Current Issue : October - December Volume : 2013 Issue Number : 4 Articles : 5 Articles
Anti-angiogenic and anti-lymphangiogenic gene therapy is a new potential method for the treatment of epithelial \r\novarian carcinoma. We studied the usefulness and feasibility of diffusion-weighted magnetic resonance imaging \r\n(DW-MRI) and relaxation measurements as surrogate markers of AdsVEGFR-2, AdsVEGFR-3, AdsNRP-1 and \r\nAdsNRP-2 gene therapy treatment responses in an intraperitoneal ovarian cancer mouse model (n= 40). Gene \r\ntherapy was also combined with paclitaxel and carboplatin chemotherapy. Gene therapy was performed when visible \r\ntumors were noticed in MRI. Adenoviral gene transfer was dosed intravenously (2Ã?â??109 pfu), while chemotherapy \r\nwas dosed intraperitoneally. The study groups were: AdLacZ as controls (group I); AdsVEGFR-2 and AdsVEGFR-3 \r\n(group II); combination of AdsVEGFR-2, AdsVEGFR-3 and chemotherapy (group III) and AdsNRP-1 and AdsNRP-2 \r\n(group IV). Antitumor effectiveness was assessed by sequential MRI, immunohistochemistry, microvessel density, \r\noverall tumor growth, formation of ascites and survival time. Early responses in tumor tissue were evaluated with \r\nMRI measurements using relaxation times T2\r\n, T1?, TRAFF2, TRAFF4 and water apparent diffusion coefficient (ADC). The \r\nmean survival of mice (30 days) was significantly prolonged in group II as compared to controls (24 days) or other \r\ntreatment groups (p= 0.003). Microvessel density (MVD) and total vascular area (TVA) were significantly lower \r\ncompared to controls in all groups: group II (p= 0.001), group III (p= 0.002), group IV (p= 0.026). T2\r\n relaxation times \r\nwere significantly increased at day 8 after the gene transfer in the combination gene therapy and chemotherapy \r\ngroup III compared to controls (p= 0.005). ADC values in the tumors were significantly increased in group IV at four \r\ndays compared to controls (p= 0.044). Early changes in T2\r\n relaxation times and ADC values after gene therapy \r\nsuggest the potential of T2\r\n relaxation time measurements and DW-MRI as early markers of treatment response after \r\nanti-angiogenic gene therapy and chemotherapy....
Gene therapy provides an efficient approach for treatment of cardiovascular disease. To realize the therapeutic\r\neffect, both efficient delivery to the target cells and sustained expression of transgenes are required. Ultrasound\r\ntargeted microbubble destruction (UTMD) technique has become a potential strategy for target-specific gene and\r\ndrug delivery. When gene-loaded microbubble is injected, the ultrasound-mediated microbubble destruction may\r\nspew the transported gene to the targeted cells or organ. Meanwhile, high amplitude oscillations of microbubbles\r\nincrease the permeability of capillary and cell membrane, facilitating uptake of the released gene into tissue and\r\ncell. Therefore, efficiency of gene therapy can be significantly improved. To date, UTMD has been successfully\r\ninvestigated in many diseases, and it has achieved outstanding progress in the last two decades. Herein, we discuss\r\nthe current status of gene therapy of cardiovascular diseases, and reviewed the progress of the delivery of genes to\r\ncardiovascular system by UTMD....
Methods for human skin gene therapy requires efficient and stable introduction of genes into skin cells. Transient\r\ncutaneous gene therapy is an attractive approach in the treatment of skin diseases. The ââ?¬Ë?Achilles heelââ?¬â?¢ of adenoviral\r\ngene therapy is its immunogenicity and many aspects of adenovirus induced cutaneous immune reaction still\r\nremain unanswered, particularly the role of keratinocytes. Therefore, human keratinocytes were transfected with\r\nadenoviral DNA and cytokine expression was analyzed. Moreover, adenoviral transduction of full-skin was\r\nperformed ex vivo and in vivo. We observed cytokine induction after cytoplasmatic internalization of adenoviral DNA\r\ninto epidermal cells. Inhibition of AIM2, NALP3, DAI or mda5 downregulated the cytokine response. Transduction of\r\nimmunocompetent mice led to a detectable transgene expression for 12 days. Re-application of the vector led to a\r\ndecrease in intensity and duration of transgene expression limited to 4 days and an increased cytokine expression.\r\nIn contrast, immunodeficient mice showed a reduced expression of cytokines after DNA internalization. AIM2,\r\nNALP3, DAI and mda5 are essential in the induction of an innate immune response towards adenoviral DNA. This\r\nimmune reaction leads to a decrease in transduction efficiency of the vector after re-application and modulation of\r\nthese receptor systems stabilizes transgene expression....
