title: Comparative studies on the ultrastructure of the rat lungs after intratumor treatment of Morris hepatoma with rhTNF-alpha and its muteins.
abstract: The aim of the present study was the comparative analysis of morphological changes found in the lungs of Buffalo rats in the course of Morris hepatoma 5123 after i.t. treatment with recombinant human TNF-alpha (rhTNF-alpha) and its muteins. Modification of the native TNF-alpha molecule and synthesis of mutagenized analogues can prevent undesirable symptoms observed in the case of therapeutic administration of rhTNF-alpha. TNF-alpha has been shown to interact with two distinct membrane receptors (TNF-R): p55R and p75R. Mutagenized mutein V binds selectively with p55R. Mutein VI fails to recognize either TNF-R. The cytokines were applied in a dose of 10 micrograms protein in a cycle of 8 days. The control group consisted of tumor-bearing animals which were given PBS. Ultrastructural examinations were based on transmission electron microscope (TEM). Mutein VI-receiving animals showed enhanced changes of cytotoxic nature. Severe damage to endothelial cells (necrosis inclusive) was observed. Blood vascular lumen showed accumulation of neutrophils and monocytes. Features of enhanced activity of endothelial cells were noted. Focally, within pulmonary alveoli conglomerates of fibrin and fragments of damaged cells were found, with erythrocytes, neutrophils and macrophages in their vicinity. The epithelium of pulmonary alveoli showed signs of considerable damage, including necrosis. The lumen of pulmonary capillaries in rhTNF-alpha-treated animals showed a predominance of eosinophils and monocytic cells. Features of endothelial stimulation were observed, although without a tendency to form microthrombi. Much less pronounced changes both in the lung capillary bed and in the alveolar epithelial cells were noted in the mutein V-given animals. Our findings confirm the possibility of peripheral activation of cells involved in the cytokine-induced antitumor response. Mutein V with the smallest effect on the lung tissue rebuilding seems to be a rhTNF-alpha derivative which can delimit the undesirable symptoms in the course of antitumor therapy reduced to i.t. injections.
authors.affiliation: Department of Gynecology and Septic Obstetrics, Medical University of Bialystok, Poland.
authors.forename: S
authors.initials: S
authors.lastname: Terlikowski
authors.forename: S
authors.initials: S
authors.lastname: Sulkowski
authors.forename: M
authors.initials: M
authors.lastname: Sulkowska
authors.forename: H F
authors.initials: HF
authors.lastname: Nowak
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002196:Capillaries / Q000187:drug effects / Q000648:ultrastructure; D005260:Female; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000648:ultrastructure; D017348:Microscopy, Electron, Scanning Transmission; D009368:Neoplasm Transplantation; D051381:Rats; D011915:Rats, Inbred BUF; D011994:Recombinant Proteins / Q000627:therapeutic use / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C109426:mutein 5; C105965:mutein 6