title: Historical perspective and recent insights into our understanding of the molecular and biochemical basis of the antitumor properties of mda-7/IL-24.
abstract: A subtraction hybridization approach combined with a differentiation therapy model of human melanoma identified melanoma differentiation associated gene-7 (mda-7) as a gene upregulated during induction of terminal differentiation. Based on conserved structure, chromosomal location and cytokine-like properties, mda-7, has now been classified as a member of the expanding interleukin (IL)-10 gene family and designated as mda-7/IL-24. Extensive in vitro and in vivo human tumor xenograft studies confirm that mda-7/IL-24 induces apoptosis specifically in tumor cells without harming normal cells. Unique properties of mda-7/IL-24 action also include potent "bystander antitumor" activity, an ability to exert anti-angiogenic effects, immune modulating ability and a capacity to enhance the sensitivity of tumor cells to radiotherapy, chemotherapy and monoclonal antibody therapy. Very recent studies from our groups further reveal autocrine regulation and chemoprevention facilitating properties of mda-7/IL-24. Based on these remarkable antitumor attributes, mda-7/IL-24 was evaluated by intratumoral injection with a replication incompetent adenovirus expressing this gene (Ad.mda-7; INGN 241) in a phase I clinical trial in patients with metastatic melanomas and other advanced solid cancers. mda-7/IL-24 was well tolerated with significant clinical activity. This review highlights our current understanding of the molecular and biochemical basis of mda-7/IL-24 antitumor properties and highlights its potential as a viable gene-based therapy for a wide spectrum of primary and advanced cancers.
authors.affiliation: Departments of Neurosurgery and Oncological Sciences, Mount Sinai School of Medicine, New York, NY, USA. Luni.Emdad@mountsinai.org
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.forename: Irina V
authors.initials: IV
authors.lastname: Lebedeva
authors.forename: Zhao-zhong
authors.initials: ZZ
authors.lastname: Su
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
authors.forename: Moira
authors.initials: M
authors.lastname: Sauane
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D017321:Clinical Trials, Phase I as Topic; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000502:physiology*; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008954:Models, Biological; D016896:Treatment Outcome; D000099180:Interleukin-24
chemical_list: D007378:Interleukins; D000099180:Interleukin-24