The ultimate objective of this proposal is to produce cures of human glioblastomas by enhancement of the radiosensitivity of the tumor through selective biochemical modulation of incorporation of 5-iodo-2' -deoxyuridine (IdUrd) into tumor DNA. Using a rat glioblastoma cell line, C-6, growing in vitro and growing as subcutaneous tumors in the rat, we will develop regimens of combinations of 5-fluoro-2' -deoxyuridine (FdUrd) (to lower thymidine pools) and IdUrd to achieve a level of IdUrd replacement of thymidine necessary to enhance radiation effectiveness at least 2.0 fold. Emphasis will be placed on the development of regimens which from the standpoint of systemic toxicity would be anticipated to be compatible with intermittent administration over a period of weeks so as to be able to sensitize and eliminate cells asynchronously entering cycle over time. Concomitant with development of these regimens in the rat model, the ability of FdUrd to modulate the incorporation of IdUrd in human glioblastomas will be studied. The initial regimens to be studied in man will be those compatible with standard clinical management of these patients which includes catheterization of the internal carotid artery for angiography followed 24 hours later by computer-assisted stereotactic serial brain biopsy. Each of the brain biospies will be examined biochemically to determined the extent of IdUrd incorporation and autoradiographically to estimate the proportion of tumor cells incorporating the drug. When the opitmal regimen for enchancing IdUrd incorporation into tumor in the rat model is determined, the initial clinical evaluation will be done in patients with advanced metastatic disease of the liver where arterial catheterization can be accomplished with greater safety than in the brain. After documentation of the effectiveness of the regimen in enhancing incorporation of IdUrd into metastatic tumors in the liver, the regimen will be tested for comparable efficacy in glioblastoma patients. After documentation of incorporation of IdUrd into glioblastoma DNA at a level expected from the model systems to enhance radiation sensitivity 2.0 fold, a clinical trail with radiation will be necessary to document activity to provide the basis for a randomized comparative study.
| Maruno, M; Kovach, J S; Kelly, P J et al. (1997) Distribution of endogenous tumour necrosis factor alpha in gliomas. J Clin Pathol 50:559-62 |
| Maruno, M; Kovach, J S; Kelly, P J et al. (1991) Transforming growth factor-alpha, epidermal growth factor receptor, and proliferating potential in benign and malignant gliomas. J Neurosurg 75:97-102 |
