title: mda-7/IL-24, novel anticancer cytokine: focus on bystander antitumor, radiosensitization and antiangiogenic properties and overview of the phase I clinical experience (Review).
abstract: Subtraction hybridization applied to a 'differentiation therapy' model of cancer employing human melanoma cells resulted in the cloning of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24). Initial studies confirm an inverse correlation between mda-7 expression and melanoma development and progression. Forced expression of mda-7 by means of a plasmid or via a replication incompetent adenovirus (Ad.mda-7) promotes growth suppression and induces apoptosis in a broad array of human cancers. In contrast, mda-7 does not induce growth suppressive or toxic effects in normal cells. Based on structure (containing an IL-10 signature motif), secretion by cells (including subsets of T-cells) and location on chromosome 1q (in an area containing IL-10-family genes), mda-7 has now been renamed mda-7/IL-24. Studies by several laboratories have uncovered many of mda-7/IL-24's unique properties, including cancer-specific apoptosis-induction, cell cycle regulation, an ability to inhibit angiogenesis, potent 'bystander antitumor activity' and a capacity to enhance the sensitivity of tumor cells to radiation, chemotherapy and monoclonal antibody therapy. Moreover, based on its profound cancer tropism, substantiated by in vivo human xenograft studies in nude mice, mda-7/IL-24 (administered as Ad.mda-7) was evaluated in a phase I clinical trial in patients with melanomas and solid cancers. These studies document that mda-7/IL-24 is well tolerated and demonstrates evidence of significant clinical activity. In these contexts, mda-7/IL-24 represents a unique cytokine gene with potential for therapy of human cancers. The present review focuses on three unique properties of mda-7/IL-24, namely its potent 'bystander antitumor activity', ability to sensitize tumor cells to radiation, and its antiangiogenesis properties. Additionally, an overview of the phase I clinical trial is provided. These studies affirm that mda-7/IL-24 has promise for the management of diverse cancers.
authors.affiliation: Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Lebedeva
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authors.lastname: Sauane
authors.forename: Devanand
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authors.lastname: Sarkar
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Staudt
authors.forename: Shi-Jian
authors.initials: SJ
authors.lastname: Liu
authors.forename: Mohiuddin M
authors.initials: MM
authors.lastname: Taher
authors.forename: Ruoyu
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authors.lastname: Xiao
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authors.lastname: Barral
authors.forename: Seok-Geun
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authors.lastname: Lee
authors.forename: Dongning
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authors.lastname: Wang
authors.forename: Nicollaq
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authors.lastname: Vozhilla
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Park
authors.forename: Lejuan
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authors.lastname: Chatman
authors.forename: Habib
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authors.lastname: Boukerche
authors.forename: Rajagopal
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authors.lastname: Ramesh
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Sunil
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authors.lastname: Chada
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Anthony L
authors.initials: AL
authors.lastname: De Pass
authors.forename: Parameshwar J
authors.initials: PJ
authors.lastname: Mahasreshti
authors.forename: Igor P
authors.initials: IP
authors.lastname: Dmitriev
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Adly
authors.initials: A
authors.lastname: Yacoub
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Neil
authors.initials: N
authors.lastname: Senzer
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authors.initials: JJ
authors.lastname: Nemunaitis
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authors.lastname: Fisher
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D009361:Neoplasm Invasiveness; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D019076:Transgenes; D000099180:Interleukin-24
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007378:Interleukins; D011838:Radiation-Sensitizing Agents; D000099180:Interleukin-24