Da. Hess et al., THE HYDROXYLAMINE OF SULFAMETHOXAZOLE SYNERGIZES WITH FK506 AND CYCLOSPORINE-A, INHIBITING T-CELL PROLIFERATION, The Journal of pharmacology and experimental therapeutics, 281(1), 1997, pp. 540-548
We previously demonstrated the capacity of the hydroxylamine metabolit
e of sulfamethoxazole (SMX-HA) to inhibit mitogen-induced T-cell proli
feration. We studied the interaction of SMX-HA with the immuno-suppres
sants cyclosporin A (CsA), FK506 and rapamycin. Human peripheral blood
mononuclear leukocytes were treated with SMX-HA and combined in cultu
re with CsA or FK506 or rapamycin. The cells were stimulated with phyt
ohaemaglutinin, and phorbol myristate acetate and proliferation was de
termined by cellular uptake of H-3-thymidine, Using median-effect anal
ysis and concentration reduction index calculations to assess immunosu
ppressive drug interactions, we produced synergistic immunosuppression
by SMX-HA/CsA and SMX-HA/FK506. Concentration reductions at the 50% i
nhibitory level of over 46-fold and 64-fold with CsA and FK506, respec
tively, were observed with 25 mu M SMX-HA, and this effect was not ass
ociated with reduced cell viability, SMX-HA failed to augment the supp
ressive capacity of rapamycin in inhibiting mitogen-induced cellular p
roliferation. SMX-HA at immunosuppressive concentrations also failed t
o interfere with interleukin-2 mRNA transcription and interleukin-2 pr
otein production, which suggests that signaling events proximal to cyt
okine production are not affected by the metabolite, Synergy between S
MX-HA/FK506 and SMX-HA/CsA suggests that the mechanism(s) of action of
reactive sulfonamide metabolites may occur in later stages of lymphoc
yte activation.