[Ischemic preconditioning. Does this animal experiment phenomenon have clinical relevance?]. / Ischämische Präkonditionierung. Hat dieses tierexperimentelle Phänomen eine klinische Relevanz?

BACKGROUND: Infarct size following coronary artery occlusion can be markedly reduced by brief preceding periods of ischemia in several animal models. This phenomenon is called "ischemic preconditioning" and is one of the most powerful mechanisms of cardioprotection known to date. PRECONDITIONING IN HUMANS: There is increasing evidence that preconditioning effects exist in humans as well. The occurrence of angina prior to myocardial infarction might result in reduction of infarct size depending on the time pattern of preinfarct-angina. Similarly, "walking-through-angina", i.e., the relief of exercise-induced anginal symptoms with continuing exercise, is attributed to cardioprotection by ischemic preconditioning. During coronary angioplasty, a lesser shift of ST segments in the intracardial ECG and reduced anginal symptoms are registered during a second balloon inflation in comparison with the first balloon inflation. These findings might represent a "preconditioning-like" effect of the first balloon inflation. THERAPEUTICAL IMPLICATIONS: With respect to the mechanisms of ischemic preconditioning identified in animal models some pharmacological agents that exhibit a "preconditioning-like" cardioprotective effect have been intensively investigated. In clinical studies it was demonstrated that application of adenosine, adenosine-receptor-agonists, and dipyridamole--a nucleoside-transport inhibitor--prior to coronary angioplasty results in reduced ischemia during the subsequent balloon inflation. In a randomized trial the treatment with nicorandil, an activator of the ATP-sensitive potassium channel (K-ATP channel) in patients with unstable angina resulted in a marked reduction of myocardial ischemia which also can be attributed to a "preconditioning-like" effect. Therapeutical applications of ischemic preconditioning have been developed in different clinical settings: brief periods of ischemia and "pharmacologic preconditioning" prior to coronary angioplasty, prior to cardiac surgery, and for protection of donor heart for cardiac transplantation were performed to induce cardioprotection. Moreover, possible "anti-preconditioning effects" of several drugs have to be carefully considered for the treatment of patients with coronary artery disease. In particular, patients treated for acute myocardial infarction by coronary angioplasty with concomitant sulfonylurea drug therapy using glibenclamide demonstrated an increased early mortality. CONCLUSION: To raise the step from "laboratory-based protection" to "evidence-based medicine" further research should focus on clinical studies transferring the results from animal models to the clinical setting.

In vitro invasiveness of human epithelioid-sarcoma cell lines: association with cell motility and inverse correlation with the expression of tissue inhibitor of metalloproteinases.

Epithelioid sarcoma (ES) is a very aggressive soft-tissue tumor in vivo, but no experimental data on its invasive and metastatic behavior have been reported. In the present study, 3 different clonal sub-populations (GRU-1A, GRU-1B and GRU-1C), derived from the same human ES cell line, GRU-1, were investigated for in vitro invasiveness in relation to migration, adhesion and the expression of different invasion- and metastasis-related genes. Tumor spheroids of GRU-1A were markedly more invasive in the chick-heart invasion assay (CHIA) than spheroids of GRU-1B and GRU-1C. These results were paralleled by a significantly higher cell motility of GRU-1A than GRU-1B and GRU-1C (p < 0.05) on distinct substrates, suggesting that the observed differences in invasion result at least in part from differences in motility. When invasion was assayed with suspended tumor cells in the Matrigel assay, differences between the 3 cell lines were much more pronounced than in the CHIA, where cell-cell contacts are established. These results indicate that interclonal differences in ES invasion result mainly from differences in motility, but also partly depend on differences in cell-cell adhesion. On the molecular level, low invasive potential was associated with over-expression of distinct tissue inhibitor of metalloproteinases (TIMPs) relative to matrix metalloproteinase-2 and -9. However, no association was found between invasion and the expression of CD44 splicing variants or nm23 isoforms. Our results suggest that differences in invasion between GRU-1A, GRU-1B and GRU-1C are caused mainly by interclonal differences in migration, and might result from differences in the expression of distinct TIMPs.