Department of microbiology and molecular genetics
Faculty profile
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Istvan Fodor Center for Molecular Biology & Gene Therapy |
- PhD - USSR Academy of Sciences, Moscow, 1968, mol. biology
- DSc - USSR Academy of Sciences, Moscow, 1986, mol. biology
- DSc - Hungarian Academy of Sciences, Budapest, 1991, mol. biology
- Visiting scientist: University of California, San Francisco 1975-1976 (1 year)
- Visiting scientist: Yale University, New Haven 1979 (3 months)
- Visiting professor: University of Maryland, College Park 1990 (3 months)
- Current research interests
- Recent publications
- Teaching
Cancer gene therapy
Gene therapy provides a significant opportunity to design novel strategies for the control and cure of cancer. Current approaches typically employ virus-based vectors to deliver the therapeutic genes into human cancer cells. The use of vaccinia virus (VV) vectors has become a promising new method of gene delivery and cancer gene therapy. The ability of VV to lyse cancer cells suggests that the virus itself has potential as an oncolytic agent. We use recombinant VV expressing tumor suppressors, cytokines and suicide genes to examine the biological effects in human and murine glioma cells. We found that glioma cells infected with rVV-p53 exhibited growth inhibition and apoptosis. In an ex-vivo experiment, mice implanted with vaccinia virus-infected rat glioma cells remained tumor free until the end of the observation period, while animals implanted with non-infected cells rapidly died from cancer. The oncolytic effect was greater with the virus expressing tumor suppressor p53. Local treatment of glioma with VV vector, and especially rVV-p53, greatly reduced the tumor growth in mice. The high dose virus treatment did not induce disease symptoms in immuno-deficient athymic mice.
Replication-deficient VV vectors for gene delivery are also capable of prolonged expression of transgenes in cultured cells and animals, although the anti-tumor effect is significantly lower than that of replication-competent viruses. Recently in a collaborative study, we investigated the potential of bladder tumor therapy in an orthotopic model of C57/Bl6 mice. Intravesical instillation of the control virus had a significant effect on survival of tumor-bearing mice, which was further enhanced by using a recombinant virus expressing p53. The study showed that intravesical instillation of VV is safe and has a therapeutic effect. Immunotherapy with low doses of vaccinia mediated interleukin-2 and interleukin-12 also induced significant antitumor effect in a glioma model. Combination of tumor suppressor therapy with immunotherapy was found to be superior compared with a single modality treatment. Furthermore, sensitization of radiation treatment prior to VV-mediated tumor suppressor gene therapy could be also a promising strategy, as it was shown in our recent study.
Molecular virology
We study the mechanisms of regulation of VV gene expression and replication. Analyzing early gene expression of UV-inactivated VV, we found that inactivated viruses can effectively infect and express transgenes in mammalian cells and thus, can be utilized for gene therapy purposes. To monitor the infection and dissemination of vaccinia virus in real time in vivo, we use a recombinant vaccinia virus (VVr/g) expressing fused reporter genes of Renilla luciferase (ruc) and jellyfish green fluorescent protein (gfp). Gene expression can be detected using two highly sensitive methods: low light video imaging and fluorescence microscopy. Using this virus in several murine tumor models, we found that VV can be an effective agent for non-invasive imaging of solid tumors and metastases. The mechanisms of selective replication of VV in tumor cells and host cell-virus interaction are being investigated in our lab.
To improve the safety features of VV vaccines, we constructed a Lister vaccine derivative (vVVr/g8) lacking genes for INF-alpha/beta and INF-gamma receptor homologs involved in evasion of immune response. The mutant is similar to the parental strain regarding gene expression and virus production, as well as immunogenicity in mice. However, it is less pathogenic and thus, safer for human vaccinations. To facilitate our VV-related studies, a convenient new method of construction of recombinant VV was developed.
I. Fodor, T. Timiryasova, B. Denes, J. Yoshida, H. Ruckle, M. Lilly. Vaccinia virus-mediated p53 gene therapy of bladder cancer in an orthotopic murine model. J Urol (in press).
B. Denes, D.S. Gridley, T. Timiryasova, N. Fodor, Z. Takatsy, I. Fodor. Hyper-attenuated vaccine strain of vaccinia virus. Mol Therapy 9, Suppl. 1, S306, 2004.
