Differentiation therapy of human cancer: basic science and clinical applications

Expression analysis and genomic characterization of human melanoma differentiation associated gene-5, mda-5: a novel type I interferon-responsive apoptosis-inducing gene

“…IFNs elicit diverse cell-type-specific responses, including growth inhibition, differentiation and apoptosis, which are frequently exploited in cancer treatment (Fisher and Grant, 1985;Stark et al, 1998;Barber, 2001). Various IFNs have been used as cancer therapeutics alone and in combination with other chemotherapeutics, including etoposide and tamoxifen, for diverse cancers, including melanoma, breast cancer, osteosarcoma and glioblastoma (Packer et al, 1991;Jia et al, 1999;Lindner et al, 2000;Leszczyniecka et al, 2001). However, the efficacy of IFNs as cancer therapeutics has been shown to vary widely depending on cancer type and genetic background (Sangfelt and Strander, 2001).…”

“…The conserved genomic and protein structure of mda-5 in human and mouse will permit Introduction Differentiation therapy of cancer is based on the hypothesis that transformed tumor cells are derived from normal cells displaying defects in their ability to terminally differentiate thereby resulting in a loss of normal growth control mechanisms (Jiang et al, 1994;Fusenig et al, 1995;Scott, 1997;Garattini and Terao, 2001;Lotem and Sachs, 2002). A logical extension of this concept is that cancer cells can be induced to differentiate by suitable treatment to reactivate endogenous growth control mechanisms, which in a mutated and genetically damaged cancer cell context can culminate in apoptosis Leszczyniecka et al, 2001). This possibility has been addressed experimentally utilizing various model systems with the capacity to undergo in vitro differentiation (Lovat et al, 1997;Petersen et al, 1998;Wang and Chen, 2000;Leszczyniecka et al, 2001).…”

“…A logical extension of this concept is that cancer cells can be induced to differentiate by suitable treatment to reactivate endogenous growth control mechanisms, which in a mutated and genetically damaged cancer cell context can culminate in apoptosis Leszczyniecka et al, 2001). This possibility has been addressed experimentally utilizing various model systems with the capacity to undergo in vitro differentiation (Lovat et al, 1997;Petersen et al, 1998;Wang and Chen, 2000;Leszczyniecka et al, 2001). Analysis of gene expression changes in differentiation therapy models provides a powerful experimental tool for delineating and understanding biochemical and molecular events mediating growth arrest of transformed cells Huang et al, 1999a, b;Jiang et al, 2000;Zhang et al, 2000).…”

Insights from pre-clinical studies for new combination treatment regimens with the Bcr-Abl kinase inhibitor imatinib mesylate (Gleevec/Glivec) in chronic myelogenous leukemia: a translational perspective

“…Several recent review articles summarize information about new anti-leukemic agents that translate insights from basic science into clinical application. [48][49][50][51][52] Here we focus on in vitro data for combinations of novel agents with imatinib. In particular, we emphasize novel combinations which are moving towards phase I/II clinical studies.…”

Activation of Ras/Raf protects cells from melanoma differentiation-associated gene-5-induced apoptosis

“…[1][2][3] Melanoma differentiation-associated gene-5 (mda-5) was initially identified by subtraction hybridization as an upregulated transcript in terminally differentiated HO-1 human melanoma cells. 3,4 The encoded MDA-5 protein was recognized as the first molecule with a unique structural combination: an N-terminal caspase recruitment domain (CARD) and a C-terminal putative RNA helicase domain.…”