Comparison of the cytotoxic effects of receptor tyrosine kinase inhibitors on macrophage functions; possible side effects in the immune defense.
Certain receptor tyrosine kinase (RTK) inhibitors reduced the phagocytic capacity of rat macrophages, without influencing the binding of bacteria to macrophage surface. The NO production of elicited rat macrophages was also decreased due to the inhibition of the expression of NOS II. The most potent inhibitory compound was PD166326 (6-(2,6-dichloro-phenyl)-2-(4-hydroxy-phenylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one) belonging to a family of RTK inhibitors of broad spectra. These impairing effects could be explained by the apoptosis inducing property of the inhibitor, evidenced by the destroyed mitochondrial membrane potential. The MTT cell viability test indicated a slight, but significant injury of macrophages. In addition to this compound, two other tested RTK inhibitors caused less marked impairment of macrophage functions, while four compounds were not efficient on macrophages at all. Nevertheless, these damaging effects of the inhibitors did not reduce the anti-tumor effect of the RTK inhibitors on COS 7 cells as evidenced by MTT test and apoptosis study. However, these side effects may be important when RTK inhibitors are selected against tumor growth, indicating that certain inhibitors may impair the immune defense during therapeutical application.
Hrabák
András
A
Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary. hbarak@puskin.sote.hu
Bökönyi
Gyöngyi
G
Orfi
László
L
Bajor
Tamás
T
Kéri
György
G
D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
C473352:PD 166326; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D020794:Receptor Protein-Tyrosine Kinases