No abstract

Novel beta-sheet-forming peptide 33-mers, betapep peptides, have been designed by using a combination approach employing basic folding principles and incorporating short sequences from the beta-sheet domains of anti-angiogenic proteins. One of these designed peptides (betapep-25), named anginex, was observed to be potently anti-angiogenic. Anginex specifically inhibits vascular endothelial cell proliferation and induces apoptosis in these cells, as shown by flow-cytometric detection of sub-diploid cells, TUNEL (terminal deoxyribonucleotidyl transferase-mediated dUTP-nick-end labelling) analysis and cell morphology. Anginex also inhibits endothelial cell adhesion to and migration on different extracellular matrix components. Inhibition of angiogenesis in vitro is demonstrated in the sprout-formation assay and in vivo in the chick embryo chorio-allantoic membrane angiogenesis assay. Comparison of active and inactive betapep sequences allows structure-function relationships to be deduced. Five hydrophobic residues and two lysines appear to be crucial to activity. This is the first report of a designed peptide having a well-defined biological function as a novel cytokine, which may be an effective anti-angiogenic agent for therapeutic use against various pathological disorders, such as neoplasia, rheumatoid arthritis, diabetic retinopathy and restenosis.

The unknown primary tumour (UPT) is an intriguing clinical phenomenon found in approximately 5% of all newly diagnosed patients with cancer. It is unclear whether UPT forms a distinct biological entity with specific genetic and phenotypic characteristics, or whether it is merely a clinical presentation of metastases in patients in whom the primary tumour cannot be detected and does not result in any visible clinical signs. Understanding the basic biology of UPT may shed light on this issue and, moreover, may have a direct impact on clinical care. A review of the literature revealed only a limited number of publications describing the genetic and phenotypic features of UPT, most of which focus only on the potential of these markers to predict prognosis. The question as to whether the biology of UPT is different from tumours of known primaries therefore remains unanswered. Further insight into the molecular mechanisms underlying the oncogenesis of UPT, e.g. by applying newly available DNA and gene profiling microarray techniques, will be necessary to understand its specific biology and to develop more effective treatments.

It has been shown that the clinical course of sickle cell (SS) patients can be ameliorated by administration of hydroxyurea (HU). Induction of hemoglobin F (HbF) is thought to be the mechanism responsible for clinical improvement in some patients. However, HU has a variable effect on HbF production and there exists no good correlation between the extent of HbF increase and clinical response. On the other hand, the degree of adherence of SS to vascular endothelium and neutrophil counts correlate well with clinical severity. Being a cytotoxic drug, used in myeloproliferative diseases, HU may alter proliferation among various cell lines. Moreover, HU has been reported to reduce red blood cell (RBC) adhesion receptor expression in young SS individuals and induces changes in endothelial cells in vitro. It should be conceived that in addition to its effects on HbF production, HU may change the clinical symptoms of SS patients by affecting the degree of adherence of different blood cells, by influencing the activity of endothelium as well as the activity of white blood cells (WBC) and platelets. To analyze whether several of the determinants of adhesion are modulated by HU treatment we studied the levels of endothelial activity (soluble vascular adhesion molecule-1, (sVCAM-1), interleukin-8 (IL-8), fibronectin, neutrophil activity (sL-selectin, sIL-6 receptor-α, myeloperoxidase) and platelet activity (von Willebrand factor) in relation to clinical symptoms, hematological data and HbF levels in 8 SS patients before and during 5 months of HU therapy. Steady state sVCAM-1 levels are increased compared to normal controls and a significant decrease is noted during HU treatment, suggesting a decrease in the interactions between RBC and vascular endothelium. The IL-8 levels are comparable to those in normal controls and remain unaffected by HU therapy. Intercurrent infection and crises reveal striking increases in IL-8 which are accompanied by leukocytosis, but otherwise the IL-8 levels do not correlate with hematological data. HU has no demonstrable effect on fibronectin or soluble neutrophil adhesion molecules, but the levels of myeloperoxidase decrease significantly while WBC counts do not, implying a reduction in neutrophil activity which may help attenuate the propagation phase of a vasoocclusive crisis.

Unknown primary tumours (UPTs) are defined by the absence of a primary tumour in biopsy proved metastatic cancer. These tumours have a specific biology with clinical characteristics of rapid progression and random atypical metastases. Cytogenetic abnormalities have been demonstrated, particularly deletion of chromosome 1p. Diagnostic evaluation that includes pathology review, physical examination, chest radiography, computed tomography of the abdomen, and mammography is directed at the identification of treatable subsets. Based on clinicopathological criteria, therapy responsive subsets of patients with UPTs can be defined. These subsets have a better prognosis than the average median survival time of four months in patients with UPTs.