Abstract
The universal response surface approach (URSA) was developed to assess the nature and intensity of drug interactions, ie, synergism. antagonism and additivity. URSA consists of fitting a concentration-effect surface to experimental data with maximum likelihood approaches, with the estimation of parameters, including: ID5os, concentration-effect slopes and the synergism-antagonism parameter α When α is positive, synergism is indicated, when α is negative, antagonism is indicated and when α is zero. additivity is indicated. URSA was applied to data from a set of 45 in vitro growth inhibition experiments with the L929 mouse cell line. The cytokine, tumour necrosis factor (TNF), was combined with one of nine eicosanoid synthesis inhibitors: indomethacin, Ro 20-5720, ibuprofen (cyclooxygenase inhibitors): nordihydroguaiaretic acid, nafazatrom, esculetin (lipoxygenase inhibitors): or BW-755C, p henidone, timegadine [cyclo- and lipoxygenase inhibitors). Five different schedules were used with various orders and durations of drug exposure. Examples of all three types of drug interaction were found for combinations of TNF with all three classes of drugs. The largest synergism found was for TNF plus BW-755C (α = 4.30±1.3 [SE]). In general, for each combination, the degree of synergism was greater for schedules in which cells were exposed to TNF before exposure to the other agent.