CIRCADIAN DYNAMICS OF TUMOR-NECROSIS-FACTOR-ALPHA (CACHECTIN) LETHALITY

Recombinant human tumor necrosis factor-alpha (TNF-alpha) has demonstr able antitumor activity in transplantable murine tumor models and pati ents with cancer but is highly toxic to both animals and human beings. The narrow therapeutic index of TNF-alpha has limited its anticancer utility Toxicity associated with many standard anticancer drugs is hig hly dependent upon the circadian timing of their administration. The e ffect of time of day of TNF-alpha administration on lethal toxicity wa s examined in 238 BALB/c female mice in two studies. Each mouse receiv ed a single intravenous injection of human TNF-alpha at one of six equ ispaced times within the first contiguous 24-h cycle. The probability of dying across all times of day of TNF-alpha treatment was not equal (p<0.01) and varied up to ninefold. Significant time of day dependence of TNF-alpha toxicity was present over a full order of magnitude of T NF-alpha dose. The frequency of TNF-alpha-induced lethality was greate st and the time to death was most brief when TNF-alpha was administere d just before awakening. The survival probability was highest when TNF -alpha was administered in the second half of the daily activity span corresponding roughly to late afternoon and evening hours for human be ings. The optimization of TNF-alpha administration timing is a strateg y that warrants further investigation for improving the toxic/therapeu tic ratio of this important cytokine. From a more fundamental perspect ive, these data may be essential for achieving a fuller understanding of TNF-alpha in vivo biology.