title: Melanoma differentiation associated gene-7, mda-7/IL-24, selectively induces growth suppression, apoptosis and radiosensitization in malignant gliomas in a p53-independent manner.
abstract: Malignant gliomas are extremely aggressive cancers currently lacking effective treatment modalities. Gene therapy represents a promising approach for this disease. A requisite component for improving gene-based therapies of brain cancer includes tumor suppressor genes that exhibit cancer constrained inhibitory activity. Subtraction hybridization identified melanoma differentiation associated gene-7 (mda-7) as a gene associated with melanoma cell growth, differentiation and progression. Ectopic expression of mda-7 by means of a replication-incompetent adenovirus (Ad), Ad.mda-7, induces growth suppression and apoptosis selectively in diverse human cancers, without producing any apparent harmful effect in normal cells. We presently demonstrate that Ad.mda-7 induces growth inhibition and apoptosis in malignant human gliomas expressing both mutant and wild-type p53, and these effects correlate with an elevation in expression of members of the growth arrest and DNA damage (GADD) gene family. In contrast, infection with a recombinant Ad expressing wild-type p53, Ad.wtp53, specifically affects mutant p53 expressing gliomas. When tested in early passage normal and immortal human fetal astrocytes, growth inhibition resulting from infection with Ad.mda-7 or Ad.wtp53 is significantly less than in malignant gliomas and no toxicity is evident in these normal cells. Moreover, infection of gliomas with Ad.mda-7 or treatment with purified GST-MDA-7 protein sensitizes both wild-type and mutant p53 expressing tumor cells to the growth inhibitory and antisurvival effects of ionizing radiation, and this response correlates with increased expression of specific members of the GADD gene family. Since heterogeneity in p53 expression is common in evolving gliomas, the present findings suggest that Ad.mda-7 may, in many instances, prove more beneficial for the gene-based therapy of malignant gliomas than administration of wild-type p53.
authors.affiliation: Department of Pathology, Columbia university, College of Physicians and Surgeons, New York , NY 10032, USA.
authors.forename: Zao-Zhong
authors.initials: ZZ
authors.lastname: Su
authors.forename: Irina V
authors.initials: IV
authors.lastname: Lebedeva
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Rahul V
authors.initials: RV
authors.lastname: Gopalkrishnan
authors.forename: Moira
authors.initials: M
authors.lastname: Sauane
authors.forename: Carter
authors.initials: C
authors.lastname: Sigmon
authors.forename: Adly
authors.initials: A
authors.lastname: Yacoub
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Valerie
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D001253:Astrocytes / Q000166:cytology* / Q000528:radiation effects; D001932:Brain Neoplasms / Q000473:pathology* / Q000628:therapy; D002455:Cell Division / Q000528:radiation effects; D002461:Cell Line, Transformed / Q000166:cytology / Q000528:radiation effects; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004249:DNA Damage; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000494:pharmacology; D005910:Glioma / Q000473:pathology* / Q000628:therapy; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000502:physiology*; D011836:Radiation Tolerance / Q000235:genetics; D011991:Receptors, Virus / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D000099180:Interleukin-24
chemical_list: D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D007378:Interleukins; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D000099180:Interleukin-24; C568771:CLMP protein, human