title: Phase I trial of intravenously administered endotoxin (Salmonella abortus equi) in cancer patients.
abstract: We report a phase I study in cancer patients being treated with i.v. bolus injections of highly purified lipopolysaccharide (LPS) Salmonella abortus equi. Twenty-four patients with disseminated cancer received escalating doses of LPS at 2-week intervals. Dose escalation was performed in six dose levels treating 3-6 patients at each level. Dose levels 1 and 2 consisted of 0.15 and 0.3 ng/kg, respectively. Further dose escalation up to 5.0 ng/kg was enabled by pretreatment with ibuprofen, which attenuated the constitutional side effects of LPS. The maximum tolerated dose was 4.0 ng/kg with dose-limiting toxicity being World Health Organization grade III hepatic toxicity. Hematological changes included transient decreases in WBCs affecting granulocytes, monocytes, and lymphocytes in a marked different pattern. Endogenous cytokine release occurred in an LPS dose-dependent manner as measured by tumor necrosis factor-alpha, interleukin-6, and macrophage colony-stimulating factor serum levels. Moderate antitumor activity in colorectal cancer was observed in the case of 2 patients. Phase II trials of LPS are currently in progress.
authors.affiliation: Medizinische Klinik I, Albert-Ludwigs-Universität, Freiburg, Federal Republic of Germany.
authors.forename: R
authors.initials: R
authors.lastname: Engelhardt
authors.forename: A
authors.initials: A
authors.lastname: Mackensen
authors.forename: C
authors.initials: C
authors.lastname: Galanos
mesh_terms: D004334:Drug Administration Schedule; D004341:Drug Evaluation; D004731:Endotoxins / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000097:blood; D007958:Leukocyte Count / Q000187:drug effects; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D016173:Macrophage Colony-Stimulating Factor / Q000097:blood; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D010976:Platelet Count / Q000187:drug effects; D012475:Salmonella; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D004731:Endotoxins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor