New prospectives of prostate cancer gene therapy: molecular targets and animal models.

Prostate cancer is the most common cancer and the second leading cause of cancer-related death among North American men. The low cure rate for prostate cancer is associated with the fact that many patients have metastatic disease at the time of disease presentation. Currently available therapeutic modalities for prostate cancer, such as surgery, radiation, hormone therapy, and chemotherapy, have failed to cure patients because these therapies are not sufficiently tumor-specific, resulting in dose-limiting toxicity. Therefore, gene therapy may offer great promise in this regard. In this article, we summarize current advances in gene therapy technologies for the treatment of cancer in general, and future prospects for treatment of human prostate cancer metastasis. We specifically emphasize current studies for improvement, both in the efficiency and the specificity of viral and nonviral vectors, and restricted transgene expression in tumors, to achieve selective targeting with minimized host organ toxicity, based on the molecular understanding of potential regulatory differences between normal and tumor cells. Cell and animal models used to study prostate cancer growth, invasion, and metastasis, and their usefulness in preclinical evaluation of therapeutic vectors in the treatment of prostate cancer skeletal metastasis are also discussed.

Peripheral nerve regeneration using silicone rubber chambers filled with collagen, laminin and fibronectin.

A 10 mm gap of rat sciatic nerve was created between the proximal and distal nerve stumps, which were sutured into silicone rubber tubes filled with an extracellular gel containing collagen, laminin and fibronectin. Empty silicone rubber tubes were used as controls. Six weeks after implantation, all extracellular elements were completely degraded and absorbed, and 90% of the animals from the extracellular gel group exhibited regeneration across the nerve gaps, whereas only 60% in the control group. Both qualitative and quantitative histology of the regenerated nerves revealed a more mature ultrastructural organization with 28% larger cross-sectional area and 28% higher number of myelinated axons in the extracellular gel group than the controls. These results showed that the gel mixture of collagen, laminin and fibronectin could offer a suitable growth medium for the regeneration of axons.

Effect of acupuncture stimulation on peripheral nerve regeneration using silicone rubber chambers.

The purpose of this study was to determine whether acupuncture could affect the regeneration of a 10-mm gap of rat sciatic nerve created between the proximal and distal nerve stumps, which were sutured into silicone rubber tubes. Empty silicone rubber tubes with no further treatment were used as controls. Six weeks after implantation, the animals received the acupuncture or the electroneedling treatment exhibited a more mature ultrastructural nerve organization with significantly higher numbers in the axon density, the blood vessel area, and the percentage of blood vessel area occupied in total nerve area than the controls. In addition, the electroneedling could combine both the needling and the electrical stimulation to potentiate the nerve-growth promoting effect of the acupuncture treatment. These results showed that acupuncture treatment could elicit positive effects on regenerated peripheral nerves.

Effects of buyang huanwu decoction on peripheral nerve regeneration using silicone rubber chambers.

This study investigated the effect of buyang huanwu decoction on the regeneration of a 10-mm gap of rat sciatic nerve created between the proximal and distal nerve stumps, which were sutured into silicone rubber tubes. Empty silicone rubber tubes with no further treatment were used as controls. Six weeks after implantation, 89% of the animals orally administered the buyang huanwu decoction exhibited regeneration across the nerve gaps, whereas only 70% had regenerated in the control group. Both qualitative and quantitative histology of the regenerated nerves revealed a more mature ultrastructural organization with significantly higher numbers of myelinated axons, larger endoneurial areas, higher axon densities and a larger percentage of axon area per total nerve area in the buyang huanwu group than in the controls. These results showed that the buyang huanwu decoction had a growth-promoting effect on the regenerated nerves.

Remodeling of rabbit abdominal aorta and Cx43 gap junctions after stent placement: effect of balloon injury plus cholesterol-enriched diet.

AIM: To examine the effect of stenting and cholesterol-enriched diet (CED) on vascular remodeling, including the expression of connexin43 (Cx43) gap junctions in smooth muscle cells (SMC). METHODS: Rabbits abdominal aortae were either implanted stent made of 316 stainless steel (group 1) or denuded followed by stent placement 28 days later (groups 2 and 3). Animals were given normal chow except those of group 3, which were fed CED after the denudation. Eight weeks later, the development of neointima and the expression of connexin43 (Cx43) were examined. In parallel, human aortic SMC were grown on 316 stainless steel or treated with C-reactive protein (CRP) followed by analysis of Cx43. RESULTS: The results showed that, serum CRP levels became transiently elevated after denudation and stent implantation. For the stented aortic segments, the dimensions of neointima were group 3 > group 2 > group 1 (P<0.05). In groups 1 and 2, Cx43 gap junctions are less in amount in neointima of the stented segment, compared to the unstented upstream neointima or medial layer (all P<0.01). In culture experiments, Cx43 in SMC grown on stent material was up-regulated in growth medium but down-regulated in differentiation medium, and CRP did not affect Cx43 expression. CONCLUSION: Vascular remodeling post stent implantation varied according to the presence of balloon injury, CED, or both. Cx43 expression in SMC is altered after exposure to stent and the regulation depended on the milieu.

Effects of percutaneous electrical stimulation on peripheral nerve regeneration using silicone rubber chambers.

The purpose of this study was to determine whether 0.8-1 mA, 2 Hz of percutaneous electrical stimulation could affect the regeneration of a 10-mm gap of rat sciatic nerve created between the proximal and distal nerve stumps, which were sutured into silicone rubber tubes. Six weeks after implantation, though the group receiving the electrical stimulation had a lower success percentage of regeneration (57%) compared with the controls receiving no stimulation (70%), quantitative histology of the successfully regenerated nerves revealed that the mean values of the axon density, blood vessel number, blood vessel area, and percentage of blood vessel area in total nerve area in the group with the electrical stimulation were all significantly larger than those in the controls (p < 0.05). These results showed that the electrical stimulation could elicit rehabilitating effects on the regenerated nerves.