Colchicine analogues: effect on amyloidogenesis in a murine model and, in vitro, on polymorphonuclear leukocytes.
Colchicine has been used in diverse clinical settings such as gout, familial Mediterranean fever, liver cirrhosis, Behcet's disease and pericarditis. It also has an antimitotic potential hitherto unexplored due to its narrow therapeutic toxic ratio. The aim of the present study was to compare the effectiveness and the toxicity of colchicine and three analogues: thiocolchicine, 2,3 dimethyl-colchicine and 3-dimethylthiocolchicine in the blockage of amyloid synthesis in a murine model. 3-demethylthiocolchicine was equipotent to colchicine in the blockage of casein induced amyloidogenesis. However, it was markedly less toxic (LD50 11.3 mg kg-1 vs. 1.6 mg kg-1). Thiocolchicine was toxic (LD50 1.0 mg kg-1) and 2,3 didemethyl-colchicine was far less effective. The effect of 3-dimethylthiocolchicine on polymorphonuclear leukocytes was then compared to colchicine. The effect of this analogue on inhibition of chemotaxis was equivalent to that of colchicine whereas the latter was superior to the analogue in the suppression of phagocytosis (by a ratio of 2:1) and in the inhibition of bactericidal activity (by a ratio of 10:1). Since in therapeutic concentrations the only detectable effect of colchicine on PMNs is inhibition of chemotaxis, our data may point to 3-demethylthiocolchicine as an optional, perhaps superior alternative to colchicine for some of its therapeutic indications.
Wolach
B
B
Department of Pediatrics, Sackler Faculty of Medicine Tel-Aviv University, Israel.
Gotfried
M
M
Jedeikin
A
A
Lishner
M
M
Brossi
A
A
Ravid
M
M
D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D000686:Amyloidosis / Q000188:drug therapy; D000818:Animals; D002633:Chemotaxis / Q000187:drug effects; D003078:Colchicine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D009504:Neutrophils / Q000187:drug effects*; D010587:Phagocytosis / Q000187:drug effects
D000682:Amyloid; C046480:3-demethylthiocolchicine; C014856:thiocholchicine; C078633:2,3-didemethylcolchicine; D003078:Colchicine