Antitumor effects of Interferons
Study of Antitumour Effectiveness of Interferones-gamma and alfa 2b in Cultures of Tumour Cells of Peripheral Blood and Marrow at Patients with Multiple Myeloma, Chronic Lympholeukemia and Myeloleukemia
Tech Area / Field
- MED-DRG/Drug Discovery/Medicine
3 Approved without Funding
State Research Center for Applied Microbiology, Russia, Moscow reg., Obolensk
- Vladimirsky Regional Clinical Research Institute, Russia, Moscow
Project summaryThe project concerns study of one of the basic directions in up-to-date oncohaematology, the problem of anti-tumor activity of recombinant interferons a 2b and g at chronical lympho-proliferative processes (multiplex myeloma (М М), chronic myeloleukosis (CML), chronic lympholeukosis (CLL)).
Clinical observations show convincingly enough that interferon a is highly efficient at a number of oncohaematological diseases.
Work direced at revealing mechanism of anti-tumor activity of interferons a 2b and g is of particular interest. It has been determined that they possess not only anti-proliferative effect, but influence on processes of programmed death of cells.
Information on molecular mechanisms taking place in peripheral blood and marrow of oncohaematological patients under effect of interferons a 2b and g (in vitro) is interesting not only as it is, but in clinical light as well.
Ambiguous mechanism of interferon effect on tumor cells is of great significance in clinical practice. It has been noted that in some cases they not only reduce cell proliferation but stimulate it as well. That is why, at empirical prescription of interferon preparations there is a great risk of obtaining negative outcome.
Urgency of the problem is of no doubt. The goal of the given project is to create a test, which will allow to draw a conclusion on interferon optimal dose, necessary to reach desirable effect, taking into account disease phase and inpidual susceptibility of blood and marrow cells of patients having М М, CML, and CLL.
To achieve the set goal the following tasks will be implemented:
– study of receptor expression to human interferons (a 2b and g) on tumor cells of patients' peripheral blood and marrow;
– study of anti-proliferative effect of recombinant interferons on tumor cells isolated from patients' peripheral blood and marrow (analysis of receptor expression to TNF- a and FAS-ligand pre- and post recombinant interferon exposure both separately and in combination);
– study of recombinant interferon dose-dependent effect on tumor cells isolated from patients' peripheral blood and marrow, taking into account disease phase;
– comparative analysis of clinical effectiveness of IFN- a 2b in patients with high and low susceptibility of tumor cells in vitro.
The following methodical approach is proposed:
– to assess availability of receptors to human interferons (a 2b and g) as well as to apoptosis receptors (TNFR and FAS) on tumor cells using the method of flow cytofluorimetry;
– to assess dose-dependent anti-proliferative effect of rIFN-g and IFN-a (developed at SRC AM) on tumor cells using the method of flow cytofluorimetry and RT-PCR;
– to assess dose-dependant expression of apoptosis receptors (TNFR and FAS) on tumor cells using the method of flow cytofluorimetry and RT-PCR;
– to examine concentrations of rIFN-g and IFN-a causing activation of tumor cells to apoptosis using mixed cell cultures of patients’ blood and marrow;
– to examine two groups of patients with high and low susceptibility of tumor cells in vitro to IFN- б 2b to determine differentials of clinical effectiveness.
The proposed work is directed at application of fundamental research in clinical practice.
Basic nature of the planned investigations is in the study of mechanisms of anti-tumor effect of recombinant interferons a 2b and g in cultures of peripheral blood and marrow tumor cells at М М, CML, and CLL, including their effect on apoptosis.
Applied nature of the given research is in working out definite criteria for effectiveness assessment when using recombinant IFN- g and a 2b in patients with above-mentioned diseases. At this, disease phase and patient inpidual susceptibility are taken into account. It will allow to exclude therapy empirical principle and to use interferons a 2b in clinical practice only in cases when a good clinical outcome can be forecasted by susceptibility in vitro.
The results of the research are planned to be published in foreign and domestic scientific journals and reported at scientific conferences.