Interference with the urokinase plasminogen activator system: a promising therapy concept for solid tumours

There is abundant evidence that the plasminogen activator (PA) system with its key components uPA (urokinase-type plasminogen activator), its cell surface receptor uPAR (CD87) and its inhibitor PAI1 plays a key role in tumour invasion and metastasis. Elevated levels of these factors in tumour tissue are associated with tumour aggressiveness and poor patient outcome. Animal models suggest that the PA system is not essential for fertility or survival under physiological conditions. Thus, it seems well suited as a therapeutic target for patients with solid malignant tumours. Novel therapy concepts targeting the uPA system are currently being explored. A variety of different synthetic uPA inhibitor classes have been developed over the last decades. First generation inhibitors displayed a low uPA inhibitory potency combined with broad specificity. More recently, structure based design, x-ray crystallographic screening or NMR based screening have revealed a large number of new, potent and selective uPA-inhibito...