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

Paul B. Fisher, Devanand Sarkar, Irina V. Lebedeva, Luni Emdad, Pankaj Gupta, Moira Sauane, Zao zhong Su, Steven Grant, Paul Dent, David T. Curiel, Neil Senzer, John Nemunaitis

Research output: Contribution to journalReview article

71 Scopus citations

Abstract

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.".

Original languageEnglish
Pages (from-to)300-307
Number of pages8
JournalToxicology and Applied Pharmacology
Volume224
Issue number3
DOIs
StatePublished - Nov 1 2007
Externally publishedYes

Keywords

  • Apoptosis
  • Metastatic melanoma
  • Phase I clinical trial
  • mda-7/IL-24

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    Fisher, P. B., Sarkar, D., Lebedeva, I. V., Emdad, L., Gupta, P., Sauane, M., Su, Z. Z., Grant, S., Dent, P., Curiel, D. T., Senzer, N., & Nemunaitis, J. (2007). Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24): Novel gene therapeutic for metastatic melanoma. Toxicology and Applied Pharmacology, 224(3), 300-307. https://doi.org/10.1016/j.taap.2006.11.021