title: MDA-7/IL-24 plus radiation enhance survival in animals with intracranial primary human GBM tumors.
abstract: Melanoma differentiation associated gene-7/interleukin 24 (mda-7/IL-24) is a cytokine displaying selective apoptosis-inducing activity in tumors, including glioblastoma (GBM), without damaging normal cells. The present studies focused on defining whether an adenovirus expressing MDA-7/IL-24, Ad.mda-7, infused into pre-formed invasive primary human GBM tumors growing in athymic mouse brains altered tumor cell growth and animal survival, and whether Ad.mda-7 radiosensitized GBM cells and enhanced the survival benefit of irradiation. Ad.mda-7 directly radiosensitized glioma cells in vitro in a JNK1-3- and caspase 9-dependent fashion and demonstrated bystander-effect killing and radiosensitization of GBM cells when primary human astrocytes were infected with Ad.mda-7. Infusion of Ad.mda-7 into pre-formed glioma tumors caused a rapid decrease in proliferation and blood vessel density and an increase in cell killing. Irradiation of Ad.mda-7 infected tumors enhanced cell death. Cell killing correlated with pro-caspase 3 cleavage, enhanced phosphorylation of JNK1-3 and reduced phosphorylation of ERK1/2. Ad.mda-7 enhanced the survival of animals implanted with GBM6 and GBM12 tumors, and significantly increased the survival benefit of irradiation in animals bearing GBM12 tumors. Ad.mda-7 toxicity was evident against CD133+ and CD133- GBM cells; upon tumor re-growth approximately 70-100 days after virus infusion, the relative CD133+ level within the tumor was profoundly reduced with lower Ki67 reactivity and increased beta-galactosidase staining. Infusion of Ad.mda-7 into an immune competent rat brain did not cause normal tissue toxicity 1-4 weeks after infusion using T1 and T2 weighted MRI and H&E staining. Our data demonstrate that Ad.mda-7 prolongs the survival of animals bearing GBM tumors and does so through multiple mechanisms including direct tumor cell killing and selection for surviving cells that are more differentiated and potentially displaying a putatively senescent phenotype.
authors: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298-0035, USA.
authors: Adly
authors: A
authors: Yacoub
authors: Hossein
authors: H
authors: Hamed
authors: Luni
authors: L
authors: Emdad
authors: Wagner
authors: W
authors: Dos Santos
authors: Pankaj
authors: P
authors: Gupta
authors: William C
authors: WC
authors: Broaddus
authors: Viswanathan
authors: V
authors: Ramakrishnan
authors: Devanand
authors: D
authors: Sarkar
authors: Khalid
authors: K
authors: Shah
authors: David T
authors: DT
authors: Curiel
authors: Steven
authors: S
authors: Grant
authors: Paul B
authors: PB
authors: Fisher
authors: Paul
authors: P
authors: Dent
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy*; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy*; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D007378:Interleukins / Q000235:genetics* / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System; D051379:Mice; D009368:Neoplasm Transplantation; D010455:Peptides; D013997:Time Factors; D016896:Treatment Outcome; D000099180:Interleukin-24
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D066246:ErbB Receptors; D006023:Glycoproteins; D007378:Interleukins; D010455:Peptides; D000099180:Interleukin-24; C000606023:PROM1 protein, human; C000606024:Prom1 protein, mouse; C000606025:Prom1 protein, rat