Biological response to intravenously administered endotoxin in patients with advanced cancer.
The purpose of the study was to evaluate the toxicity and biological activity of highly purified lipopolysaccharide (LPS) administered intravenously to cancer patients in order to establish an optimum dosage scheme. An initial subtoxic dose was increased in weekly increments in accordance with individual regimens that maintained patient reaction at a safe and acceptable level. Purified LPS from Salmonella abortus equi was administered to 11 patients with advanced solid tumors on a weekly schedule with intraindividually escalating dosage as determined by patient response. Biological response was monitored by complete blood count, C-reactive protein, and cytokine measurements at different time points after LPS injection. Tumor necrosis factor-alpha (TNF) and interleukin-1 beta serum levels were measured by enzyme-linked immunosorbent assay and interleukin-6 (IL-6) by bioassay. Dose-limiting toxicities including chills and fever (WHO grade III) were reached at 1.0 ng/kg of body weight (maximal tolerated dose-1, MTD-1). Pretreatment with ibuprofen (1,600 mg) abrogated these side effects, allowing further escalation of LPS doses up to 10 ng/kg of body weight. At dose levels greater than 8.0 ng/kg of body weight (MTD-2), the aforementioned side effects occurred again and, additionally, hepatic toxicity (WHO grade III) was observed. Hematological changes included neutropenia followed by a pronounced neutrophilia contributed to by up to 30% bands, marked monocytopenia for 3 h, and retarded lymphopenia. By 24 h, all hematological parameters returned to pretreatment values. TNF serum levels increased from 10 pg/ml before treatment to 7,000 pg/ml as a function of dosage. Maximum serum levels were reached at 60 to 90 min after LPS injection. Similarly, IL-6 serum concentrations increased from less than 4 to 2,500 U/ml; peak levels were obtained 30 min after TNF peak values. Prior administration of ibuprofen had no effect on the above-mentioned hematological changes nor on cytokine release. LPS can be administered intravenously in weekly intervals at escalating doses from 0.15-10.0 ng/kg of body weight, when patients are protected by pretreatment with ibuprofen at dose levels above 1.0 ng/kg of body weight. Cytokine release as measured by TNF and IL-6 increased in a dose-dependent manner although the constitutional symptoms are completely attenuated.
Engelhardt
R
R
Medizinische Klinik I, Department of Hematology and Oncology, Albert-Ludwigs-Universität, Freiburg, F.R.G.
Mackensen
A
A
Galanos
C
C
Andreesen
R
R
D000328:Adult; D000368:Aged; D002097:C-Reactive Protein / Q000032:analysis; D005260:Female; D006403:Hematologic Tests; D006801:Humans; D007052:Ibuprofen / Q000627:therapeutic use; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000627:therapeutic use* / Q000633:toxicity; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000628:therapy*; D013618:Tachyphylaxis / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D007052:Ibuprofen