Ex vivo activity of XR5000 against solid tumors

Topoisomerases I and II unravel DNA during transcription, DNA replication a nd DNA repair. Inhibitors of both enzymes are important anticancer drugs, b ut only now are combined inhibitors becoming available for clinical use. In this study we have used an ATP-based chemosensitivity assay to determine t he activity of XR5000 and possible combinations against ovarian cancer, a t umor sensitive to current topoisomerase inhibitors, and melanoma, an insens itive tumor. A further six tumors of other types were also tested. The resu lts from 20 ovarian cancer and 18 melanoma biopsies show remarkably little difference between the tumor types in terms of IC50, IC90 or two summary in dices of chemosensitivity based on all of the concentrations tested, XR5000 on its own shows a steep concentration-response curve in most tumors, only achieving high reduction (above 95%) of ATP levels at 2440 ng/ml (6 mu M). The results were often similar to the combination of etoposide and topotec an, particularly at the higher concentrations tested. The combinations with greatest activity in ovarian cancer were with paclitaxel or cisplatin, whi le melanoma showed greatest improvement with paclitaxel or treosulfan. The results are encouraging for the clinical introduction of this agent, and su ggest that it will be effective in combination with currently available dru gs for both ovarian cancer and melanoma. [(C) 2000 Lippincott Williams & Wi lkins].