Background: One of the cardinal requirements for effective therapeutic management of tumors is the selective\r\ndelivery of cancer drugs to the right site by ligand-decorated nanomedicines. Screening of 2 Ã?â?? 109 clone landscape\r\nphage library provides a reliable avenue for generating protein ligands specific for tumor cells. It was shown that\r\nselective phage proteins derived from landscape phage libraries against breast and prostate cancer cells are able to\r\nnavigate drug or siRNA loaded liposomes to corresponding cancer cells with minimal toxicity to non-neoplastic\r\ncells. In an alternative platform, glioma cell-specific phage proteins were used for assembling in vivo cancer-specific\r\nphage-like particles, named ââ?¬Ë?phagemid infective particlesââ?¬â?¢ as targeted gene-delivery vehicles.\r\nMethods: To extend the panel of anticancer cell phages, we have screened a 2 Ã?â?? 109 clone landscape phage\r\nlibrary f8/8 to select phage clones specific for metastatic prostate cancer cell PC-3M. The phage clones were\r\ncharacterized for their selective interaction with PC-3M cells using phage capture assay, immunofluorescence\r\nmicroscopy and electron microscopy. A prostate cancer selective phage was converted to phage-like particles\r\nharboring emerald green fluorescent protein.\r\nResults: Phage clone EPTHSWAT (designated by the sequence of inserted peptide) was found to be most selective\r\nfor PC-3M cells and was observed to internalize PC-3M cells as revealed by immunofluorescence microscopy and\r\nelectron microscopy. Conversion of this phage to phage-like particles harboring emerald green fluorescent protein\r\nand the expression of emerald green fluorescent protein in the phage-like particles treated PC-3M cells showed\r\npotential of adoption of this phage-like particle in prostate cancer therapeutic gene delivery.\r\nConclusion: Successful employment of phage-like particles expressing emerald green fluorescent protein genes\r\ntargeted to prostate cancer cells PC-3M confirms a prospect of their use for targeted delivery of therapeutic genes\r\nto cancer cells....
Current cancer treatments may create profound iatrogenic outcomes. The adverse effects of these treatments still remain, as the serious problems that practicing physicians have to cope with in clinical practice. Although, non-specific cytotoxic agents constitute an effective treatment modality against cancer cells, they also tend to kill normal, quickly dividing cells. On the other hand, therapies targeting the genome of the tumors are both under investigation, and some others are already streamlined to clinical practice. Several approaches have been investigated in order to find a treatment targeting the cancer cells, while not affecting the normal cells. Suicide gene therapy is a therapeutic strategy, in which cell suicide inducing transgenes are introduced into cancer cells. The two major suicide gene therapeutic strategies currently pursued are: cytosine deaminase/5-fluorocytosine and the herpes simplex virus/ganciclovir. The novel strategies include silencing gene expression, expression of intracellular antibodies blocking cells' vital pathways, and transgenic expression of caspases and DNases. We analyze various elements of cancer cells' suicide inducing strategies including: targets, vectors, and mechanisms. These strategies have been extensively investigated in various types of cancers, while exploring multiple delivery routes including viruses, non-viral vectors, liposomes, nanoparticles, and stem cells. We discuss various stages of streamlining of the suicide gene therapy into clinical oncology as applied to different types of cancer. Moreover, suicide gene therapy is in the center of attention as a strategy preventing cancer from developing in patients participating in the clinical trials of regenerative medicine. In oncology, these clinical trials are aimed at regenerating, with the aid of stem cells, of the patients' organs damaged by pathologic and/or iatrogenic factors. However, the stem cells carry the risk of neoplasmic transformation. We discuss cell suicide inducing strategies aimed at preventing stem cell-originated cancerogenesis....
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