S. Umphress, T. Timiryasova, T. Arakawa, S. Hilliker, I. Fodor, W. Langridge. Vaccinia virus mediated expression of human APC induces apoptosis in colon cancer cells. Transgenics, 4: 19-33, 2003
T. Timiryasova, D.S. Gridley, B. Chen, M.L. Andres, R. Dutta-Roy, G. Miller, E.J.M. Bayeta, I. Fodor. Radiation enhances the anti-tumor effects of vaccinia-p53 gene therapy in glioma. Technol Cancer Res Treat, 2, 223-235, 2003.
Z. Boldogkoi, A. Bratincsak, I. Fodor. Evaluation of pseudorabies virus as a gene transfer vector and an oncolytic agent for human tumor cells. Anticancer Res, 22:2153-9, 2002.
B. Chen, T.M. Timiryasova, P. Haghighat, M.L. Andres, E.H. Kajioka, R. Dutta-Roy, D.S. Gridley, I. Fodor. Low-dose vaccinia virus-mediated cytokine gene therapy of glioma. J Immunother, 24:46-57, 2001
B. Chen, T.M. Timiryasova, D.S. Gridley, M.L. Andres, R. Dutta-Roy, I. Fodor. Evaluation of cytokine toxicity induced by vaccinia virus-mediated IL-2 and IL-12 antitumor immuno-therapy. Cytokine, 15: 305-314, 2001.
T.M. Timiryasova, B. Chen, N. Fodor, I Fodor. New methods for construction of recombinant vaccinia viruses using PUV-inactivated virus as a helper. Biotechniques, 31:534-540, 2001.
T.M. Timiryasova, B. Chen, I. Fodor. Replication-deficient vaccinia virus gene therapy vector: evaluation of exogenous gene expression mediated by PUV-inactivated virus in glioma cells. J Gene Med, 3: 468-477, 2001.
B. Chen, T.M. Timiryasova, M.L. Andres, E.H. Kajioka, R. Dutta-Roy, D.S. Gridley, I. Fodor. Evaluation of combined vaccinia virus-mediated antitumor gene therapy with wild-type p53, IL-2 and IL-12 in a glioma model. Cancer Gene Ther, 7:1437-1447, 2000.
P. Haghighat, T. Timiryasova, B. Chen, E. Kajioka, D.S. Gridley, I. Fodor. Antitumor effect of Il-2, p53, and bax gene transfer in C6 glioma cells. Anticancer Res, 20: 1337-1342, 2000.
I. Fodor, L. Kucsera, N. Fodor, V. Pálfi and V. I. Grabko. Gene immuni-zation of mice with plasmid DNA expressing rabies glycoprotein. Acta Veter Hung, 48: 229-236, 2000.
Z. Boldogköi, A. Braun, I. Fodor. Replication and virulence of early protein and long latency transcript deficient mutants of the Aujeszky's disease (Pseudorabies) virus. Microbes and Infection, 2: 1321-1328, 2000.
Z. Boldogkoi, F. Erdelyi, I. Fodor. A putative latency promoter/enhancer (PLAT2) region of pseudorabies virus contains a virulence determinant. J Gen Virol, 81: 415-420, 2000.
M.M. Zaripov, O.S. Morenkov, N. Fodor, A. Braun, V.V. Schmatchenko, I. Fodor. Distribution of B-cell epitopes on the pseudorabies virus glycoprotein B. J Gen Virol, 80: 537-541, 1999.
I. Fodor, E. Horvath, N. Fodor, V.N. Vakharia, A. Rencendorsh, S.K. Dube. Induction of protective immunity in chickens immunized with plasmid DNA encoding infectious bursal disease virus antigens. Acta Veter Hung, 47: 481-492, 1999.
T.M. Timiryasova, J. Li, B. Chen, D.Chong, W. H. R. Langridge, D. S. Gridley, I. Fodor. Antitumor activity of vaccinia virus in glioma model. Oncol Res, 11: 133-144, 1999.
T.M. Timiryasova, B. Chen, P. Haghighat, I. Fodor. Vaccinia virus-mediated expression of wild-type p53 suppresses glioma cell growth and induces apoptosis. Intern J Oncol, 14:845-854, 1999.
CMBL 502 Molecular Biology of Prokaryotes and Eukaryotes
MICR 536 Laboratory Methods in Gene Transfer and Gene Expression
MICR 565 Virology
School of Medicine - Graduate School - Loma Linda University