Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors.

The knowledge on how tumor-associated stroma influences efficacy of anti-cancer therapy just started to emerge. Here we show that lung fibroblasts reduce melanoma sensitivity to the BRAF inhibitor (BRAFi) vemurafenib only if the two cell types are in close proximity. In the presence of fibroblasts, the adjacent melanoma cells acquire de-differentiated mesenchymal-like phenotype.

Targeting inhibitor of apoptosis proteins in combination with dacarbazine or TRAIL in melanoma cells.

Melanoma is a highly aggressive malignant tumor with an exceptional ability to develop resistance and no curative therapy is available for patients with distant metastatic disease. The inhibitor of apoptosis protein (IAP) family has been related to therapy resistance in cancer. We examined the importance of the IAPs in the resistance to the commonly used chemotherapeutic agent dacarbazine (DTIC) and the apoptosis inducer TRAIL (TNF-related apoptosis inducing ligand) in malignant melanoma.

Aldehyde dehydrogenase (ALDH) activity does not select for cells with enhanced aggressive properties in malignant melanoma.

Background: Malignant melanoma is an exceptionally aggressive, drug-resistant and heterogeneous cancer. Recently it has been shown that melanoma cells with high clonogenic and tumourigenic abilities are common, but markers distinguishing such cells from cells lacking these abilities have not been identified. There is therefore no definite evidence that an exclusive cell subpopulation, i.

Photochemical internalization: a new tool for drug delivery.

The utilisation of macromolecules in the therapy of cancer and other diseases is becoming increasingly important. Recent advances in molecular biology and biotechnology have made it possible to improve targeting and design of cytotoxic agents, DNA complexes and other macromolecules for clinical applications. In many cases the targets of macromolecular therapeutics are intracellular.

Combined treatment with Ad-hTRAIL and DTIC or SAHA is associated with increased mitochondrial-mediated apoptosis in human melanoma cell lines.

Background: Currently, dacarbazine (DTIC) is the only approved systemic treatment for metastatic malignant melanoma. However, the modest treatment effect encourages studies on novel therapeutic molecules, delivery systems and combination therapies. Full-length TRAIL, delivered from an adenoviral vector (Ad-hTRAIL), was studied in combination with DTIC or the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in human melanoma cell lines.

Photochemically mediated delivery of AdhCMV-TRAIL augments the TRAIL-induced apoptosis in colorectal cancer cell lines.

Tumor targeting is an important issue in cancer gene therapy. We have developed a light-specific transduction method, named photochemical internalization (PCI), to enhance gene expression from adenoviral vectors selectively in illuminated areas. Tumor necrosis factor related apoptosis inducing ligand (TRAIL) has been shown to induce apoptosis in cancer cells, and the aim of this study was to investigate the potential of PCI to enhance transgene expression from AdhCMV-TRAIL and evaluate its impact on apoptotic induction in the two human colorectal cancer cell lines HCT116 and WiDr.

Photochemically enhanced adenoviral transduction in a multicellular environment.

Photochemical internalization (PCI) enhances adenovirus (Ad) transgene expression in a variety of cell lines in vitro. However, measurements of the photochemical effect on transduction in multicellular environments are lacking. In this study, spheroids of DU 145 prostate cancer cells were used as a model to evaluate Ad serotype 5 (Ad5) transduction in a multicellular environment in response to PCI treatment.

Photochemical treatment with endosomally localized photosensitizers enhances the number of adenoviruses in the nucleus.

Background: In the present study the physical targeting technique photochemical internalization (PCI) has been used in combination with adenovirus. We have previously shown that PCI enhances transgene expression from AdhCMV-lacZ, and the aim of the present study was to further increase the understanding of photochemically mediated adenoviral transduction.

Methods: Two colorectal carcinoma cell lines, WiDr and HCT116, were pre-incubated with the photosensitizer TPPS(2a) or methylene blue derivates (MBD) followed by infection with adenovirus and light exposure.

Photochemically enhanced transduction of polymer-complexed adenovirus targeted to the epidermal growth factor receptor.

Background: The development of methods for specific delivery of genes into target tissues is an important issue for the further progress of gene therapy. Biological and physical targeting techniques may be combined to redirect gene therapy vectors to specific cells and enhance gene transfer.

Methods: The polymer poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA) was conjugated with avidin or poly(ethylene glycol) (PEG) and complexed with adenovirus serotype 5 (Ad5).

Melanoma-specific expression in first-generation adenoviral vectors in vitro and in vivo -- use of the human tyrosinase promoter with human enhancers.

Current treatment regimens for patients with metastatic melanoma are not curative, and new treatment strategies are needed. One possible approach is targeted treatment using the tyrosinase promoter for melanoma-specific expression of genes delivered by adenoviral (Ad) vectors. In this study, a vector with the human minimal tyrosinase promoter and two human enhancer elements (2hE-hTyrP) was compared with different hybrid promoter constructs, containing tyrosinase regulatory sequences and the viral simian virus 40 (SV40) promoter.

PCI-enhanced adenoviral transduction employs the known uptake mechanism of adenoviral particles.

The development of methods for efficient and specific delivery of therapeutic genes into target tissues is an important issue for further development of in vivo gene therapy. In the present study, the physical targeting technique, photochemical internalization (PCI), has been used together with adenovirus. The combination of PCI and adenoviral transduction has previously been shown to be favorable compared to adenovirus used alone, and the aim of this study was to verify the role of the adenoviral receptors and identify the uptake pathway used by adenoviral particles in photochemically treated cells.

Photochemical internalisation in drug and gene delivery.

This article reviews a novel technology, named photochemical internalisation (PCI), for light-induced delivery of genes, proteins and many other classes of therapeutic molecules. Degradation of macromolecules in endocytic vesicles after uptake by endocytosis is a major intracellular barrier for the therapeutic application of macromolecules having intracellular targets of action. PCI is based upon the light activation of a drug (a photosensitizer) specifically locating in the membrane of endocytic vesicle inducing the rupture of this membrane upon illumination.

Photochemical transfection: a technology for efficient light-directed gene delivery.

Most synthetic gene delivery vectors are taken up in the cell by endocytosis, and inefficient escape of the transgene from endocytic vesicles often is a major barrier for gene transfer by such vectors. To improve endosomal release we have developed a new technology, named photochemical internalization (PCI). PCI is based on photochemical reactions initiated by photosensitizing compounds localized in endocytic vesicles, inducing rupture of these vesicles upon light exposure.

Photochemically enhanced gene delivery with cationic lipid formulations.

Entrapment and degradation of transfecting DNA in endocytic vesicles often hampers the use of lipidic vectors for gene delivery purposes. Photochemical internalisation (PCI) is a technology for achieving light-induced release of DNA trapped inside these vesicles, and therefore represents a way of overcoming the endocytic membrane barrier and improving gene transfer. The technology is based on utilising photosensitizers which localise in the membranes of endocytic vesicles, causing photochemical damages that rupture the vesicles upon illumination.

Light-induced adenovirus gene transfer, an efficient and specific gene delivery technology for cancer gene therapy.

A main issue for further clinical progress of cancer gene therapy is to develop technologies for efficient and specific delivery of therapeutic genes to tumor cells. In this work, we describe a photochemical treatment that substantially improves gene delivery by adenovirus, one of the most efficient gene delivery vectors known. Transduction of two different cell lines was studied by microscopy, flow cytometry, and an enzymatic assay, employing a beta-galactosidase-encoding adenovirus.