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."