Evidence for the involvement of calmodulin in natural cytotoxicity using a range of calmodulin antagonists of varying potency and improved specificity.
The calmodulin antagonist W7 and 4 of its analogues were examined for their ability to inhibit human NK cell mediated cytotoxicity. With the exception of one of these compounds, which is extremely hydrophobic, there was a good correlation between the ability of drugs to inhibit human NK antitumour cytotoxicity and calmodulin-dependent phosphodiesterase activity in vitro. The most potent of the compounds, 5-iodo-1-C8, an analogue of W7, has an IC50 of 3 microM upon biological and biochemical assay. This particular compound is both more potent and specific than the parent compound W7, is non-toxic to cells over the range used and is also capable of inhibiting the biological activity of NK cells upon pre-treatment of the effector cells, inferring the mechanism of NK cytotoxicity to be calmodulin dependent.
Rees
R C
RC
Department of Virology, University of Sheffield Medical School.
Parker
S
S
Platts
A
A
Blackburn
M G
MG
MacNeil
S
S
D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects*; D009282:Naphthalenesulfonates / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
D002147:Calmodulin; D009282:Naphthalenesulfonates; D013449:Sulfonamides; C017967:W 7; D010727:Phosphoric Diester Hydrolases