A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarker
Abstract Background Disulfiram and metals inactivate key oncoproteins resulting in anti-neoplastic activity. The goal of this study was to determine the maximum tolerated dose of copper when administered with disulfiram in patients with advanced solid tumors and liver involvement. Methods Disulfiram...
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| Language: | English |
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BMC
2021-05-01
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| Series: | BMC Cancer |
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| Online Access: | https://doi.org/10.1186/s12885-021-08242-4 |
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doaj-1960d709654346b28eb07dc1080b90ac |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Kristen C. Kelley Kenneth F. Grossman Mary Brittain-Blankenship Kelli M. Thorne Wallace L. Akerley Moises C. Terrazas Ken M. Kosak Kenneth M. Boucher Saundra S. Buys Kimberly A. McGregor Theresa L. Werner Neeraj Agarwal John R. Weis Sunil Sharma John H. Ward Thomas P. Kennedy Douglas W. Sborov Paul J. Shami |
| spellingShingle |
Kristen C. Kelley Kenneth F. Grossman Mary Brittain-Blankenship Kelli M. Thorne Wallace L. Akerley Moises C. Terrazas Ken M. Kosak Kenneth M. Boucher Saundra S. Buys Kimberly A. McGregor Theresa L. Werner Neeraj Agarwal John R. Weis Sunil Sharma John H. Ward Thomas P. Kennedy Douglas W. Sborov Paul J. Shami A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarker BMC Cancer Disulfiram Copper gluconate S-glutathionylation |
| author_facet |
Kristen C. Kelley Kenneth F. Grossman Mary Brittain-Blankenship Kelli M. Thorne Wallace L. Akerley Moises C. Terrazas Ken M. Kosak Kenneth M. Boucher Saundra S. Buys Kimberly A. McGregor Theresa L. Werner Neeraj Agarwal John R. Weis Sunil Sharma John H. Ward Thomas P. Kennedy Douglas W. Sborov Paul J. Shami |
| author_sort |
Kristen C. Kelley |
| title |
A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarker |
| title_short |
A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarker |
| title_full |
A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarker |
| title_fullStr |
A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarker |
| title_full_unstemmed |
A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarker |
| title_sort |
phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using s-glutathionylation as a biomarker |
| publisher |
BMC |
| series |
BMC Cancer |
| issn |
1471-2407 |
| publishDate |
2021-05-01 |
| description |
Abstract Background Disulfiram and metals inactivate key oncoproteins resulting in anti-neoplastic activity. The goal of this study was to determine the maximum tolerated dose of copper when administered with disulfiram in patients with advanced solid tumors and liver involvement. Methods Disulfiram 250 mg was administered daily in 28-day cycles. Four doses of copper gluconate were tested (2, 4, 6, and 8 mg of elemental copper) in a standard 3 + 3 dose escalation design. Patients were evaluated for dose limiting toxicities and response. Protein S-glutathionylation was evaluated as a pharmacodynamic marker. Results Twenty-one patients were enrolled and 16 patients were evaluable for dose limiting toxicities. Among the 21 patients, there was a median of 4 lines of prior chemotherapy. Five Grade 3 toxicities were observed (anorexia, elevated aspartate aminotransferase or AST, elevated alkaline phosphatase, fever, and fatigue). Response data was available for 15 patients. Four patients had stable disease with the longest duration of disease control being 116 days. The median duration of treatment for evaluable patients was 55 days (range 28–124). Reasons for discontinuation included functional decline, disease progression, and disease-associated death. Increased S-glutathionylation of serum proteins was observed with treatment. Conclusion Disulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase in S-glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function. Trial registration NCT00742911 , first posted 28/08/2008. |
| topic |
Disulfiram Copper gluconate S-glutathionylation |
| url |
https://doi.org/10.1186/s12885-021-08242-4 |
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doaj-1960d709654346b28eb07dc1080b90ac2021-05-09T11:45:50ZengBMCBMC Cancer1471-24072021-05-012111810.1186/s12885-021-08242-4A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarkerKristen C. Kelley0Kenneth F. Grossman1Mary Brittain-Blankenship2Kelli M. Thorne3Wallace L. Akerley4Moises C. Terrazas5Ken M. Kosak6Kenneth M. Boucher7Saundra S. Buys8Kimberly A. McGregor9Theresa L. Werner10Neeraj Agarwal11John R. Weis12Sunil Sharma13John H. Ward14Thomas P. Kennedy15Douglas W. Sborov16Paul J. Shami17Department of Internal Medicine, University of UtahDivision of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of UtahDepartment of Internal Medicine, University of UtahHuntsman Cancer Institute, University of UtahDivision of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of UtahDivision of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute, University of UtahDivision of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute, University of UtahDepartment of Internal Medicine, University of UtahDivision of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of UtahDivision of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of UtahDivision of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of UtahDivision of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of UtahDivision of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of UtahDivision of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of UtahDivision of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of UtahPulmonary Diseases, Critical Care and Environmental Medicine, Tulane UniversityDivision of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute, University of UtahDivision of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute, University of UtahAbstract Background Disulfiram and metals inactivate key oncoproteins resulting in anti-neoplastic activity. The goal of this study was to determine the maximum tolerated dose of copper when administered with disulfiram in patients with advanced solid tumors and liver involvement. Methods Disulfiram 250 mg was administered daily in 28-day cycles. Four doses of copper gluconate were tested (2, 4, 6, and 8 mg of elemental copper) in a standard 3 + 3 dose escalation design. Patients were evaluated for dose limiting toxicities and response. Protein S-glutathionylation was evaluated as a pharmacodynamic marker. Results Twenty-one patients were enrolled and 16 patients were evaluable for dose limiting toxicities. Among the 21 patients, there was a median of 4 lines of prior chemotherapy. Five Grade 3 toxicities were observed (anorexia, elevated aspartate aminotransferase or AST, elevated alkaline phosphatase, fever, and fatigue). Response data was available for 15 patients. Four patients had stable disease with the longest duration of disease control being 116 days. The median duration of treatment for evaluable patients was 55 days (range 28–124). Reasons for discontinuation included functional decline, disease progression, and disease-associated death. Increased S-glutathionylation of serum proteins was observed with treatment. Conclusion Disulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase in S-glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function. Trial registration NCT00742911 , first posted 28/08/2008.https://doi.org/10.1186/s12885-021-08242-4DisulfiramCopper gluconateS-glutathionylation |