Novel EGF receptor or c-erbB2 pathway inhibitors can be identified in the NCI drug screen by correlation of cytotoxicity patterns with EGF receptor or c-erbB2 mRNA expression levels.

These results demonstrate that satraplatin and JM-118 have preclinical antitumor activity in human prostate cancer and other tumor types as well, including several cell lines displaying drug resistance to cisplatin, docetaxel and mitoxantrone. In addition, the results suggest that PSA should be further evaluated as a relevant marker of clinical response in patients with prostate cancer treated with satraplatin.

The overall survival rate of patients suffering from carcinomas has remained poor and nearly unchanged over the last decades. This is mainly due to the so-called minimal residual disease, i.e., remaining tumor cells that overcome surgery and/or radiotherapy and are the cause of locoregional and distant metastases. To metastasize, tumor cells take advantage of proteases to invade and remodel surrounding tissues. Here, we analyzed the efficiency of WX-UK1, a novel 3-amidinophenylalanine-based inhibitor of the uPA system, at inhibiting the invasive capacity of carcinoma cells. First, uPAR expression was characterized in different carcinoma cell lines, including SCCHN, breast and cervical carcinoma. Thereafter, the invasive potential of these cell lines was determined using Matrigel invasion chambers and a spheroid cocultivation model with human fibroblasts. uPAR expression levels correlated positively with invasion capacity, which could be significantly inhibited by WX-UK1. Despite improvements in surgical and radiotherapeutic techniques, the 5-year survival rate of patients suffering from SCCHN has remained poor and nearly unchanged over the last decades, primarily due to their tendency to develop locoregional and distant metastases. 1 This underlines the necessity of new modalities to treat MRD, 2 i.e., the spread of occult malignant cells to locoregional and/or distant sites and inhibition of metastasis formation. Both MRD and metastasis formation are major causes of recurrence and therefore death in cancer patients.Tumor invasion and metastasis formation are complex biologic processes depending on matrix-degrading proteolytic systems that allow tumor cells to detach from their primary site; migrate through the surrounding tissue, blood or lymph vessels; and distribute to distant sites. 3 One of the major proteolytic systems involved in these processes is the urokinase-type plasminogen activation system with its key components: uPA, the cell-surface receptor uPAR (CD87) and the inhibitor PAI-1. 4,5 Plasmin, generated from its precursor plasminogen by activators such as uPA, catalyzes the degradation of extracellular matrix components and is important for fibrinolysis. Proteases such as plasmin and others increase the invasion capacity and tissue-remodeling ability of carcinoma cells. 6 Upon binding to its receptor on the surface of various cell types, the activator can induce direct plasmin-mediated proteolysis or indirect activation of other proteinases, like metalloproteases, by triggering signal-transduction pathways and thereby facilitate matrix degradation and tumor invasion. 6 uPA can also be activated by cysteine proteases like cathepsin B or L, which are located intracellularly and at tumor cell surfaces. 7 Additionally, components of the uPA system are overexpressed in malignant tumors such as breast, gastric, esophageal, lung, prostate, colorectal and others, 8 correlating with a poor prognosis. High levels of uPA components were also measured in head-and-neck carcinomas and can be used as a prognostic...

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