Drug-coated balloons in the lower limb.

Even if recently the first positive results were presented for a paclitaxel releasing drug eluting stent there are still concerns about stent implantation in the femoro-popliteal artery. This makes any stentless technology attractive that achieves at least as good acute and longer term results in this vessel area. Three randomized studies investigating the value of short time paclitaxel release using a drug coated balloon gave promising results with significantly improved patency rates compared to plain balloon angioplasty in femoro-popliteal lesions and at least as good patency results as for the majority of bare metal nitinol stents (THUNDER, FEMPAC, LEVANT 1). Below-the-knee this promising concept is still under evaluation (PICCOLO study) whereas the first positive results for drug eluting stents in shorter lesions had been recently presented (YUKON BTK, DESTINY). This article gives an overview upon already published and presented data and still ongoing trials on drug releasing balloons in the peripheral arteries.

Advances on drug-coated balloons.

During the last decades considerable advances have been made in intravascular interventions for the treatment of coronary and peripheral arterial disease. However, long-term outcome remains an area of concern in many applications. Restenosis is still a challenge in endovascular medicine and has thus been referred to as the Achilles' heel of percutaneous intervention. Therefore, novel strategies have been developed to overcome this problem. These include drug-eluting stents, though still associated with stent thrombosis and in-stent restenosis, and the more recently introduced non-stent based local drug delivery systems, especially the paclitaxel-eluting balloon. Results of several preclinical and clinical studies indicate that short-term exposure of injured arteries to paclitaxel eluted from regular PTA and PTCA balloons may be sufficient to reduce late lumen loss and restenosis rates during a critical period of time after angioplasty of diseased coronary and peripheral arteries. Although the number of published trials and patients treated is still limited, available data seem to prove that restenosis inhibition by immediate drug release is feasible. This article reviews the rationale for the use of paclitaxel-coated balloons, data from preclinical and clinical studies, and the perspective of drug-coated balloons in peripheral arterial disease.

Effect of BJcuL (a lectin from the venom of the snake Bothrops jararacussu) on adhesion and growth of tumor and endothelial cells.

Lectins are polyvalent carbohydrate-binding proteins of non-immune origin. Recently, we have isolated and characterized a lectin from the venom of the snake Bothrops jararacussu. This lectin (BJcuL) has been shown to bind to lactose moieties and induce agglutination of erythrocytes. In the present work, we observed that cells from human metastatic breast cancer (MDA-MB-435) and human ovarian carcinoma (OVCAR-5) cell lines adhere, although weakly, to BJcuL. However, BJcuL did not inhibit adhesion of these cells to the extracellular matrix proteins fibronectin, laminin and type I collagen. Importantly, viability of these tumor cells and cells from other human tumor cell lines and a bovine brain endothelial cell line was suppressed by BJcuL. These findings suggest that the lectin BJcuL may serve as an interesting tool for combating tumor progression by inhibiting tumor cell and endothelial cell growth.

Anti-invasive effect of contortrostatin, a snake venom disintegrin, and TNF-alpha on malignant glioma cells.

BACKGROUND: The snake venom disintegrin contortrostatin has been shown to bind to integrins alpha IIb beta 3, alpha v beta 3, alpha v beta 5, and alpha 5 beta 1 and to exert an anti-tumor activity in vitro and in vivo. The cytokine TNF-alpha has been demonstrated to have anti-invasive properties in vitro. MATERIALS AND METHODS: The human glioblastoma cell line T98G was treated with controtrostatin or colloidal gold-TNF-alpha (CG-TNF-alpha) alone, or in combination. Vitronectin- and fibronectin-dependent adhesion of untreated and treated glioma cells was studied and compared. Invasion through a reconstituted basement membrane (Matrigel) was also examined. RESULTS: Although both contortrostatin and CG-TNF-alpha inhibited invasion of T98G cells through Matrigel, the mechanism of inhibition appears to be different. Contortrostatin significantly decreased cell adhesion to vitronectin and fibronectin; CG-TNF-alpha did not. Contortrostatin binds to T98G integrins in an RGD-dependent manner, whereas protein kinase C (PKC) appears to be involved in CG-TNF-alpha actions, leading to inhibition of cell invasion. The efficiency of contortrostatin in inhibiting cell invasion was enhanced by combination with CG-TNF-alpha. CONCLUSION: The combined use of contortrostatin and CG-TNF-alpha may have potential for malignant glioma therapy by effectively inhibiting glioma cell invasion.

Purification and characterization of fibrolase isoforms from venom of individual southern copperhead (Agkistrodon contortrix Contortrix) snakes.

Fibrolase, a zinc metalloproteinase possessing direct-acting fibrinolytic activity, has been previously purified from southern copperhead (Agkistrodon contortrix contortix) snake venom. We recently reported that a pool of southern copperhead venom from different geographical locations possesses two isoforms of fibrolase (fib1 and fib2) [Loayza, S. L. et al. (1994) J. Chromat. B, in press]. We now report that venom from individual southern copperhead snakes contains the two isoforms which can be separated by a three-step high performance liquid chromatography (HPLC) procedure consisting of hydrophobic interaction chromatography, hydroxylapatite chromatography and weak cation exchange chromatography. Utilizing mass spectrometry we determined that fib1 has a molecular mass of 22,879 atomic mass units (amu) compared to 22,753 amu for fib2. These results support earlier observations during amino acid sequence analysis that a truncated version of the enzyme is produced which is missing the amino-terminal amino acid (< Glu-Arg-Phe-Pro vs. the intact enzyme < Glu-Gln-Arg-Phe-Pro, where < Glu is cyclized glutamine). The truncated version of fibrolase (fib2) has full fibrinolytic activity compared to fib1. EC50 values (concentration of enzyme required to degrade 50% of fibrin in a micro-fibrin plate assay) are 6.4 (+/- 1.0) microM and 5.2 (+/- 0.8) microM for fib 1 and fib2, respectively. Therefore, loss of the amino-terminal amino acid does not appear to influence enzymatic activity. We conclude that the two isoforms of fibrolase arise from variations in the molecular processing of the enzyme by the snake venom gland rather than being caused by the pooling of southern copperhead venoms from different geographical locations.