Glivec (imatinib) bremst das Pankreaskarzinomwachstum in vitro — ein neuer Therapieansatz in der Behandlung des Pankreaskarzinoms?

Abstract

Autocrine and paracrine growth regulating loops contribute to the aggressiveness of pancreatic carcinoma, one of the most lethal human cancers, in which incidence and mortality almost coincide. The evaluation of the expression of protein-kinase receptors and their ligands in human cancers is of particular interest since selective protein-kinase inhibitors have been developed. One of these molecules, the tyrosine kinase inhibitor Glivec, has been shown to inhibit besides other receptors, the c-kit tyrosine kinase. Preclinical and clinical studies have shown the ability of Glivec to exert significant cytotoxic effects in chronic myeloid leukemia, and in gastrointestinal stromal tumors, which express c-kit in a high percentage of cases. In the present study, the effects of the natural c-kit ligand stem cell factor (SCF) and of the c-kit tyrosine-kinase inhibitor Glivec on the growth of several pancreatic cancer cell lines and of the normal pancreatic ductal cell line TAKA-1 were assessed. In addition, the concomitant expression and distribution of SCF and c-kit were examined in 17 normal and 26 cancerous human pancreatic tissues and in 6 cultured pancreatic cancer cell lines. SCF showed a dose-dependent growth inhibitory effect on TAKA-1 cells (p < 0.001), whereas pancreatic cancer cells were resistant to the SCF-induced growth inhibition. Nonetheless, the growth of TAKA-1 cells and pancreatic cancer cells was dose-dependently inhibited by the c-kit tyrosine kinase inhibitor Glivec. SCF immunoreactivity was absent in acinar, ductal and islet cells of the normal pancreas and faint in pancreatic cancer tissues and cell lines, whereas c-kit was clearly present in some normal and hyperplastic ducts of the normal pancreas, in the cancer cells of 73% of the tumor samples and in all pancreatic cancer cell lines tested. In conclusion, the SCF-c-kit system may have a growth-regulating role in the normal pancreas, which is altered during malignant transformation. Glivec has the potential to exert growth inhibitory/cytotoxic effects which are mediated at least in part through the SCF-c-kit system.