THE POTENTIAL OF TOPOISOMERASE-I INHIBITORS IN THE TREATMENT OF CNS MALIGNANCIES - REPORT OF A SYNERGISTIC EFFECT BETWEEN TOPOTECAN AND RADIATION

Despite innovations in imaging, surgery, and radiation therapy, local failure remains the principle clinical problem in most CNS malignancie s. To date, chemotherapy has not made a major impact in the treatment of most adult CNS tumors. The inroads made by chemotherapy in pediatri c CNS malignancies suggest that novel drugs, or drug combinations, may improve therapy. Topoisomerase I (Topo I) inhibitors are a relatively new group of chemotherapy drugs with a novel mechanism of action. Dru gs in this group currently undergoing clinical trials are the Camptoth ecin analogues Topotecan, CPT-11, and 9-aminocamptothecin. There is su bstantial preclinical and some clinical evidence to suggest that these drugs could be useful in the treatment of CNS malignancies. Preclinic al studies with the water soluble Topo I inhibitor, Topotecan, demonst rate antineoplastic activity in a variety of CNS malignancies. In addi tion, Topotecan has good CNS penetration in primates, and recent preli minary phase I and II clinical trials of Topotecan in pediatric and ad ult CNS malignancies have been promising. In this paper, we describe t he unique mechanism of action, antineoplastic activity, and radiosensi tizing properties of Topo I inhibitors. We present the first report de monstrating potentiation of radiation lethality by Topotecan in a huma n glioma (D54) cell line. The dose enhancement ratio was 3.2 at 10% su rvival. Thus, there is evidence to suggest that Topo I inhibitors may be beneficial in the treatment of CNS neoplasms on the basis of their antineoplastic activity alone, as well as their radiosensitizing effec ts. Two clinical trials which utilize concurrent Topotecan and radiati on in the treatment of pediatric and adult CNS malignancies are discus sed.