Historical perspective and recent insights into our understanding of the molecular and biochemical basis of the antitumor properties of mda-7/IL-24

Abstract

A subtraction hybridization approach combined with a differentiation therapy model of human melanoma identified melanoma differentiation associated gene-7 (mda-7) as a gene upregulated during induction of terminal differentiation. Based on conserved structure, chromosomal location and cytokine-like properties, mda-7, has now been classified as a member of the expanding interleukin (IL)-10 gene family and designated as mda-7/IL-24. Extensive in vitro and in vivo human tumor xenograft studies confirm that mda-7/IL-24 induces apoptosis specifically in tumor cells without harming normal cells. Unique properties of mda-7/IL-24 action also include potent "bystander antitumor" activity, an ability to exert anti-angiogenic effects, immune modulating ability and a capacity to enhance the sensitivity of tumor cells to radiotherapy, chemotherapy and monoclonal antibody therapy. Very recent studies from our groups further reveal autocrine regulation and chemoprevention facilitating properties of mda-7/IL-24. Based on these remarkable antitumor attributes, mda-7/IL-24 was evaluated by intratumoral injection with a replication incompetent adenovirus expressing this gene (Ad.mda-7; INGN 241) in a phase I clinical trial in patients with metastatic melanomas and other advanced solid cancers. mda-7/IL-24 was well tolerated with significant clinical activity. This review highlights our current understanding of the molecular and biochemical basis of mda-7/IL-24 antitumor properties and highlights its potential as a viable gene-based therapy for a wide spectrum of primary and advanced cancers.

Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) improves therapeutic efficacy in low CAR prostate cancer cells

“…[16][17][18] To engender an optimum therapeutic response using mda-7/IL-24, defining ways of ensuring efficient delivery of the molecule to the target cancer tissue would be helpful. By permitting virus entry in a CAR-independent manner, Ad.5/3 removes one important roadblock to effective in vivo delivery of therapeutic viruses.…”

“…[12][13][14][15][16][17] Forced expression of mda-7/IL-24, using Ad.5 (Ad.5-mda-7), inhibits growth and kills a broad spectrum of established cancer cell lines in vitro, without exerting injurious effects in multiple types of normal human epithelial cells, fibroblasts, melanocytes or astrocytes. [16][17][18][19][20][21] Considering its robust cancer-specific apoptosis-inducing ability (by inducing endoplasmic reticulum stress) and tumor growth-suppressing properties in nude mice human tumor xenograft models, Ad.mda-7 (INGN 241) was evaluated in a phase I clinical trial in patients with advanced cancers. The results obtained from this trial demonstrate both safety and clinical efficacy.…”

Towards novel paradigms for cancer therapy

“…Interestingly, phase I clinical trials using mda-7 as single agent for the treatment of malignant melanoma demonstrated significant activity and good tolerability (Lebedeva et al, 2007;Eager et al, 2008;Emdad et al, 2009) (Table 1). However, it has been observed that subsets of tumor cells are either inheritably resistant to mda-7 or can acquire resistance upon exposure to the cytokine.…”

Novel oncolytic adenovirus sensitizes renal cell carcinoma cells to radiotherapy via mitochondrial apoptotic cell death

“…has been demonstrated to suppress growth and induce apoptosis in a wide range of human cancer types without apparent cytotoxicity to normal cells (4). Recent studies have shown that IL-24 radiosensitizes various cancer cells, including non-small cell lung carcinoma, renal carcinoma and malignant glioma cells (5).…”