? In vitro sensitivity of BT4C glioma cells transduced with the HSV-tk gene to antiviral agents.
? Selective radiosensitivity of BT4C-tk cells by antiherpes agents.
? Determine the effectiveness of in vitro gene transfer of the HSV-tk gene for the treatment of BT4C glioma cells with antiviral pyrimidine and purine nucleoside analogues.
? Determine the effectiveness of in vivo gene transfer of HSV-tk gene for the treatment of BT4C glioma in the rat brain with antiviral pyrimidine and purine nucleoside analogues.
? Optimization of current viral vectors and development of novel vectors in order to improve gene delivery of the HSV-tk genome.
? Determine the magnitude of the effect of antiherpes agents on the radiation response of BT4C glioma transduced in vivo with the HSV-tk gene.
? Determine acute and late effects of critical normal tissues (brain).
? Consider safety and toxicity aspects of antiherpes agents and radiation combination therapy in a sub-human clinical system - spontaneous gliomas in the dog brain.
It is estimated that in 1997, more than 40.000 new cases of central nervous system cancers will occur within the European Community accompanied by approximately 30.000 deaths.
Malignant glioma of the brain is one of the most lethal cancers in humans. The median survival time after diagnosis is 50 weeks for glioblastoma multiforme. The majority of patients die of local recurrence, despite aggressive medical intervention including surgery, radiotherapy, and nitrosourea based chemotherapy.
Recent attention has been focused on gene therapy of gliomas. One particularly appealing approach has been to incorporate the viral gene which codes for the enzyme thymidine kinase into the replicating cancer cell, so that the viral-derived thymidine kinase can toxify a systematically administered antiviral drug. Although a large number of institutions including our own are engaged in a variety of clinical trials there is as yet no unambiguous proof that gene therapy has cured a single patient. The objective of this proposal is to test the hypothesis that the radiosensitivity of tumor cells transduced with a viral vector containing an HSV-tk gene would be selectively enhanced by antiviral agents. Specifically, we will attempt to determine the potential clinical applicability of this novel approach, using in vivo gene transfer of the HSV-tk gene for the treatment of malignant glioma of the rat brain and later of the dog brain. Our conjecture is that thymidine kinase activated antiviral drugs, nucleoside analogues derived from either purine or pyrimidine building blocks, may be potent radiation sensitizers to virus infected mammalian cells and that the addition of radiation therapy may provide additional benefit. The techniques of gene therapy have been shown to be clinically feasible. Moreover, the techniques involved in pinpointing radiation delivery to a small region in the brain, so called "radiosurgery", are routinely applied in many cancer centers. What has been lacking is experimental evidence demonstrating that cancer cells, transduced with virus derived thymidine kinase, are selectively vulnerable to radiation when in the presence of antiviral drugs.
Gene therapy, thymidine kinase, gliomas, radiation, DNA-repair, viral vectors
Funding SchemeCSC - Cost-sharing contracts
SE5 8AF London
751 21 Uppsala