Preclinical testing of recombinant adenoviral herpes simplex virus-thymidine kinase gene therapy for central nervous system malignancies.

OBJECTIVES Adenoviral gene transfer and killing efficiency using the thymidine kinase (TK)/ganciclovir (GCV) mechanism was evaluated in human cancer cells occurring as central nervous system tumors. The effectiveness of this approach was tested in vitro and in experimental models for brain tumor and leptomeningeal metastases in rats in vivo. Recombinant adenoviruses with different promoters were compared. METHODS Adenoviral vectors harboring a marker (lacZ) or a TK gene were constructed. Transcription of genes was under the control of either the adenovirus Type 2 major late promoter (MLP) or the human cytomegalovirus (CMV) immediate early gene promoter. lacZ expression and GCV killing efficiency after TK gene transfer in several human tumor cells was evaluated in vitro. The 9L rat brain tumor and leptomeningeal metastases models were used to determine the effectiveness of adeno-TK and subsequent GCV treatment in vivo. MLP and CMV containing adenoviral vectors were compared. RESULTS Gene expression and the killing of tumor cells were very efficient in all human tumor cell lines tested. The adenovirus containing the CMV promoter showed cytopathic effects in cultured tumor cells at high multiplicity of infections but also greater cell killing efficiency after TK/GCV treatment, as compared to the MLP promoter. Although both the MLP and CMV vectors showed a significant dose-dependent therapeutic effect, animals treated with recombinant adenovirus containing the CMV promoter showed significantly longer survival time (brain tumors) or symptom-free periods (leptomeningeal metastases). CONCLUSION This study demonstrates the therapeutic efficiency and feasibility of the TK/GCV approach in experimental brain tumors and leptomeningeal metastases. It also demonstrates that the promoter driving the transgene in an adenoviral vector influences toxicity and efficiency of treatment.

[1]  C. Avezaat,et al.  Treatment of leptomeningeal metastases in a rat model using a recombinant adenovirus containing the HSV-tk gene. , 1996, Journal of neurosurgery.

[2]  M. Zanta,et al.  In vitro and in vivo gene transfer to pulmonary cells mediated by cationic liposomes. , 1996, Biochimica et biophysica acta.

[3]  C. Avezaat,et al.  Herpes simplex virus thymidine kinase gene therapy for rat malignant brain tumors. , 1996, Human gene therapy.

[4]  B. Dörken,et al.  The thymidine kinase/ganciclovir-mediated "suicide" effect is variable in different tumor cells. , 1995, Human gene therapy.

[5]  P. Ryan,et al.  Effect of herpes simplex virus thymidine kinase expression levels on ganciclovir-mediated cytotoxicity and the "bystander effect". , 1995, Human gene therapy.

[6]  M. Perricaudet,et al.  The constitutive expression of the immunomodulatory gp19k protein in E1-, E3- adenoviral vectors strongly reduces the host cytotoxic T cell response against the vector. , 1995, Gene therapy.

[7]  M. Wood,et al.  Adenovirus gene transfer causes inflammation in the brain , 1995, Neuroscience.

[8]  G. Nemerow,et al.  Upregulation of integrins alpha v beta 3 and alpha v beta 5 on human monocytes and T lymphocytes facilitates adenovirus-mediated gene delivery , 1995, Journal of virology.

[9]  L. Soroceanu,et al.  Comparison of genetically engineered herpes simplex viruses for the treatment of brain tumors in a scid mouse model of human malignant glioma. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[10]  R. Haselkorn,et al.  Department of Health and Human Services, National Institutes of Health, Recombinant DNA Advisory Committee. Minutes of Meeting, December 1-2, 1994 , 1995 .

[11]  Z. Ram,et al.  Adenovirally mediated gene transfer into experimental solid brain tumors and leptomeningeal cancer cells. , 1995, Journal of neurosurgery.

[12]  J. Park,et al.  Long-term survival of rats harboring brain neoplasms treated with ganciclovir and a herpes simplex virus vector that retains an intact thymidine kinase gene. , 1994, Cancer research.

[13]  R. Grossman,et al.  Adenovirus‐mediated gene therapy of experimental gliomas , 1994, Journal of neuroscience research.

[14]  K. Hunt,et al.  Stereotactic delivery of a recombinant adenovirus into a C6 glioma cell line in a rat brain tumor model. , 1994, Neurosurgery.

[15]  G. Nemerow,et al.  Integrin alpha v beta 5 selectively promotes adenovirus mediated cell membrane permeabilization , 1994, The Journal of cell biology.

[16]  H. Shepard,et al.  Development and characterization of recombinant adenoviruses encoding human p53 for gene therapy of cancer. , 1994, Human gene therapy.

[17]  Z. Ram,et al.  Intrathecal gene therapy for malignant leptomeningeal neoplasia. , 1994, Cancer research.

[18]  R. Grossman,et al.  Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Perricaudet,et al.  Lung gene therapy: in vivo adenovirus-mediated gene transfer to rhesus monkey airway epithelium. , 1994, Human gene therapy.

[20]  G. Nemerow,et al.  Integrins α v β 3 and α v β 5 promote adenovirus internalization but not virus attachment , 1993, Cell.

[21]  Sanford H. Feldman,et al.  Direct in vivo gene transfer to ependymal cells in the central nervous system using recombinant adenovirus vectors , 1993, Nature Genetics.

[22]  W F Anderson,et al.  Gene therapy for the treatment of brain tumors using intra-tumoral transduction with the thymidine kinase gene and intravenous ganciclovir. , 1993, Human gene therapy.

[23]  Z. Ram,et al.  In situ retroviral-mediated gene transfer for the treatment of brain tumors in rats. , 1993, Cancer research.

[24]  Z. Ram,et al.  In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. , 1992, Science.

[25]  T. Hoshino.  Cell kinetics of glial tumors. , 1992, Revue neurologique.

[26]  R. Versteeg,et al.  Sensitivity of melanoma cell lines to natural killer cells: a role for oncogene-modulated HLA class I expression? , 1991, Seminars in cancer biology.

[27]  F. Moolten,et al.  Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. , 1990, Journal of the National Cancer Institute.

[28]  R. Evans,et al.  Lymphoma regression induced by ganciclovir in mice bearing a herpes thymidine kinase transgene. , 1990, Human gene therapy.

[29]  J. Horváth,et al.  Nonpermissivity of human peripheral blood lymphocytes to adenovirus type 2 infection , 1988, Journal of virology.

[30]  K. Wood,et al.  Firefly luciferase gene: structure and expression in mammalian cells , 1987, Molecular and cellular biology.

[31]  K. Tsuboi,et al.  Estimation of growth fraction with bromodeoxyuridine in human central nervous system tumors. , 1986, Journal of neurosurgery.

[32]  W. Shapiro,et al.  Isolation, karyotype, and clonal growth of heterogeneous subpopulations of human malignant gliomas. , 1981, Cancer research.

[33]  J. Pontén,et al.  Properties of human malignant glioma cells in vitro. , 1978, Medical biology.

[34]  S. Aaronson,et al.  In vitro cultivation of human tumors: establishment of cell lines derived from a series of solid tumors. , 1973, Journal of the National Cancer Institute.

[35]  P. Wolf,et al.  A COMPARATIVE STUDY OF A SERIES OF NEW INDOLYL COMPOUNDS TO LOCALIZE BETA-GALACTOSIDASE IN TISSUES. , 1963, Laboratory investigation; a journal of technical methods and pathology.

[36]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .