Role of tumour necrosis factor in the tumour-necrotizing activity of agents with diverging toxicity

Abstract

We investigated the ability of various tumour-necrotizing agents with diverging toxicity to induce tumour necrosis factor (TNF) and cytostatic activity in Propionibacterium-acnes-primed Swiss and tumour-bearing BALB/c mice, and the capacity of anti-TNF antibodies to inhibit induction of tumour necrosis by the agents. Lipid A and especially its combination with muramyl dipeptide induced high TNF levels in Swiss mice, as measured in the serum. Lower levels were induced by detoxified lipid A and the nontoxic dsRNA, polyadenylic.polyuridylic acid, either alone or combined with muramyl dipeptide. The toxic agents also appeared the strongest inducers of mediators with cytostatic activity against cultured endothelial cells and MethA tumour cells. Anti-TNF antibodies partially reduced the cytostatic activity of the sera against MethA cells. Tumour-bearing BALB/c mice produced only low levels of TNF and cytostatic factors in response to all agents. Recombinant mouse TNF hardly reduced the DNA synthesis of MethA cells, unless normal mouse serum was added. Serum from P.-acnes-treated Swiss mice and tumour-bearing BALB/c mice, that were inhibitory on their own, failed to potentiate the action of TNF. Serum from Swiss mice treated with toxic, but not detoxified, lipid A caused extensive tumour necrosis upon injection into MethA-bearing BALB/c mice. This activity was completely abolished by pre-incubation of the serum with anti-TNF. The tumour-necrotizing activity of the agents could be partially reduced by prior injection of these antibodies. Results show that the capacity of the agents to induce TNF and cytostatic activity is not related to their antitumour potential. Although TNF is likely to be a crucial mediator of the tumour-necrotizing action of the toxic as well as the nontoxic agents, it is probably not the sole mediator. Data also indicate that induction of tumour necrosis does not require induction of high and, thus toxic, TNF levels in the serum.

Phase I study of OM-174, a lipid A analogue, with assessment of immunological response, in patients with refractory solid tumors

“…This antitumor activity is related to lipids A, a component of LPS with oligosaccharide core and polysaccharide chain [16-19]. Lipids A do not induce direct cytotoxicity on tumor cells but trigger the immune system [16,19] stimulating expression and secretion of several cytokines [20,21], and activating the inducible nitric oxide synthase (NOSII) [22]. They also induce activation of various immune cells which infiltrate the tumors [15,17,23,24].…”

Mechanisms of the antitumoral effect of lipid A

“…Since 1975, the antitumoral effect of LPS has been attributed to a circulating factor: (38) TNF-a. Though several types of lipid A were shown to induce necrosis of tumors in mice by a TNF-adependent mechanism, (10) in vitro this cytokine principally induces apoptosis in the target cells. This process is mediated by the death domain of the TNF-a receptor which, by recruiting the intracellular adaptor protein TNF receptor-associated death domain (TRADD), initiates the activation of the caspase cascade leading to cell death.…”

Antitumoral Effects of Lipid A: Preclinical and Clinical Studies

“…7 Treatments using the three types of synthetic lipid A studied in rodents—DT 5461 (Daiichi Pharmaceutical Co, Tokyo, Japan), ONO-4007 (Ono Pharmaceutical Co, Osaka, Japan), and OM-174 (OM Pharma, Geneva, Switzerland)—have been administered with protocols of injected doses in the range of 1 to 5 mg/kg. Most of these studies achieved a decrease in tumor growth and a general increase in the survival of mice, 1,6,14 rats, 5,7,8,15 and rabbits. 16 The lipid A analog SDZ MRL 953 (Sandoz, Vienna, Austria) induced regression of peritoneal carcinomas in 30% of treated rats, 15 and ONO-4007 cured subcutaneous tumors without affecting the development of intraperitoneal or lung cancers.…”

“…LPSs are components of the outer membrane of Gram-negative bacteria and are composed of a polysaccharide, an oligosaccharide core, and lipid A. These compounds have the property of inducing the secretion of various cytokines, such as tumor necrosis factor-α (TNF-α), 1 interferon-γ (IFN-γ), 2 interleukin 1-β (IL1-β), 3 and interleukin-6 (IL-6), 4 as well as activating immune cells, including neutrophils, 5 macrophages, 6 and CD4 and CD8 T lymphocytes that infiltrate the tumors. 7,8 Furthermore, these compounds have been shown to decrease suppressive cytokines such as transforming growth factor-β (TGF-β).…”