MIA (melanoma inhibitory activity) promoter mediated tissue-specific suicide gene therapy of malignant melanoma

Abstract

Suicide gene therapy of malignant melanoma essentially requires efficient gene transfer and highly selective therapeutic gene expression. To achieve this, recombinant adeno-associated virus (rAAV) particles were constructed containing the tissue-specific promoter of the human melanoma inhibitory activity (hMIA) gene combined with four copies of the enhancer element of the murine tyrosinase gene. Three melanoma and one cervix carcinoma cell line were infected with rAAV particles carrying a reporter gene under control of the enhancer/hMIA promoter in order to determine transcriptional activity and specificity of this system. Viral particles containing the enhancer/hMIA promoter mediated reporter gene activity only in melanoma cells, whereas infection with a cytomegalovirus (CMV)-based promoter construct induced unspecific gene expression. Correspondingly, transient transduction with viral particles bearing the HSVtk gene under the control of the enhancer/MIA promoter elements followed by treatment with ganciclovir (GCV) resulted in growth inhibition only in melanoma cells, whereas the CMV promoter-based construct induced unspecific cytotoxicity. In vivo experiments in nude mice demonstrated that tumors originating from human melanoma cells disappeared after stable, but not transient transduction with vectors bearing the HSVtk gene under the control of the enhancer/hMIA promoter in response to GCV application. In face of higher transduction efficiency, these rAAV particles might therefore be a useful tool for suicide gene therapy of malignant melanoma.

Treatment of human disease by adeno-associated viral gene transfer

“…For instance, selective killing of hepatocellular carcinoma cells with gancyclovir was reported with AAV-2 vectors when HSV-tk expression was controlled by an albumin/alphafetoprotein hybrid promoter (Su et al 1996(Su et al , 1997. Similarly, tumor-selective cytotoxicity was reported for melanoma tumor cells with AAV2-HSVtk expression controlled by the melanoma inhibitory activity promoter (Schoensiegel et al 2004). Transcriptional targeting of tumor cells based on higher levels of glucose metabolism is a related approach that can achieve proliferating tumor cell selective killing with AAV2-HSVtk therapy.…”

Targeted gene therapy of the HSV-TK/hIL-12 fusion gene controlled by the hSLPI gene promoter of human non-small cell lung cancer in�vitro

“…The cytomegalovirus (CMV) promoter is frequently used in tumor gene therapy due to its efficient transcription activity in mammalian cells; however, its lack of tumor specificity is a limitation (16,17). In vivo host cells transfected with the CMV promoter can be killed using the metabolites of precursor drugs, which have side effects in normal tissues (16,17); therefore, further studies are required in order to understand how to improve the specificity of the TK gene, thus reducing the side effects.…”

“…In vivo host cells transfected with the CMV promoter can be killed using the metabolites of precursor drugs, which have side effects in normal tissues (16,17); therefore, further studies are required in order to understand how to improve the specificity of the TK gene, thus reducing the side effects.…”

Reactive Oxygen Species in the Biology of Melanoma

“…One major strategy of gene therapy to provide effective and specific activation of medical products inside the tumour mass implicates the control of the therapeutic agent activity by a Tumour Specific Promoter (TSP). TSPs corresponding to genes differentially activated in cancer cells have been used to control viral replication inside the tumour or the antitumour activity of therapeutic genes in melanoma (Cao et al, 1999;Diaz et al, 1998;Schoensiegel et al, 2004). Selection of a TSP is central for the design of a well defined medical product for gene transfer.…”