SYNERGISTIC CYTOTOXICITY OF TOPOISOMERASE-I INHIBITORS WITH ALKYLATING-AGENTS AND ETOPOSIDE IN HUMAN BRAIN-TUMOR CELL-LINES

To evaluate potential synergistic interactions between topoisomerase I (Topo I) inhibitors, i.e. camptothecin (CPT) and topotecan (TPT), and chemotherapeutic agents known to be active in treatment of brain tumo rs, in vitro studies were conducted with human glioma and medulloblast oma cell lines. Tumor cells were exposed to CPT or TPT alone or in com bination with cisplatin, 4-hydroperoxycyclophosphamide (4-HC), BCNU or etoposide (VP-16), Cytotoxicity was assessed by colony formation assa ys. Drug interactions were evaluated by means of a novel analytical mo del which permits statistical evaluation over a range of dose combinat ion. Experimental results were corroborated by published models of dru g interaction. Our findings indicate that in vitro cytotoxic interacti ons in brain tumor cells between Topo I inhibitors and alkylating agen ts or etoposide depend on drug dose, dose schedule and tumor cell line . Treatment of DAOY medulloblastoma cells with CPI and either cisplati n, 4-HC or VP-16 produced significant synergistic cytotoxicity over a wide range of dose combinations, When VP-16 was administered after CPT , synergy was reduced to a narrow range of dose combinations, For U251 glioma cells, incubation with CPT and cisplatin or 4HC also produced synergistic cytotoxicity over a broad range of dose combinations. By c ontrast, antagonistic interactions were observed after administration of CPT with BCNU or VP-16. Treatment of U251 cells with CPT and cispla tin produced synergistic or antagonistic cytotoxicity depending on the dose combination used. These findings support a role for pharmacokine tic analysis in multiagent phase II trials involving Topo I inhibitors and have important implications for clinical trial design strategies. [(C) 1998 Lippincott Williams & Wilkins.].