Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism.

Abstract

Recombinant human tumor necrosis factor (rH-TNF) is a cytotoxic monokine with pleiotropic effects. A phase I trial of rH-TNF was initiated using a five-day continuous intravenous (IV) infusion repeated every 28 days. Thirty-eight courses of therapy were administered to 19 patients. The starting dose was 5 X 10(4) U/m2/d, with escalations to 1.0 X 10(5), 2.0 X 10(5), 2.4 X 10(5), and 3.0 X 10(5) U/m2/d. Systemic side effects, including fever, chills, hypotension, fatigue, anorexia, and headaches, were mild and self-limiting. At the maximum tolerated dose of 3.0 X 10(5) U/m2/d, dose-limiting hematologic toxicity was manifested by transient thrombocytopenia and leukopenia. Elevated bilirubin levels were also seen at the higher dose levels. Lipoprotein analysis demonstrated that the five-day treatment with rH-TNF was associated with decreases in high-density lipoproteins, as well as increases in triglycerides and very-low-density lipoproteins. Pharmacokinetic studies using an enzyme-linked immunosorbent assay (ELISA) test indicated plasma rH-TNF levels less than 0.2 U/mL. The recommended phase II dose of rH-TNF administered as a five-day continuous infusion is 2.4 X 10(5) U/m2/d.

Tumour necrosis factor: a cytokine with multiple biological activities

“…The half-line of rTNF administered intravenously was 20 min. Side-effects include fever, chills, rigor, fatigue, diarrhoea, headache, nausea and vomiting, severe hypotension, and fluid retention most likely consequent to a capillary-leakage syndrome similar to that described for IL-2 (Chapman et al, 1987;Creaven et al, 1987;Kimura et al, 1987;Mortiz et al, 1989;Sherman et al, 1988 Kimura et al, 1987). Transient thrombocytopenia and leukopenia have also been observed (Sherman et al, 1988).…”

“…Large studies are currently underway but, for the time being, no consensus has emerged from preliminary results concerning the clinical efficacy of this lymphokine in the treatment of malignancy, little evidence of TNF anti-tumour activity having been observed in vivo. Although partial remissions were documented in individual patients with colon and pancreatic cancer and B cell lymphomas, only a few clinically significant benefits have been observed (Blick et al, 1987;Creaven et al, 1989;Herrmann, 1989;Moritz et al, 1989;Selby et al, 1987;Sherman et al, 1988) One of the most promising approaches is represented by the use of TNF in association with other interleukins, and in particular with IL-2 since a synergism occurs between TNFalpha and IL-2 in the generation of lymphokine activated killer (LAK) cells (Chouaib et al, 1988;Owen-Schaub et al, 1988;Matossian-Rogers et al, 1989;Yang et al, 1989). The interaction between IL-2 and TNF on LAK precursors results in a reduction of the IL-2 concentration required for the differentiation of granular lymphocytes into LAK cells.…”

“…In vivo use of TNF: present status and future directions In rabbits it has been shown that TNF is cleared from the plasma with a half-life of 6-7 min (Beutler et al, 1985b al., 1987;Chapman et al, 1987;Creaven et al, 1987Creaven et al, , 1989Sherman et al, 1988). TNF was administered by the intravenous and subcutaneous rute (Chapman et al, 1987).…”

Linkage with cathepsin B-sensitive dipeptide promotes the in vitro and in vivo anticancer activity of PEGylated tumor necrosis factor-alpha (TNF-α) against murine fibrosarcoma

“…However, it is cleared rapidly from the circulation and widely distributed to various tissues after intravenous administration, resulting in limited bioavailability. Although systemic administration of TNF-α causes the regression of various transplanted solid tumors [6], the high doses required for significant clinical anti-tumor effects often also elicit unexpected side-effects, such as tissue inflammation and injury, as well as the lethal endotoxic shock-like syndrome [7,8]. Similar in vivo drawbacks to those seen with TNF-α are also found in clinical applications of other bioactive proteins [9].…”

An investigation of adverse effects caused by the injection of high-dose TNFα-expressing adenovirus vector into established murine melanoma

“…The body weight reduction and sudden death we observed previously in response to intratumoral injection of Ad-TNFa or AdRGD-TNFa at 10 10 VP potentially resulted from TNFa, which is a proinflammatory cytokine that induces critical side effects when administered systemically at high doses. [10][11][12] Furthermore, an inflammatory reaction is known to occur in highly Ad-infected organs due to an immune response to Ad. [13][14][15] In response to these data, we first investigated the mRNA level of Ad receptors in murine major organs by reverse transcription-polymerase chain reaction (RT-PCR) analysis 5 and the rate of Ad leakage from established B16 BL6 tumors that had been injected with AdRGD or conventional Ad carrying the luciferase reporter gene (AdRGD-Luc and Ad-Luc, respectively).…”