"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-beta) 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.