On the mechanism of action of interferons: interaction with nonsteroidal anti-inflammatory agents, pentoxifylline (Trental) and cGMP inducers.
In earlier studies, we showed that when interferon alpha (IFN alpha) binds to cell receptors, it alters membrane potentials. In IFN-sensitive Daudi cells derived from Burkitt's lymphoma patients, IFNs produce dose-dependent hyperpolarization, decreased plasma membrane viscosity, modulation of the microfilament system, and altered synthesis of cAMP, cGMP and prostaglandins. No such changes were seen in IFN alpha-resistant Daudi cells. In this study, we found that indomethacin, pentoxifylline, or the cGMP inducer sodium azide (NaN3) had no significant effect on the IFN alpha induced membrane potential changes, or on membrane viscosity changes as measured by flow cytometry and electron spin resonance spectrometry. In tissue culture, indomethacin did not alter the anti-proliferative effect of IFN alpha on Daudi cells. Indomethacin may influence IFN synthesis, but not it's antiproliferative actions. Relatively high doses of pentoxifylline slightly inhibited proliferation of Daudi cells and synergized with IFN alpha. Measurement of early biophysical changes induced by IFNs may represent a new screening method to rapidly explore certain types of IFN alpha potentiating agents.
Aszalos
A
A
Division of Research and Testing, FDA, Washington, DC.
Grimley
P M
PM
Balint
E
E
Chadha
K C
KC
Ambrus
J L
JL
D001386:Azides / Q000494:pharmacology*; D002051:Burkitt Lymphoma / Q000473:pathology; D006152:Cyclic GMP / Q000378:metabolism; D004347:Drug Interactions; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology*; D016898:Interferon-alpha / Q000378:metabolism / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D010431:Pentoxifylline / Q000494:pharmacology*; D019810:Sodium Azide; D014407:Tumor Cells, Cultured / Q000187:drug effects
D001386:Azides; D016898:Interferon-alpha; D019810:Sodium Azide; D006152:Cyclic GMP; D010431:Pentoxifylline; D007213:Indomethacin