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Is mda-7/IL-24 a "Magic Bullet" for Cancer?

Departments of Pathology, Urology, and Neurosurgery, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York

Requests for reprints: Paul B. Fisher, Department of Pathology, Columbia University Medical Center, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. Phone: 212-305-3642; Fax: 212-305-8177; E-mail: pbf1{at}columbia.edu.

The "holy grail" of cancer therapy is to identify and exploit genetic elements and signal transduction pathways capable of selectively destroying tumor cells without eliciting harmful effects in normal cells or tissues. To achieve this objective, subtraction hybridization was combined with a "differentiation therapy" model of cancer in which human melanoma cells were induced to revert to a more "normal" state, growth arrest irreversibly, and terminally differentiate by treatment with fibroblast IFN and mezerein. This strategy permitted the cloning of a variety of genes involved in regulating important physiologic processes, including cell cycle, response to cytokines and viruses, tumorigenesis and metastasis, cancer growth control, apoptosis, and senescence. A specific gene, melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), displaying cancer-specific apoptosis-inducing properties isolated using this scheme has now come into the limelight as a new gene therapy for divergent cancers. Although the mechanism of cancer cell selectivity of mda-7/IL-24 remains to be delineated, numerous attributes enable this gene as an effective therapy for cancer, including an ability to discriminate between normal and cancer cells, induce apoptosis in diverse tumor cells, promote "bystander" antitumor effects, inhibit tumor growth and angiogenesis in animal models, synergize with radiation, and modulate immune responses. These unique features combined with successful transition into the clinic instill confidence that mda-7/IL-24, as a single or more likely as part of a combinatorial approach, may provide profound therapeutic benefit for cancer patients.

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