Angiogenesis in cancer: molecular mechanisms, clinical impact.

BACKGROUND: Angiogenesis, the formation of new blood vessels from the endothelium of the existing vasculature, is fundamental in tumor growth, progression, and metastasis. Inhibiting tumor angiogenesis is a promising strategy for treatment of cancer and has been successfully transferred from preclinical to clinical application in recent years. Whereas conventional therapeutic approaches, e.g. chemotherapy and radiation, are focussing on tumor cells, antiangiogenic therapy is directed against the tumor supplying blood vessels. MATERIALS AND METHODS: This review will summarize important molecular mechanisms of tumor angiogenesis and advances in the design of antiangiogenic drugs. Furthermore, clinical implications of antiangiogenic therapy in surgical oncology will be discussed. RESULTS: First antiangiogenic drugs have been approved for treatment of advanced solid tumors in several countries. Leading antiangiogenic drugs are designed to inhibit vascular endothelial growth factor-mediated tumor angiogenesis. Combining antiangiogenic agents with conventional chemotherapy or radiation is currently investigated clinically with great emphasis to realize a multimodal tumor therapy, targeting both the tumor cell and tumor vascular compartment. CONCLUSION: Antiangiogenic tumor therapy represents a promising strategy for treatment of cancer and will most likely exhibit its clinical potential in combination with established standard tumor therapies in the future.

High-energy phosphates in the frontal lobe correlate with Wisconsin Card Sort Test performance in controls, not in schizophrenics: a 31phosphorus magnetic resonance spectroscopic and neuropsychological investigation.

In recent years, a number of 31phosphorus magnetic resonance spectroscopy (P-MRS) studies on the frontal lobe of schizophrenics have been performed, reporting alterations of phospholipids and high-energy phosphates. Deicken et al. (1994b) recently found positive correlations between left frontal phosphomonoester% (PME%) levels and the performance of a specific frontal lobe task, the Wisconsin Card Sorting Test (WCST), in schizophrenics. In the present paper, the correlations between phospholipids and high-energy phosphates in the frontal lobe of 26 schizophrenics and 23 controls measured with a volume-selective P-MRS method were investigated. Overall, we could not find any correlations between WCST results and phospholipid levels, but in controls phosphocreatine% (PCr%) and PCr/adenenosine triphosphate (ATP) ratios were negatively correlated with test performance. Since PCr behaves as a buffer of ATP, in the sense that when ATP is consumed by neuronal activity PCr is catalysed rapidly to ATP, increased PCr% values and, moreover, increased PCr/ATP ratios point to a decreased ATP consumption. Thus, the correlations found between PCr% and PCr/ATP and test performance in controls point to an association between reduced performance in a specific frontal lobe task and decreased energy demanding processes at rest. This association was not found in schizophrenics, possibly due to the influence of neuroleptic medication or the disease process per se.

Jun NH2-terminal kinase is constitutively activated in T cells transformed by the intracellular parasite Theileria parva.

When T cells become infected by the parasite Theileria parva, they acquire a transformed phenotype and no longer require antigen-specific stimulation or exogenous growth factors. This is accompanied by constitutive interleukin 2 (IL-2) and IL-2 receptor expression. Transformation can be reversed entirely by elimination of the parasites using the specific drug BW720c. Extracellular signal-regulated kinase and jun NH2-terminal kinase (JNK) are members of the mitogen-activated protein kinase family, which play a central role in the regulation of cellular differentiation and proliferation and also participate in the regulation of IL-2 and IL-2 receptor gene expression. T. parva was found to induce an unorthodox pattern of mitogen-activated protein kinase expression in infected T cells. JNK-1 and JNK-2 are constitutively active in a parasite-dependent manner, but have altered properties. In contrast, extracellular signal-regulated kinase-2 is not activated even though its activation pathway is functionally intact. Different components of the T cell receptor (TCR)-dependent signal transduction pathways also were examined. The TCRzeta or CD3epsilon chains were found not to be phosphorylated and T. parva-transformed T cells were resistant to inhibitors that block the early steps of T cell activation. Compounds that inhibit the progression of T cells to proliferation, however, were inhibitory. Our data provide the first example, to our knowledge, for parasite-mediated JNK activation, and our findings strongly suggest that T. parva not only lifts the requirement for antigenic stimulation but also entirely bypasses early TCR-dependent signal transduction pathways to induce continuous proliferation.