No abstract

The serine protease urokinase-type plasminogen activator (uPA) interacts with a specific receptor (uPAR) on the surface of various cell types, including tumor cells, and plays a crucial role in pericellular proteolysis. High levels of uPA and uPAR often correlate with poor prognosis of cancer patients. Therefore, the specific inhibition of uPA with small molecule active-site inhibitors is one strategy to decrease the invasive and metastatic activity of tumor cells. We have developed a series of highly potent and selective uPA inhibitors with a C-terminal 4-amidinobenzylamide residue. Optimization was directed toward reducing the fast elimination from circulation that was observed with initial analogues. The x-ray structures of three inhibitor/uPA complexes have been solved and were used to improve the inhibition efficacy. One of the most potent and selective derivatives, benzylsulfonyl-D-SerSer-4-amidinobenzylamide (inhibitor 26), inhibits uPA with a K i of 20 nM. This inhibitor was used in a fibrosarcoma model in nude mice using lacZ-tagged human HT1080 cells, to prevent experimental lung metastasis formation. Compared with control (100%), an inhibitor dose of 2 ؋ 1.5 mg/kg/day reduced the number of experimental metastases to 4.6 ؎ 1%. Under these conditions inhibitor 26 also significantly prolonged survival. All mice from the control group died within 43 days after tumor cell inoculation, whereas 50% of mice from the inhibitor-treated group survived more than 117 days. This study demonstrates that the specific inhibition of uPA by these inhibitors may be a useful strategy for the treatment of cancer to prevent metastasis.The detachment of malignant cells from the primary tumor and their subsequent migration within the surrounding tissue, including intravasation and extravasation into blood and lymph vessels, leads to tumor dissemination and the formation of metastases at distant loci. Whereas a solid tumor can be removed by surgery or treated by radio-, chemo-, or hormone therapy, invasive tumor cells that have spread over the whole body can form secondary tumors leading to poor prognosis or death of cancer patients. Several proteases, such as matrix metalloproteases, the cysteine proteases cathepsin B and L, the aspartyl protease cathepsin D, and serine proteases, e.g. plasmin and uPA, 1 are involved at multiple stages during growth, invasion and progression of tumors, including metastases formation (1). High levels of expression of these proteases often correlate with poor prognosis for cancer patients (2). However, in several clinical cancer trials with different types of nonspecific matrix metalloprotease inhibitors, disappointing results with poor benefit and severe side effects were observed (3). This stimulated the search for alternative proteases with matrix degrading activity as new targets for anti-cancer drugs. An important role in metastasis has been recently ascribed to the plasmin-plasminogen activation system and especially to uPA.Both, uPA and the second endogenous plasminogen activator tPA are...

The L1 cell adhesion molecule is implicated in the control of proliferation, migration, and invasion of several tumor cell types in vitro. Recently, L1 overexpression was found to correlate with tumor progression of ovarian carcinoma, one of the most common causes of cancer-related deaths in gynecologic malignant diseases. To evaluate L1 as a potential target for ovarian cancer therapy, we investigated the effects of anti-L1 monoclonal antibodies (chCE7 and L1-11A) on proliferation and migration of L1-positive human SKOV3ip ovarian carcinoma cells in vitro and the therapeutic efficacy of L1-11A against i.p. SKOV3ip tumor growth in nude mice. In vitro, both anti-L1 antibodies efficiently inhibited the proliferation of SKOV3ip cells as well as other L1-expressing tumor cell lines (renal carcinoma, neuroblastoma, and colon carcinoma). On two cell lines, hyper-cross-linking of L1-11A with a secondary antibody was necessary for significant inhibition of proliferation, indicating that cross-linking of L1 is required for the antiproliferative effect. L1-negative prostate carcinoma cells were not influenced by antibody treatment. Biweekly treatment of ovarian carcinoma-bearing mice with L1-11A led to a dose-dependent and significant reduction of tumor burden (up to À63.5%) and ascites formation (up to À75%). This effect was associated with reduced proliferation within the tumors. L1-directed antibody-based inhibition of peritoneal growth and dissemination of human ovarian carcinoma cells represents important proof-of-principle for the development of a new therapy against one of the leading gynecologic malignant diseases. (Cancer Res 2006; 66(2): 936-43)

A door-to-ECLS implantation time <30 min significantly improves 30-day outcomes in patients with OHCA.

Introduction Pumpless interventional lung assist (iLA) is used in patients with acute respiratory distress syndrome (ARDS) aimed at improving extracorporeal gas exchange with a membrane integrated in a passive arteriovenous shunt. In previous studies, feasibility and safety of the iLA system was demonstrated, but no survival benefit was observed. In the present pilot study we tested the hypothesis that timely initiation of iLA using clear algorithms and an improved cannulation technique will positively influence complication rates and management of lung protective ventilation.

Matrix metalloproteinases (MMPs), and in particular gelatinases (MMP-2 and MMP-9), play a key role in cancer progression. However, clinical trials in which MMP inhibitors were tested in cancer patients have been disappointing. Whereas many reasons have been postulated to explain the failure of the clinical trials, lack of inhibitor selectivity was a major limitation. Thus, despite the consensus opinion that MMP-mediated proteolysis is essential for cancer progression and that certain MMPs represent important targets for intervention, effective and selective inhibition of those MMPs remains a major challenge in drug development. We previously reported the first mechanism-based MMP inhibitor, designated SB-3CT, which is a selective gelatinase inhibitor. Here we report that SB-3CT (5-50 mg/kg/d) is a potent inhibitor of liver metastasis and increases survival in an aggressive mouse model of T-cell lymphoma. This study shows that mechanism-based inhibition of gelatinases represents a novel approach to inhibitor design that promises to be a successful anticancer therapy. (Cancer Res 2005; 65(9): 3523-6)

In our cohort of cardiovascular patients ECPR was associated with better short- and long-term survival over CCPR, with a good neurological outcome in the majority of the patients with refractory in-hospital cardiac arrest.

The human tissue kallikrein family of serine proteases (hK1-hK15 encoded by the genes KLK1-KLK15) is involved in several cancer-related processes. Accumulating evidence suggests that certain tissue kallikreins are part of an enzymatic cascade pathway that is activated in ovarian cancer and other malignant diseases. In the present study, OV-MZ-6 ovarian cancer cells were stably co-transfected with plasmids expressing hK4, hK5, hK6, and hK7. These cells displayed similar proliferative capacity as the vector-transfected control cells (which do not express any of the four tissue kallikreins), but showed significantly increased invasive behavior in an in vitro Matrigel invasion assay (p<0.01; Mann-Whitney U-test). For in vivo analysis, the cancer cells were inoculated into the peritoneum of nude mice. Simultaneous expression of hK4, hK5, hK6, and hK7 resulted in a remarkable 92% mean increase in tumor burden compared to the vector-control cell line. Five out of 14 mice in the 'tissue kallikrein overexpressing' group displayed a tumor/situs ratio greater than 0.198, while this weight limit was not exceeded at all in the vector control group consisting of 13 mice (p=0.017; chi2 test). Our results strongly support the view that tumor-associated overexpression of tissue kallikreins contributes to ovarian cancer progression.