Tumor survival following radiotherapy is largely a result of DNA repair. While the majority of strategies to improve local control of high grade gliomas have focused on increasing initial radiation damage, few if any investigations have focused on inhibition of DNA repair resulting from radiotherapy. We plan to systematically explore the role of DNA repair inhibitors as radiation and chemotherapy sensitizers for the treatment of high grade gliomas, tumors which are resistant to therapy and fail locally. Hydroxyurea is a ribonucleotide reductase inhibitor which penetrates the blood brain barrier. It is a potent DNA repair inhibitor and is synergistic with other repair inhibitors such as the methylxanthines, ara- c and aphidicolin. Pentoxifylline, a methylxanthine derivative with hemorrheologic activity, is a radiosensitizer of equal potency to caffeine but with less CNS toxicity. In our initial phase 1 trail, hydroxyurea will be given at a set dose of 3 grams/day via continuous infusion with escalating doses of continuous infusion pentoxifylline. Both drugs will be given during a course of accelerated hyperfractionated radiotherapy to patients with glioblastoma.
