INTERACTION OF IONIZING-RADIATION WITH TOPOTECAN IN 2 HUMAN TUMOR-CELL LINES

The effect of topotecan, a topoisomerase 1 inhibitor, on ionizing radi ation-induced cytotoxicity was studied in 2 human tumor cell lines cha racterized by a different expression of the target enzyme. The cytotox icity of topotecan alone or in combination with radiation was assessed in exponentially growing non-small-cell lung cancer (H460) and gliobl astoma (GBM) cells using the colony-forming assay. An isobologram meth od was used to evaluate the treatment interaction. An apparent supra-a dditive effect in cell killing following drug-radiation-combined treat ment was observed only in GEM cells exposed to topotecan for 24 hr. In the case of H460 cells, interaction varied from a strong infra-additi ve effect at low radiation doses to a slight supra-additive effect whe n cells were exposed to radiation doses greater than 3 Gy. Northern bl ot analysis indicated that topoisomerase 1 expression in H460 cells wa s 8-fold higher than that of GBM cells. Although the H460 cell line ex hibited an increased sensitivity to topotecan, only in the GEM cell li ne (which expressed a lower level of topoisomerase 1) did the drug pot entiate the radiation cytotoxicity. The observation that the radiosens itization by topotecan was related to topoisomerase 1 level is consist ent with a putative role of the enzyme in processes involved in the re pair of radiation damage. It is conceivable that the modulation of enz yme function results in an effective reduction of cellular capability for repair of radiation damage only if the enzyme is not over-expresse d. Although a precise role of topoisomerase 1 in the cellular response to ionizing radiations (in particular, in DNA repair) remains to be d ocumented, such results suggest the potential interest of topoisomeras e 1 inhibitors in combination with radiation therapy for tumors expres sing low topoisomerase 1 levels. (C) 1996 Wiley-Liss, Inc.