The development of MDA-7/IL-24 as a cancer therapeutic.
The cytokine melanoma differentiation associated gene 7 (mda-7) was identified by subtractive hybridization as a protein whose expression increased during the induction of terminal differentiation, and that was either not expressed or was present at low levels in tumor cells compared to non-transformed cells. Based on conserved structure, chromosomal location and cytokine-like properties, MDA-7, was classified as a member of the interleukin (IL)-10 gene family and designated as MDA-7/IL-24. Multiple studies have demonstrated that expression of MDA-7/IL-24 in a wide variety of tumor cell types, but not in corresponding equivalent non-transformed cells, causes their growth arrest and rapid cell death. In addition, MDA-7/IL-24 has been noted to radiosensitize tumor cells which in part is due to the generation of reactive oxygen species (ROS) and ceramide that cause endoplasmic reticulum stress and suppress protein translation. Phase I clinical trial data has shown that a recombinant adenovirus expressing MDA-7/IL-24 (Ad.mda-7 (INGN-241)) was safe and had measurable tumoricidal effects in over 40% of patients, strongly arguing that MDA-7/IL-24 could have significant therapeutic value. This review describes what is presently known about the impact of MDA-7/IL-24 on tumor cell biology and its potential therapeutic applications.
Dent
Paul
P
Department of Neurosurgery, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA. pdent@vcu.edu
Yacoub
Adly
A
Hamed
Hossein A
HA
Park
Margaret A
MA
Dash
Rupesh
R
Bhutia
Sujit K
SK
Sarkar
Devanand
D
Wang
Xiang-Yang
XY
Gupta
Pankaj
P
Emdad
Luni
L
Lebedeva
Irina V
IV
Sauane
Moira
M
Su
Zhao-zhong
ZZ
Rahmani
Mohamed
M
Broaddus
William C
WC
Young
Harold F
HF
Lesniak
Maciej S
MS
Grant
Steven
S
Curiel
David T
DT
Fisher
Paul B
PB
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D055808:Drug Discovery / Q000379:methods* / Q000639:trends; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000099180:Interleukin-24
D000970:Antineoplastic Agents; D007378:Interleukins; D000099180:Interleukin-24