Ex vivo activity of XR5000 against solid tumors
Department of Pathology, Institute of Ophthalmology, University College London, UK. Anti-Cancer Drugs
(Impact Factor: 1.78).
08/2000; 11(6):471-8. DOI: 10.1097/00001813-200007000-00008
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.
Available from: Ian A Cree
Available from: Federica Di Nicolantonio
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ABSTRACT: Liposomal doxorubicin (Caelyx/Doxil) has been shown to be active in around 20% of recurrent ovarian cancers. As yet, there is little clinical data on combinations of existing agents with liposomal doxorubicin, despite considerable clinical experience with soluble doxorubicin in combination. In this study, we have used an ATP-based tumor chemosensitivity assay to determine the relative efficacy of high concentrations of doxorubicin tested in combination with cisplatin, treosulfan, 5-fluorouracil (5-FU) or vinorelbine against cells obtained from recurrent ovarian tumor tissue. The results show little enhancement of the efficacy of high concentrations of doxorubicin by 5-FU, cisplatin, or treosulfan. However, vinorelbine+liposomal doxorubicin showed additive inhibition, and this combination is worthy of further testing in clinical trials.
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ABSTRACT: The ATP-based chemosensitivity assay has proved particularly useful for the evaluation of new anti-cancer agents and combinations. The majority of our publications in this area have concentrated on topoisomerase inhibitors. Comparison of mitoxantrone with doxorubicin convinced us that these two agents were not completely cross-resistant and led to the design of the mitoxantrone + paclitaxel regimen which is now in clinical practice. Re-assessment of treosulfan in uveal melanoma led to the design of a new regimen combining this alkylating agent with gemcitabine, again with rapid introduction of this combination to clinical practice. The assay has recently been used to examine the concentration-activity curve to determine which tumours might benefit from liposomal preparations capable of delivering 4–16 times the standard dose without cardiotoxicity. Assay-directed use of Caelyx is producing encouraging results, and we are now examining this drug in combination with others. We recently showed that XR5000, a combined inhibitor of topoisomerase I and II, was effective against melanoma as well as ovarian cancer, but at concentrations which were unlikely to be achieved in patients. These data confirm our suggestion that use of the assay could reduce the time to introduction of new anti-cancer drugs and the cost of this process.
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