title: Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) in combination with the Apogossypol derivative BI-97C1 (Sabutoclax) improves therapeutic efficacy in low CAR colorectal cancer cells.
abstract: Adenovirus (Ad)-based gene therapy represents a potentially viable strategy for treating colorectal cancer. The infectivity of serotype 5 adenovirus (Ad.5), routinely used as a transgene delivery vector, is dependent on Coxsackie-adenovirus receptors (CAR). CAR expression is downregulated in many cancers thus preventing optimum therapeutic efficiency of Ad.5-based therapies. To overcome the low CAR problem, a serotype chimerism approach was used to generate a recombinant Ad (Ad.5/3) that is capable of infecting cancer cells via Ad.3 receptors in a CAR-independent manner. We evaluated the improved transgene delivery and efficacy of Ad.5/3 recombinant virus expressing melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), an effective wide-spectrum cancer-selective therapeutic. In low CAR human colorectal cancer cells RKO, wild-type Ad.5 virus expressing mda-7/IL-24 (Ad.5-mda-7) failed to infect efficiently resulting in lack of expression of MDA-7/IL-24 or induction of apoptosis. However, a recombinant Ad.5/3 virus expressing mda-7/IL-24 (Ad.5/3-mda-7) efficiently infected RKO cells resulting in higher MDA-7/IL-24 expression and inhibition of cell growth both in vitro and in nude mice xenograft models. Addition of the novel Bcl-2 family pharmacological inhibitor Apogossypol derivative BI-97C1 (Sabutoclax) significantly augmented the efficacy of Ad.5/3-mda-7. A combination regimen of suboptimal doses of Ad.5/3-mda-7 and BI-97C1 profoundly enhanced cytotoxicity in RKO cells both in vitro and in vivo. Considering the fact that Ad.5-mda-7 has demonstrated significant objective responses in a Phase I clinical trial for advanced solid tumors, Ad.5/3-mda-7 alone or in combination with BI-97C1 would be predicted to exert significantly improved therapeutic efficacy in colorectal cancer patients.
authors.affiliation: Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Belal
authors.initials: B
authors.lastname: Azab
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Sujit K
authors.initials: SK
authors.lastname: Bhutia
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Shen
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Quinn
authors.forename: Siddik
authors.initials: S
authors.lastname: Sarkar
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Hedvat
authors.forename: Igor P
authors.initials: IP
authors.lastname: Dmitriev
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004357:Drug Synergism; D018014:Gene Transfer Techniques; D006072:Gossypol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D000099180:Interleukin-24
chemical_list: D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D006072:Gossypol; D007378:Interleukins; D011991:Receptors, Virus; D000099180:Interleukin-24; C550162:1,1',6,6',7,7'-hexahydroxy-3,3'-dimethyl-N5-(2-phenylpropyl)-N5'-(2-phenylpropyl)-2,2'-binaphthyl-5,5'-dicarboxamide; C568771:CLMP protein, human; C568772:CLMP protein, mouse; C492806:apogossypol