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Ex vivo activity of XR5000 against solid tumors
M H Neale1, P A Charlton, I A Cree
1Department of Pathology, Institute of Ophthalmology, University College London, UK.
Abstract:
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.
Insights
New dual topoisomerase inhibitors like XR5000 show promise for treating ovarian cancer and melanoma. Combinations with existing drugs like paclitaxel demonstrated significant anticancer activity in preliminary studies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Topoisomerases I and II are crucial enzymes in DNA metabolism, targeted by anticancer drugs.
- Combined topoisomerase inhibitors are emerging as a new therapeutic strategy.
- Ovarian cancer is sensitive, while melanoma is generally insensitive to current topoisomerase inhibitors.
Purpose of the Study:
- To evaluate the efficacy of XR5000, a novel dual topoisomerase inhibitor, and its combinations against ovarian cancer and melanoma.
- To compare the chemosensitivity of different tumor types to XR5000 using an ATP-based assay.
Main Methods:
- Utilized an ATP-based chemosensitivity assay to test XR5000 and drug combinations.
- Assessed activity against biopsies from 20 ovarian cancer and 18 melanoma patients, plus six other tumor types.
- Determined IC50, IC90, and summary indices of chemosensitivity.
Main Results:
- XR5000 demonstrated a steep concentration-response curve, requiring 2440 ng/ml (6 microM) for >95% ATP reduction in most tumors.
- Chemosensitivity showed minimal differences between ovarian cancer and melanoma.
- Combinations with paclitaxel or cisplatin were most effective for ovarian cancer; paclitaxel or treosulfan for melanoma.
Conclusions:
- XR5000 exhibits potent activity, comparable to etoposide and topotecan combinations.
- The drug shows potential for clinical use, especially in combination therapies for ovarian cancer and melanoma.
- Results support further investigation of XR5000 in combination with established chemotherapeutics.