/GCV caused much greater tumor-suppression in mice bearing CD46-overexpressed cancer xenograft compared to mock group. Analysis of CRC samples revealed that patients with positive CD46 expression had a higher survival rate (p=0.031), carried tumors that were well-differentiated, but less invasive and metastatic, and with a low T stage (all p<0.05). Taken together, our study demonstrated that species B-based adenoviral gene therapy is a suitable approach for generally CD46-overexpressed CRC but would require careful consideration preceding CD46 analysis and categorizing CRC patients.
authors.affiliation: Department of Anatomy, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Cho
authors.affiliation: Department of Anatomy, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Manh-Hung
authors.initials: MH
authors.lastname: Do
authors.affiliation: Department of Anatomy, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Kwon
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju, Korea.
authors.forename: Changjong
authors.initials: C
authors.lastname: Moon
authors.affiliation: College of Pharmacy, Chonnam National University, Gwangju, Korea.
authors.forename: Kwonseop
authors.initials: K
authors.lastname: Kim
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Korea.
authors.forename: Keesook
authors.initials: K
authors.lastname: Lee
authors.affiliation: Genitourinary Cancer Branch, Research Institute of National Cancer Center, Goyang, Gyeonggi-do, Korea.
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
authors.forename: Silvio
authors.initials: S
authors.lastname: Hemmi
authors.affiliation: Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Joo
authors.affiliation: Department of Statistics, College of Natural Sciences, Chonnam National University, Gwangju, Korea.
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Chaeyong
authors.initials: C
authors.lastname: Jung
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000368:Aged; D000818:Animals; D018938:Caco-2 Cells; D046528:Chimerism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051916:Membrane Cofactor Protein / Q000096:biosynthesis*; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D023041:Xenograft Model Antitumor Assays
chemical_list: C497857:CD46 protein, human; D051916:Membrane Cofactor Protein
keywords: CD46; adenovirus; colorectal cancer; gene therapy