Despite innovations in imaging, surgery, and
radiation therapy, local failure remains the principle clinical problem in most CNS
malignancies. To date,
chemotherapy has not major impact in the treatment of most adult CNS
tumors. The inroads made by
chemotherapy in pediatric 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. Drugs in this group currently undergoing clinical trials are the
Camptothecin analogues
Topotecan,
CPT-11, and
9-aminocamptothecin. There is substantial preclinical and some clinical evidence to suggest that these drugs could be useful in the treatment of CNS
malignancies. Preclinical studies with the water soluble
Topo I inhibitor,
Topotecan, demonstrate
antineoplastic activity in a variety of CNS
malignancies. In addition,
Topotecan has good CNS penetration in primates, and recent preliminary phase I and II clinical trials of
Topotecan in pediatric and adult CNS
malignancies have been promising. In this paper, we describe the unique mechanism of action,
antineoplastic activity, and radiosensitizing properties of
Topo I inhibitors. We present the first report demonstrating potentiation of radiation lethality by
Topotecan in a human
glioma (D54) cell line. The dose enhancement ratio was 3.2
at 10% survival. 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 effects. Two clinical trials which utilize concurrent
Topotecan and radiation in the treatment of pediatric and adult CNS
malignancies are discussed.