"Differentiation therapy" provides a unique and potentially effective, less toxic treatment paradigm for cancer. Moreover, combining "differentiation therapy" with molecular approaches presents an unparalleled opportunity to identify and clone genes mediating cancer growth control, differentiation, senescence, and programmed cell death (apoptosis). Subtraction hybridization applied to human melanoma cells induced to terminally differentiate by treatment with fibroblast interferon (IFN-β) plus mezerein (MEZ) permitted cloning of melanoma differentiation associated (mda) genes. Founded on its novel properties, one particular mda gene, mda-7, now classified as a member of the interleukin (IL)-10 gene family (IL-24) because of conserved structure, chromosomal location, and cytokine-like properties has become the focus of attention of multiple laboratories. When administered by transfection or adenovirus-transduction into a spectrum of tumor cell types, melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) induces apoptosis, whereas no toxicity is apparent in normal cells. mda-7/IL-24 displays potent "bystander antitumor" activity and also has the capacity to enhance radiation lethality, to induce immune-regulatory activities, and to inhibit tumor angiogenesis. Based on these remarkable attributes and effective antitumor therapy in animal models, this cytokine has taken the important step of entering the clinic. In a Phase I clinical trial, intratumoral injections of adenovirus-administered mda-7/IL-24 (Ad.mda-7) was safe, elicited tumor-regulatory and immune-activating processes, and provided clinically significant activity. This review highlights our current understanding of the diverse activities and properties of this novel cytokine, with potential to become a prominent gene therapy for cancer.
Bibliographical noteFunding Information:
We are indebted to our numerous colleagues who have contributed to our understanding of mda-7 /IL-24. The present studies were supported in part by National Institutes of Health grants CA35675, CA097318, CA098712, and P01 CA104177 to PBF; National Institutes of Health grants DK52825, CA88906, CA72955, CA108520, and P01 CA104177 to PD; National Institutes of Health Grant CA083821, CA094084, CA93796, CA111569, and P01 CA104177 to DTC; National Institutes of Health Grant CA63753, CA93738, and CA100866 to SG; Department of Defense grant DAMD17-03-1-0262 to PD; Department of Defense grant DAMD 17-03-1-0209 to SG; Department of Defense grant W81XWH-05-1-0035 to DTC; Department of Defense Army Postdoctoral Fellowships (DS and MS); the Leukemia and Lymphoma Society 6045-03 to SG; the Lustgarten Foundation for Pancreatic Cancer Research (PBF); the Samuel Waxman Cancer Research Foundation (PBF); and the Chernow Endowment (PBF). PBF is the Michael and Stella Chernow Urological Cancer Research Scientist and an SWCRF Investigator. PD is a Universal Leaf Professor in Cell Signaling.
- Antitumor bystander activity
- Cell signaling
- Differentiation therapy of cancer
- Phase I clinical trial
- Programmed cell death