Author/Editor		Fonda, Irena
Title		Spreminjanje biološke aktivnosti dejavnika tumorske nekroze alfa (TNF-alfa) in njegovih analogov
Translated title		Changing biological activity of tumour necrosis factor alpha (TNF-alpha) and its analogues
Type		monografija
Place		Ljubljana
Publisher		Univeza v Ljubljani, Medicinska fakulteta
Publication year		2005
Volume		str. 169
Language		slo
Abstract		Tumour necrosis factor alpha (TNF) is a cytokine with many diverse and important functions in health and disease. Despite TNF marked antitumor activity its systemic application in cancer treatment is not possible because of severe side effects. To overcome high systemic toxicity of TNF, which appears to be the major obstacle for its broader use in treatment of various malignancies, several new TNF analogues, showing some interesting new properties when tested in vitro in different cell lines, were designed and prepared. Furthermore, analogue LK-805, with a simple mutation E107K in the exposed tip region of the molecule, exhibits significantly lower systemic toxicity and increased antitumour activity in SA-1 tumour bearing mouse model. It has been demonstrated that the length of the N-terminal part of TNF molecule and its basisity in vitro influence the specific cytotoxic activity (IVSCA) of TNF, since native N-terminus itself sterically interferes with TNF receptor binding. Furthermore, deletions of N-terminal part of the TNF molecule as well as the addition of Histidin-taggs to its N-terminus may drastically change protein properties, e.g. hydrophobicity, solubility, formation of inclusion bodies and susceptibility to freeze/thawing cycles. Introducing mutation to the tip region of the molecule and the influence of changed basisity on IVSCA was demonstrated in several cell lines. It was shown that the modulation of the basisity in the tip region of TNF influences IVSCA similarly in mouse and human cell lines. The analogue LK-805, with a newly introduced surface charge reversal in the tip region of the molecule, which is resulting in its increased basisity, showed enhanced cytotoxic activity in several cell lines in vitro. (Abstract truncated at 2000 characters)
Descriptors		TUMOR NECROSIS FACTOR SARCOMA, EXPERIMENTAL RECEPTORS, TUMOR NECROSIS FACTOR AMINO ACID SEQUENCE PROTEIN CONFORMATION MICE SWINE CANCER VACCINES CELL LINE TUMOR CELLS, CULTURED RECOMBINANT PROTEINS HEPARIN E-SELECTIN INTERCELLULAR ADHESION MOLECULE-1 VASCULAR CELL ADHESION MOLECULE-1 DERMATAN SULFATE