mda-7/IL-24, a novel cancer selective apoptosis inducing cytokine gene: from the laboratory into the clinic.

Paul B. Fisher, Rahul V. Gopalkrishnan, Sunil Chada, Rajagopal Ramesh, Elizabeth A. Grimm, Myrna R. Rosenfeld, David T. Curiel, Paul Dent

Research output: Contribution to journalReview article

143 Scopus citations

Abstract

An obstacle to effective gene-based cancer therapies is the limited number of cancer-specific growth suppressing and apoptosis-inducing genes. Using a differentiation induction subtraction hybridization (DISH) approach with human melanoma cells, melanoma differentiation associated (mda) genes were isolated that display elevated expression as a function of irreversible growth arrest, cancer reversion and terminal differentiation. This screening paradigm resulted in the cloning of mda-7 in the context of terminal differentiation of human melanoma cells. Based on its structure, chromosomal location, sequence homology and cytokine-like properties, mda-7 has now been renamed IL-24 and classified as a member of the expanding IL-10 cytokine gene family. Expression of mda-7/IL-24 inversely correlates with melanoma progression and administration of mda-7/IL-24 by means of a replication incompetent adenovirus, Ad.mda-7, results in growth suppression and apoptosis in melanoma cells as well as in a broad-spectrum of additional cancer cell types. In contrast, Ad.mda-7 does not elicit deleterious effects in normal cells, including those of epithelial, fibroblast, astrocyte, melanocyte or endothelial origin. Based on these distinctive properties and anti-tumor and anti-angiogenic activities in human tumor xenograft animal models, mda-7/IL-24 has now entered the clinical arena. A Phase I/II clinical trial in patients with advanced carcinomas involving intratumoral administration of mda-7/IL-24 [using a replication incompetent adenovirus; ING241 (Ad.mda-7)] has documented that this gene is safe and well tolerated by patients and a single virus injection elicits apoptosis in a majority of the tumor. Current data suggests that mda-7/IL-24 may function as a dual-acting cytokine in which its normal physiological functions may be related to specific aspects of the immune system and over-expression culminates in cancer-specific apoptosis. This review will provide a prospectus of our current understanding of mda-7/IL-24.

Original languageEnglish
Pages (from-to)S23-37
JournalCancer biology & therapy
Volume2
Issue number4 Suppl 1
StatePublished - Jan 1 2003
Externally publishedYes

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    Fisher, P. B., Gopalkrishnan, R. V., Chada, S., Ramesh, R., Grimm, E. A., Rosenfeld, M. R., Curiel, D. T., & Dent, P. (2003). mda-7/IL-24, a novel cancer selective apoptosis inducing cytokine gene: from the laboratory into the clinic. Cancer biology & therapy, 2(4 Suppl 1), S23-37.