Projects / Programmes
Development of TNF-alpha and its analogs for cancer therapy
| Code |
Science |
Field |
Subfield |
| 4.06.00 |
Biotechnical sciences |
Biotechnology |
|
| Code |
Science |
Field |
| T490 |
Technological sciences |
Biotechnology |
TNF-alpha; tumor necrosis factor; analogs; cancer therapy; sarcoma; toxicity
Researchers (13)
Organisations (3)
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.
