Imatinib mesylate (STI571; Glivec)--a new approach in the treatment of biliary tract cancer?
Non-resectable biliary tract cancer is associated with poor prognosis due to widespread resistance to chemotherapeutic agents and radiotherapy. It is therefore essential to explore new therapeutic approaches like the inhibition of tyrosine kinases. The aim of this study was to determine the expression of c-kit and platelet-derived growth factor (PDGF) receptors (PDGFRs) and the effects of the tyrosine kinase inhibitor imatinib +/- 5-fluorouracil (5-FU) on proliferation and apoptosis in biliary tract cancer cell lines. The expression of c-kit and PDGFR mRNA was examined in 12 biliary tract cancer cell lines using RT-PCR. Cells were treated with imatinib (1, 10, 20 and 50 micromol/l) +/- 5-FU (0.1 microg/ml) for 6 days and inhibition of cell growth was assessed by manual cell counting. Cell proliferation and apoptosis were analyzed by flow cytometry of BrdU and Annexin-V/propidium iodide-stained cells. c-kit and PDGF mRNA expression was detected in 50 and 75%, respectively. Imatinib (10 and 20 micromol/l) alone inhibited cell growth significantly higher in c-kit+ cell lines (p<0.02) and inhibition was independent of PDGFR status. The combination with 5-FU increased the effect of imatinib mesylate in all cell lines. Treatment of cells with imatinib +/- 5-FU was associated with a significant induction of apoptosis, but no inhibition of proliferation. We conclude that imatinib alone exerts marked effects on c-kit+ biliary tract cancer cell lines only at intermediate and high concentrations, but there is a potential role of low-dose imatinib in combination with 5-FU for the treatment of biliary tract cancers.
Wiedmann
Marcus
M
Department of Internal Medicine II, University of Leipzig, Leipzig, Germany.
Kreth
Florian
F
Feisthammel
Jürgen
J
Deininger
Michael
M
Mössner
Joachim
J
Caca
Karel
K
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001661:Biliary Tract Neoplasms; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor; D005472:Fluorouracil