SVIBOR - Project code: 1-08-210

MINISTRY OF SCIENCE AND TECHNOLOGY

Strossmayerov trg 4, HR - 10000 ZAGREB
tel.: +385 1 459 44 44, fax: +385 1 459 44 69
E-mail: ured@znanost.hr

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Project code: 1-08-210


THE STUDY OF THE DEVELOPMENT OF RESISTANCE TO GENOTOXIC AGENTS


Main researcher: OSMAK, MAJA (34303)


Assistants
Type of research: developmental
Duration from: 01/01/91. to 12/31/95.
Papers on project (total): 92
Papers on project quoted in Current Contents: 30
Institution name: Institut "Ruđer Bošković", Zagreb (98)
Department/Institute: Laboratory of Genotoxic Agents Department of Molecular Medicine
Address: Bijenička cesta 54
City: 10000 - Zagreb, Croatia
Communication
Phone: 385 (01) 4561-145
Fax: 385 (1) 425-497
Summary: The main subject of this project was to investigate the changes in human cells resistant to cytostatics induced by cytostatics or irradiation: to examine the mechanisms involved in drug resistance, the alterations in cell response to additional cytostatics, the reversal of resistance and the application of these data to the clinic. Human laryngeal and cervical carcinoma cells resistant to cisplatin, carboplatin or vincristine were isolated, clones selected and their sensitivity to additional cytostatics examined. The mechanisms involved in resistance to cisplatin and vincristine were determined as well as the effects potential modificators of resistance to cisplatin and vincristine. The cause of altered response of cell (preirradiated with repeated low doses of gamma rays) to cytostatics was determined. In mammalian cells the concentration of proteolitic enzymes - proteinases, cathepsins (especially in parental and resistant cells) were studied following the treatments with different genotoxic agents. In the collaboration with Medical School, University of Zagreb,the investigation have been started concerning the role of glutathione and glutathione transferases in diagnostic and therapy of gynecological cancers. Monoclonal antibodies against invasive ductal breast carcinoma and boronated monoclonal antibodies, a reagent for boron capture therapy, have been prepared. The plasmids and recombinant adenoviruses have been constructed for veterinary medicine purposes, as well as the monoclonal antibodies rised against the envelope of Suid herpesvirus 1.

Keywords: Cell cultures, cytostatics, irradiation, drug-resistance, modificators of drug-resistance, hyperthermia, cisplatin, carboplatin, vincristine, cathepsins, glutathione, glutathione transferase, gynecological tissue, oncogenes, P-glycoprotein, breast carcinoma, monoclonal antibodies, Suid herpesvirus, plasmid, adenovirus.

Research goals: Resistant cells are the major obstacle in tumor treatment. Therefore, the mechanisms involved in this phenomenon are of the great interest. The aim of our study was to determine the mechanisms involved in resistace to cytostatics in preirradiated cells or cells obtained with treatment with cytostatics, the cross-resistance pattern of these cells, as well as the reversal of resistance. We have shown that resistance to cytostatics is caused by numerous cell alterations, that are reflected in modified cell-response to different cytostatics. The response was dependent on the cell line examinated, on the schedule of resistance development and on the nature of the secondary agent. Also, depending on the type of cell line and the cytostatic involved in resistance development, different agents could reverse the resistance. We found that the same protective mechanisms can account for resistance after both irradiation and cytostatics. Our observations change some of the basic postulates in radiotherapy: special caution must be taken in the choice of cytostatic in combined therapy. In the collaboration with Medical School, Universitiy of Zagreb, the investigation have been started, concerning the role of glutathione and glutathione transferase (GST) in diagnostic and therapy of gynecological cancers. The preliminary results indicate GST as possible diagnostic and prognostic factor. For the purpose of early diagnostic of breast cancer, monoclonal antibodies against ductal breast carcinoma have been prepared. For cancer therapy, boronated monoclonal antibodies have been prepared, as a tool for boron-neutron capture therapy.For application in the veterine medicine, monoclonal antibodies rised against glycoprotein Suid herpesvirus 1 (diagnostic) and plasmids and adenoviruses with pseudoarabies virus genes (for vaccination) have been prepared.

COOPERATION - INSTITUTIONS


  1. Name of institution: Klinika za tumore
    Type of institution: Institution whose primary activities ar
    Type of cooperation: Joint project
    City: 10000 - Zagreb, Croatia

  2. Name of institution: Institut za medicinska istraživanja i medicinu rada Sveučilišta u Zagrebu
    Type of institution: State institute
    Type of cooperation: Joint project
    City: 10000 - Zagreb, Croatia

  3. Name of institution: Onkološki inštitut
    Type of institution: State institute
    Type of cooperation: Joint project
    City: Ljubljana, Slovenija

  4. Name of institution: Klinika za ženske bolesti i porode
    Type of institution: University/Faculty
    Type of cooperation: Joint project
    City: 10000 - Zagreb, Croatia

  5. Name of institution: Farmaceutsko kemijska industrija Pliva
    Type of institution: Economical/Production
    Type of cooperation: Joint project
    City: 10000 - Zagreb, Croatia

  6. Name of institution: Hrvatska liga protiv raka
    Type of institution: Institution whose primary activities ar
    Type of cooperation: Financial support
    City: 10000 - Zagreb, Croatia
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