DOWN-REGULATION OF THE PROINFLAMMATORY CYTOKINE RESPONSE TO ENDOTOXINBY PRETREATMENT WITH THE NONTOXIC LIPID-A ANALOG-SDZ-MRL-953 IN CANCER-PATIENTS

Interfering with the endotoxin-mediated cytokine cascade is thought to be a promising approach to prevent septic complications in gram-negat ive infections. The synthetic lipid A analog SDZ MRL 953 has been show n to be protective against endotoxic shock and bacterial infection in preclinical in vivo models. As part of a trial of unspecific immunosti mulation in cancer patients, we conducted a double-blind, randomized, vehicle-controlled phase I trial of SDZ MRL 953 to investigate, first, its biologic effects and safety of administration in humans and, seco nd, its influence on reactions to a subsequent challenge of endotoxin (Salmonella abortus equi). Twenty patients were treated intravenously with escalating doses of SDZ MRL 953 or vehicle control, followed by a n intravenous application of endotoxin (2 ng/kg of body weight [BW]). Administration of SDZ MRL 953 was safe and well-tolerated. SDZ MRL 953 itself increased granulocyte counts and serum levels of granulocyte c olony-stimulating factor (G-CSF) and interleukin-6 (IL-6), but not of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), IL-1 beta and IL-8. Compared with vehicle control, pretreatment with SDZ MRL 953 markedly reduced the release of TNF-alpha, IL-1 beta, IL-8 , IL-6, and G-CSF, but augmented the increase in granulocyte counts to endotoxin. Induction of tolerance to the endotoxin-mediated cascade o f proinflammatory cytokines by pretreatment with SDZ MRL 953 in patien ts at risk may help to prevent complications of gram-negative sepsis. (C) 1997 by The American Society of Hematology.