Ex vivo activity of XR5000 against solid tumors.
Topoisomerases I and II unravel DNA during transcription, DNA replication and DNA repair. Inhibitors of both enzymes are important anticancer drugs, but only now are combined inhibitors becoming available for clinical use. In this study we have used an ATP-based chemosensitivity assay to determine the activity of XR5000 and possible combinations against ovarian cancer, a tumor sensitive to current topoisomerase inhibitors, and melanoma, an insensitive tumor. A further six tumors of other types were also tested. The results from 20 ovarian cancer and 18 melanoma biopsies show remarkably little difference between the tumor types in terms of IC50, IC90 or two summary indices 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 microM). The results were often similar to the combination of etoposide and topotecan, particularly at the higher concentrations tested. The combinations with greatest activity in ovarian cancer were with paclitaxel or cisplatin, while melanoma showed greatest improvement with paclitaxel or treosulfan. The results are encouraging for the clinical introduction of this agent, and suggest that it will be effective in combination with currently available drugs for both ovarian cancer and melanoma.
Neale
M H
MH
Department of Pathology, Institute of Ophthalmology, University College London, UK.
Charlton
P A
PA
Cree
I A
IA
D000166:Acridines / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008163:Luminescent Measurements; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
D000166:Acridines; D000970:Antineoplastic Agents; C121181:DACA, acridine; D004273:DNA, Neoplasm; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D000255:Adenosine Triphosphate