SVIBOR - Project code: 1-08-303

MINISTRY OF SCIENCE AND TECHNOLOGY

Strossmayerov trg 4, HR - 10000 ZAGREB
tel.: +385 1 459 44 44, fax: +385 1 459 44 69
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Project code: 1-08-303


TUMORS AND METASTASES: BIOLOGY AND THERAPY


Main researcher: BAŠIĆ, IVAN (2406)


Assistants
Type of research: basic
Duration from: 01/01/92. to 12/31/96.
Papers on project (total): 22
Papers on project quoted in Current Contents: 3
Institution name: Prirodoslovno-matematički fakultet, Prirodoslovni odjeli, Zagreb (119)
Department/Institute: Department of Animal Physiology
Address: Rooseveltov trg 6, P.O. Box 933
City: 10000 - Zagreb, Croatia
Communication
Phone: 385 (0)41 441-030
Fax: 385 (0)455-2645
Summary: A) ANTIMUTAGENIC EFFECTS OF RADIOPROTECTOR WR - 2721: The antimutagenic effects of the radiation protective agent S - 2 - (3 - aminopropylamin) ethylphosphorothionic acid (WR - 2721) were studied against fission - spectrum neutron and 60Co gamma ray induced mutagenesis in mice. As "in vitro" T lymphocyte cloning technique has been developed; splenic T lymphocyte from mice were grown in round-bottom 96 microwell culture plates with or without selective agent 6 - thioguanine (6 - TG). The frequency of mutants,as a result of exposure to neutrons or 60Co photons, increased 100 - fold with dose. Doses of 150 cGy neutrons and 750 cGy 60Co photons were equally mutagenic. When animals were injected with WR-2721 at a dose of 400 mg/kg B.W., .i.p., 30 min before whole body irradiation with neutrons or photons, the frequency of mutants was significantly reduced at all radiation doses. B) RETROVIRAL EXPRESSION OF THE HEPATITIS B VIRUS X GENE: The transforming capability of normal and mutated HBV X gene was investigated. NIH 3T3 cells were transfected with plasmids carrying normal and frameshift mutant X gene. The transformed phenotype was tested using focus - forming assay and ability to grow in soft agar. The experiments showed that mutated HBV X gene has transforming capability while normal X gene is less efficient in NIH 3T3 transformation assay. B)EXPERIMENTAL TUMOR MODELS & BIOTHERAPY: The influence of single biotherapeutic agent on tumor growth and metastasis formation or combination of biotherapy and local tumor irradiation were studied using animal models. Local tumor was generated by injection of tumor cells into the footpad. Anaplastic carcinoma metastasizes spontaneously into lung of tumor bearers. To generate lung metastases of mammary carcinoma, cells were injected i.v. local irradiation of tumor growing in footpad was done by a single dose of 20 Gy fast electrons. Biotherapeutic agents were: Interleukin - 2 (IL - 2), lymphokine-activated killer (LAK) cells and bee venom, respectively. The number of ACa metastases in the lungs of the rats treated with combined therapy was smaller than that of animals treated with single therapy.Number of lung metastases were also reduced in rats treated with LAK cells and IL-2, as compared with single treatment. Bee venom given i.v. significantly reduced the number of lung metastases of MCa in CBA mice. Subcutaneous injection of bee venom delayed the tumor formation when cells were injected at the same site as bee venom, immediately after bee venom injection. It is likely that both suppression of metastasis formation and tumor growth in CBA mice were due to nonspecific stimulation of cells involved in immune reactions.

Keywords: radioprotection, mutagenesis, HPRT locus, limiting dilution assay, splenic T lymphocyte, neutrons, gamma rays, WR - 2721, hepatitis B virus, DNA, viral vectors, cytokines, interleukin 2, LAK cells, tumor growth, metastasis, bee venom, cellular immunity, humoral immunity

Research goals: A) Aminothiols have been found to protect rodents against radiation and/or chemical carcinogenesis. These data, along with data obtained using "in vitro" assays for hypoxantine - guanosine phosphoribosyl transferase (HGPT) locus mutagenesis suggest that radioprotecctors could be effective in protecting against radiation - induced mutagenesis "in vivo". With the advent of new approaches to mutagenesis, the main goal of these studies was to determine if WR - 2721 can exert its antimutagenic effect in irradiated mice. B) Hepatitis B virus (HBV) is etiologic agent of viral hepatitis and is considered to be a major factor in formation of primary hepatocellular carcinoma (PHC). The goal of these studies was to asses the transformiing capability of HBV X gene which may be involved in transcriptional activation of cellular genes responsible for the initiation of PHC. C) Studies with biological response modifiers (BRM) and their efficacy in controlling tumor growth and metastasis in animals were done to determine the effectiveness of combined therapeutic modalities (radiotherapy + IL - 2, LAK cells + rIL - 2). We also studied possible mechanism(s) of antitumor action of combined therapy. We used bee venom as possible antitumor agent to determine its effects on tumor growth and metastasis in a mouse model. The effect of bee venom on immune system was also studied to see if its effect on the immune system can be correlated with its possible antitumor activity.

COOPERATION - PROJECTS


  1. Name of project: 5 R01 CA37435 Experimental Radiotherapy, Carcinogenesis & Protectors
    Name of institution: Argonne National Laboratory Biological, Enviromental and Medical Research Division 9700 South Cass Avenue Argonne, Illinois 60439 - 4833, USA
    City: Argonne, Illinois, USA

COOPERATION - INSTITUTIONS


  1. Name of institution: Biological, Enviromental & Medical Research Division Argonne National Laboratory 9700 South Cass Avenue Argonne, Illinois 60439 - 4833 USA
    Type of institution: University/Faculty
    City: Argonne, Illinois, USA
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