mda-7/IL-24: multifunctional cancer-specific apoptosis-inducing cytokine.
"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.
Gupta
Pankaj
P
Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, United States.
Su
Zao-zhong
ZZ
Lebedeva
Irina V
IV
Sarkar
Devanand
D
Sauane
Moira
M
Emdad
Luni
L
Bachelor
Michael A
MA
Grant
Steven
S
Curiel
David T
DT
Dent
Paul
P
Fisher
Paul B
PB
D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D004249:DNA Damage; D006801:Humans; D007378:Interleukins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D008545:Melanoma / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D015398:Signal Transduction; D051176:beta Catenin / Q000502:physiology; D019892:eIF-2 Kinase / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology; D000099180:Interleukin-24
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007378:Interleukins; D019869:Phosphatidylinositol 3-Kinases; D051176:beta Catenin; D019892:eIF-2 Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D000099180:Interleukin-24