Cytotoxicity Induced by Recombinant Human Tumor Necrosis Factor-.ALPHA. Dependent on the Types of Its Receptors on Canine Cells.

Abstract

ABSTRACT. Based on the recent findings that show how recombinant human tumor necrosis factor (rh-TNF)-α has potent antitumor activity on human cancer patients when it locally administrated, we have tested the cytotoxicity of rh-TNF-α on 3 canine cultured cells: (1) canine kidney carcinoma (CKCa-1), (2) mastocytoma and (3) Mardin Darby canine kidney cells (MDCK). The cell surface expression of TNF-α receptors on these canine cells was also determined with anti-human TNF RI and RII polyclonal antibodies. Our data shows that on CKCa-1 which has TNF RI receptors rh-TNF-α induced cytotoxicity. By contrast, it exhibited no toxicity on canine mastocytoma which has mainly RII receptors. The data also suggest actinomycin D (ACT-D), an anticancer antibiotic, enhanced the cytotoxicity of rh-TNF-α. Combined with ACT-D, rh-TNF-α showed the cytotoxicity on MDCK which possessed both TNF RI and RII receptors. The results indicate that the cytotoxicity of rh-TNF-α depends on the presence of TNF RI receptors on canine tumor cells. -KEY WORDS: canine cell, cytotoxicity, rh-TNF-α, TNF-α receptor.

Nephrotoxicity of platinum complexes is related to basolateral organic cation transport

“…Members of the tumor necrosis factor receptor (TNFR) family are especially directly involved in caspase activation and subsequent cisplatin-induced renal failure [29][30][31]. Additionally, MDCK cells express TNFR1 and TNFR2 [32].…”

Preclinical Investigation of PEGylated Tumor Necrosis Factor α in Dogs with Spontaneous Tumors: Phase I Evaluation

“…It exhibits a range of biological effects, including direct tumor cell cytotoxicity, immunomodulation, and endothelial toxicity (2)(3)(4)(5). Early enthusiasm for human TNFα (hTNFα) as a systemic anticancer therapy was tempered when multiple studies indicated that hTNFα had a very short circulating half-life (14 minutes to 2.5 hours) and severe side effects, primarily hypotension (6)(7)(8).…”

“…In addition, hTNFα induces diverse molecular and biochemical events in dogs similar to those described in humans. These events include induction of endothelial intercellular adhesion molecule-1, and P-and E-selectin expression (28)(29)(30), increased circulating endothelialderived vasoactive factors (27), increased neutrophil adherence (28,31), and in vitro cytotoxicity against canine tumor cells (4,5). Preliminary studies by our group suggested that, although native hTNFα was capable of inducing the expected hemodynamic changes in normal laboratory dogs (hypotension, hypoxemia), administration of a biologically equivalent dose of PEG-hTNFα resulted in no significant hemodynamic changes with preservation of other effects such as neutrophil margination.…”

“…Preliminary studies by our group suggested that, although native hTNFα was capable of inducing the expected hemodynamic changes in normal laboratory dogs (hypotension, hypoxemia), administration of a biologically equivalent dose of PEG-hTNFα resulted in no significant hemodynamic changes with preservation of other effects such as neutrophil margination. 5 Clinical trials in pet dogs with spontaneous cancer are important translational models from rodents to practical applications in human cancer. The dog is an excellent model for the investigation of novel cancer therapeutics owing to its large size, relative outbreeding, similar responses to environmental influences, and biological/physiologic similarity to humans.…”

In Vitro Cytotoxicity of Recombinant Human-TNF-.ALPHA. and Actinomycin D on Canine Normal and Tumor Cells.

“…Actinomycin D (ACT-D), an antitumor antibiotic, has been experimentally used to treat lymphoma and malignant melanoma in small animal practice [9,23]. We previously demonstrated that incubation of canine tumor cells with ACT-D increased their susceptibility to the cytotoxic effect of recombinant human TNF-α (rh-TNF-α) [1]. Moreover, in in vivo study using tumor-bearing mice, the combined treatment of rh-TNF-α and ACT-D was reported to produce synergistic antitumor effect [15].…”