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 apoptosisinduction, cell cycle regulation, an ability to inhibit angiogenesis, potent ‘bystander antitumor activity’ and a capacity to enhance the sensitivity of tumor cells to radiation, chemo-
therapy 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.
LEBEDEVA, IRINA V.; EMDAD, LUNI; SU, ZAO-ZHONG; GUPTA, PANKAJ; SAUANE, MOIRA; SARKAR, DEVANAND; STAUDT, MICHELLE R.; LIU, SHI-JIAN; TAHER, MOHIUDDIN M.; XIAO, RUOYU; BARRAL, PAOLA; LEE, SEOK-GEUN; WANG, DONGNING; VOZHILLA, NICOLLAQ; PARK, EUN SOOK; CHATMAN, LEJUAN; BOUKERCHE, HABIB; RAMESH, RAJAGOPAL; INOUE, SATOSHI; CHADA, SUNIL; LI, RONG; DE PASS, ANTHONY L.; MAHASRESHTI, PARAMESHWAR J.; DMITRIEV, IGOR P.; CURIEL, DAVID T.; YACOUB, ADLY; GRANT, STEVEN; DENT, PAUL; SENZER, NEIL; NEMUNAITIS, JOHN J.; and FISHER, PAUL B., "mda-7/IL-24, novel anticancer cytokine: Focus on bystander antitumor, radiosensitization and antiangiogenic properties and overview of the phase I clinical experience (Review)" (2007). CUNY Academic Works.