Inhibition of transcription factors by anti-inflammatory and anti-rheumatic drugs: can variability in response be overcome?
1. The drugs used in the treatment of rheumatoid arthritis (RA) form a diverse group with unpredictable adverse effects, mostly weak efficacy and variable responses. Despite their differences, a common feature of many anti-inflammatory and disease-modifying anti-rheumatic drugs (DMARD) is inhibition of pro-inflammatory transcription factors, particularly nuclear factor (NF)-kappaB and activator protein (AP)-1. 2. The present brief review identifies those drugs capable of inhibiting transcription factors, particularly steroids, gold salts, D-penicillamine, cyclosporine A and possibly salicylates. 3. The newer biological inhibitors of tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta are capable of indirect inhibition of NF-kappaB activation, although even with these potent agents the problem of variability in response has not disappeared. 4. The development of selective inhibitors of the transcription factor NF-kappaB should have the benefit of the anti-inflammatory drugs and DMARD, both new and old. 5. It is hypothesized that this strategy will overcome much of the variability in the therapeutic response and adverse effects that limit the usefulness of the existing drugs in the treatment of RA.
Handel
M L
ML
University of New South Wales and Garvan Institute of Medical Research, Sydney, Australia. mhandel@garvan.unsw.edu.au
Nguyen
L Q
LQ
Lehmann
T P
TP
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects* / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000037:antagonists & inhibitors*
D000893:Anti-Inflammatory Agents; D018501:Antirheumatic Agents; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014157:Transcription Factors