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Projects / Programmes source: ARIS

Development of TNF-alpha and its analogs for cancer therapy

Research activity

Code Science Field Subfield
4.06.00  Biotechnical sciences  Biotechnology   

Code Science Field
T490  Technological sciences  Biotechnology 
Keywords
TNF-alpha; tumor necrosis factor; analogs; cancer therapy; sarcoma; toxicity
Evaluation (rules)
source: COBISS
Researchers (13)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  18325  PhD Simon Caserman  Biochemistry and molecular biology  Researcher  2002 - 2004  107 
2.  20381  PhD Irena Fonda  Biochemistry and molecular biology  Researcher  2002 - 2004  44 
3.  11102  PhD Rok Grahek  Chemistry  Researcher  2002 - 2004  88 
4.  17275  Ana Marija Jesenko    Researcher  2002 - 2004 
5.  16171  PhD Simona Jevševar  Biotechnology  Researcher  2002 - 2004  51 
6.  09905  PhD Darko Kocjan  Chemistry  Researcher  2002 - 2004  167 
7.  09924  PhD Anton Lavrič  Pharmacy  Researcher  2002 - 2004  57 
8.  17276  Jelka Lenarčič    Researcher  2002 - 2004 
9.  01494  PhD Viktor Menart  Biotechnology  Head  2002 - 2004  162 
10.  12060  PhD Primož Pristovšek  Chemistry  Researcher  2002 - 2004  135 
11.  16193  Nataša Sever  Pharmacy  Researcher  2002 - 2004  30 
12.  06216  PhD Jelka Svetek  Biotechnology  Researcher  2002 - 2004  29 
13.  00830  PhD Anton Štalc  Biotechnology  Researcher  2002 - 2004  158 
Organisations (3)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0104  National Institute of Chemistry  Ljubljana  5051592000  20,869 
2.  0105  National Institute of Biology  Ljubljana  5055784  13,335 
3.  0258  Lek Pharmaceutical Company d.d.  Ljubljana  1732811  8,400 
Abstract
In 1999 tumor necrosis factor-alpha (TNF-alpha) was approved for local therapy of inoperable soft tissue sarcoma in European Community. High systemic toxicity is the main obstacle for broader application of TNF in cancer therapy. We suppose that development of less toxic analogs will assure safer use with existing techniques, and in perspective, the expansion to perfusion of individual internal organs. Based on two leader compounds, LK-805 and LK-819, we shall be developing two groups of new analogs. In LK-805 group, the main goal is further reduction of systemic toxicity, while in LK-819 group, additional action on tumor endothelium is supposed. The starting point in both groups is known 3D structure of the protein. Therapeutic potential of new analogs will be assessed by anti-tumor activity on mouse models. Preparation of very pure substances and complete characterisation using modern methods of protein chemistry represent a special demand. Specific action of analogs on tumor cells will be tested using selected mouse and human tumor as well as endothelial cell lines. To measure direct cytotoxic effect on tumor and endothelial cells, various methods for determination of apoptosis will be applied. Members of LK-819 group will also be tested on chicken embryo to see a possible anti-angiogenic activity. Further, we shall try to determine which TNF toxic effects are reduced using new analogs. The main reason for preparation of new TNF analogs with reduced systemic toxicity is their future application in curing inoperable soft tissue sarcoma and skin melanoma. Significant extension of their use would represent the treatment of inoperable liver cancer, where currently no successful therapy is available. All proposed applications in cancer treatment represent important advance in saving human lives and improvement of patients' life quality. The possibility of future use of these analogs represents an improvement of national health standard as well as the opportunity to enter the world market with our own substances.
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