Anti-proliferative properties of Clozic, a disease-modifying anti-arthritic agent

Cytostatic drugs have been used in the treatment of rheumatoid arthritis but are of limited clinical application due to their severe toxic side-effects. We have discovered that 'Clozic' (ICI 55897), an agent with disease-modifying properties in rheumatoid arthritis patients, inhibits the growth of a variety of mammalian cell types including a matrix-secreting cell culture derived from neonatal rat hearts. The inhibition of growth was reversible and no loss of cell viability occurred when measured by lactate dehydrogenase released into the medium or by vital staining, suggesting a cytostatic rather than a cytotoxic mechanism. Cytostatic activity was observed at ICI 55897 concentrations within the reported therapeutic plasma concentration range and was related to the concentration of unbound compound, since the effect could be reduced by increasing the albumin concentration in the medium. Other oxyalkanoic acids inhibited cell growth. Their inhibitory potency correlated with lipophilicity. The anti-proliferative potencies of R and S enantiomers of two oxyalkanoic acids containing asymmetric centres were similar. These observations suggest that the anti-proliferative effect of the oxyalkanoic acids is due to their interaction with lipophilic cell target sites.