Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24): Novel gene therapeutic for metastatic melanoma

Journal Article · Thu Nov 01 04:00:00 EDT 2007 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2006.11.021· OSTI ID:21077840

Fisher, Paul B ^[1]; Sarkar, Devanand; Lebedeva, Irina V ^[1]; Emdad, Luni ^[1]; Gupta, Pankaj; Sauane, Moira; Zaozhong, Su ^[1]; Grant, Steven ^[2]; Dent, Paul ^[3]; Curiel, David T ^[4]; Senzer, Neil; Nemunaitis, John ^[5]

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1. Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10032 (United States)
2. Department of Medicine, Virginia Commonwealth University, Richmond, VA 23284 (United States)
3. Department of Biochemistry, Virginia Commonwealth University, Richmond, VA 23284 (United States)
4. Division of Human Gene Therapy, Departments of Medicine Pathology and Surgery, University of Alabama, Birmingham, AL 35294 (United States)
5. Mary Crowley Research Center, Dallas, TX 75246 (United States)

A potentially less toxic approach for cancer therapy comprises induction of tumor cells to lose growth potential irreversibly and terminally differentiate. Combining this scheme termed 'differentiation therapy of cancer' with subtraction hybridization to human melanoma cells resulted in the cloning of melanoma differentiation associated (mda) genes displaying elevated expression as a consequence of induction of terminal differentiation. One originally novel gene, mda-7, was found to display elevated expression in normal melanocytes and nevi with progressive loss of expression as a consequence of melanoma development and progression to metastasis. Based on structure, biochemical properties and chromosomal location, mda-7 has now been reclassified as interleukin (IL)-24, a member of the expanding IL-10 family of cytokines. In vitro cell culture and in vivo animal studies indicate that mda-7/IL-24 selectively induces programmed cell death (apoptosis) in multiple human cancers (including melanomas), without harming normal cells, and promotes profound anti-tumor activity in nude mice containing human tumor xenografts. Based on these remarkable properties, a Phase I clinical trial was conducted to test the safety of administration of mda-7/IL-24 by a replication incompetent adenovirus (Ad.mda-7; INGN 241) in patients with advanced solid cancers including melanoma. mda-7/IL-24 was found to be safe and to promote significant clinical activity, particularly in the context of patients with metastatic melanoma. These results provide an impetus for further clinical studies and document a central paradigm of cancer therapy, namely translation of basic science from the 'bench to the bedside.'.

• OSTI ID: 21077840
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 224; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ADENOVIRUS
APOPTOSIS
CELL CULTURES
CLINICAL TRIALS
CLONING
GENES
HYBRIDIZATION
IN VITRO
IN VIVO
LYMPHOKINES
MELANIN
MELANOMAS
METASTASES
MICE
PATIENTS
THERAPY
TOXICITY
TUMOR CELLS