Improving the delivery of therapeutic agents to CNS neoplasms: a clinical review.

Even though nearly thirty-years of clinical research has attempted to improve the outcomes for patients with central nervous system neoplasms, the survival remains limited for a majority of these patients. Diverse intracellular signaling pathways involving apoptosis, invasion, angiogenesis and relevant mechanisms of resistance associated with CNS neoplasms are continuing to be elucidated. Phase I and II studies of systemically delivered chemotherapeutic agents and biological agents targeting these pathways have largely resulted in modest outcomes. Although the functional blood brain barrier was identified nearly eighty years ago only recently has the complexity and relevance of the blood brain-tumor barrier (BTB) been recognized as an important factor that limits the effective treatment of CNS neoplasms. Several groups have focused their efforts at improving the delivery of therapeutic agents across the blood brain-tumor barrier. The purpose of the article is to review novel methods that have attempted to improve the delivery of therapeutic agents into the CNS for the treatment of CNS neoplasm.

Dermal wound healing properties of redox-active grape seed proanthocyanidins.

Angiogenesis plays a central role in wound healing. Among many known growth factors, vascular endothelial growth factor (VEGF) is believed to be the most prevalent, efficacious, and long-term signal that is known to stimulate angiogenesis in wounds. The wound site is rich in oxidants, such as hydrogen peroxide, mostly contributed by neutrophils and macrophages. We proposed that oxidants in the wound microenvironment support the repair process. Proanthocyanidins or condensed tannins are a group of biologically active polyphenolic bioflavonoids that are synthesized by many plants. Previously we have reported that a grape seed proanthycyanidin extract containing 5000 ppm resveratrol (GSPE) potently upregulates oxidant and tumor necrosis factor-alpha inducible VEGF expression in human keratinocytes (Free Radic. Biol. Med. 31:38-42, 2001). Our current objective was to follow up on that finding and test whether GSPE influences dermal wound healing in vivo. First, using a VEGF promoter-driven luciferase reporter construct we observed that the potentiating effect of GSPE on inducible VEGF expression is at the transcriptional level. The reporter assay showed that GSPE alone is able to drive VEGF transcription. Next, two dermal excisional wounds were inflicted on the back of mice and the wounds were left to heal by secondary intention. Topical application of GSPE accelerated wound contraction and closure. GSPE treatment was associated with a more well-defined hyperproliferative epithelial region, higher cell density, enhanced deposition of connective tissue, and improved histological architecture. GSPE treatment also increased VEGF and tenascin expression in the wound edge tissue. Tissue glutathione oxidation and 4-hydroxynonenal immunostaining results supported that GSPE application enhanced the oxidizing environment at the wound site. Oxidants are known to promote both VEGF as well as tenascin expression. In summary, our current study provides firm evidence to support that topical application of GSPE represents a feasible and productive approach to support dermal wound healing.

Gastrin induces over-expression of genes involved in human U373 glioblastoma cell migration.

Astrocytic tumors are the most common and the most malignant primary tumors of the central nervous system. We had previously observed that gastrin could significantly modulate both cell proliferation and migration of astrocytoma cells. We have investigated in the present study which genes could be targeted by gastrin in tumor astrocyte migration. Using a subtractive hybridization PCR technique we have cloned genes differentially over-expressed in human astrocytoma U373 cells treated or not with gastrin. We found about 70 genes over-expressed by gastrin. Among the genes overexpressed by gastrin, we paid particular attention to tenascin-C, S100A6 and MLCK genes because their direct involvement in cell migration features. Their gastrin-induced overexpression was quantitatively determined by competitive RT-PCR technique. We also showed by means of a reporter gene system that S100A6 and tenascin-C respective promoters were upregulated after gastrin treatment. These data show that gastrin-mediated effects in glioblastoma cells occur through activation of a number of genes involved in cell migration and suggest that gastrin could be a target in new therapeutic strategies against malignant gliomas.

Tenascin glycoproteins and the complementary ligand DSD-1-PG/ phosphacan--structuring the neural extracellular matrix during development and repair.

The differentiation and morphogenesis of neural tissues involves a diversity of interactions between neural cells and their environment. Many potentially important interactions occur with the extracellular matrix (ECM), a complex association of extracellular molecules organised into aggregates and polymers. The large modular glycoprotein, Tenascin-C, and the chondroitin sulphate proteoglycan, DSD-1-PG/Phosphacan, have complex and frequently overlapping expression patterns in the developing CNS. Their presence in zones of cell proliferation, migration, and differentiation, as well as in boundary structures, suggest that they may be involved in the modulation of an extensive range of cellular processes. They are both strongly up-regulated in a range of CNS lesions and pathologies, being components of the glial scar, and expressed by gliomas. Functional roles in many cellular processes are possible through their extensive molecular interaction sites, both with each other, and with many of the same cell surface receptors, adhesion molecules, growth factors and other matrix proteins. These multiple interactions involve sites on both their protein domains and on the heterogeneous carbohydrate groups with which they are post-translationally modified. In vitro assays demonstrate cell-type specific effects on adhesion, migration and the formation and extension of cellular processes, including neurites and axons.

Effects of NMDA receptor blockade in the developing rat somatosensory cortex on the expression of the glia-derived extracellular matrix glycoprotein tenascin-C.

The patterning of synaptic connections during development is thought to be influenced by the correlation of neuronal impulse activity. N-methyl-D-aspartate (NMDA) receptors have been implicated in the reorganization of thalamocortical afferents in the visual system. The topographic mapping of the periphery of sensory systems onto the somatosensory cortex in the whisker-barrel field of rodents has served as another important paradigm in the study of extrinsic influences on synaptic rearrangements. In a search for the molecular cues that may contribute to synaptic plasticity, we have investigated the distribution of the glia-derived extracellular matrix glycoprotein tenascin-C, which is highly expressed during the formation of the barrel field map around birth and delineates the boundaries between barrel fields after segregation of afferent inputs. Here we show that systemic and local application of NMDA receptor antagonists at postnatal day 2 inhibited the down-regulation of tenascin mRNA and protein by postnatal day 6 and prevented the appearance of tenascin-positive barrel field boundaries. Furthermore, barrels were not distinguishable by Nissl staining, and segregation of thalamocortical afferents as monitored by anterograde Dil tracing and acetylcholinesterase histochemistry was not complete. These observations indicate that expression of tenascin-C and segregation of afferent inputs are modified by NMDA receptor-dependent neuronal activity.