Parise, Robert A
(2014)
THE PRECLINICAL AND CLINICAL PHARMACOLOGY OF BENZALDEHYDE DIMETHANE SULFONATE (BEN) FOR THE TREATMENT OF RENAL CELL CARCINOMA.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Over 65,000 people acquired renal cell carcinoma (RCC) and over 13,500 people died from the disease in the United States in 2012. The median survival for persons with metastatic disease is 13 months. Recent research has identified new targets for this disease and new targeted therapies have been developed. Despite this, the overall survival remains poor, and there remains a need for new therapies for RCC. Benzaldehyde dimethane sulfonate (BEN, DMS612) is a bifunctional alkylating agent with activity against renal cell carcinoma. The goal of the research conducted was to evaluate the preclinical and clinical pharmacology of BEN.
Benzaldehyde dimethane sulfonate is stable in plasma but is metabolized in blood by aldehyde dehydrogenase into an acid that decomposes in aqueous and biological matrices. Furthermore, the acid product decomposes into 6 different species of which none are as active as BEN in the renal carcinoma cells that we have tested. We also found that BEN had greater activity in renal carcinoma cell lines that expressed higher levels of aldehyde dehydrogenase. This led us to believe that BEN acts as a pro-drug with its main carboxylic acid metabolite exerting the activity against renal carcinoma cell lines. We determined that BEN is rapidly metabolized in mice and that the pretreatment of mice with the aldehyde dehydrogenase inhibitor disulfiram greatly increases the exposure to BEN. Furthermore the carboxylic decomposition products that were detected in vitro were also found in the mice along with corresponding glucuronides. Also, we found that BEN when administered to patients is very rapidly metabolized and the same glucuronides generated in mice were also detected in humans. The maximum tolerated dose in a phase I clinical trial in humans was 9.0 mg/m2. The dose limiting toxicity was neutropenia. The information generated in this dissertation will be instrumental in the future clinical development of BEN.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
18 April 2014 |
| Date Type: |
Publication |
| Defense Date: |
2 April 2014 |
| Approval Date: |
18 April 2014 |
| Submission Date: |
16 April 2014 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
231 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Pharmacology of Banzaldehyde dimethane sulfonate |
| Date Deposited: |
18 Apr 2014 15:36 |
| Last Modified: |
18 Apr 2019 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/21261 |
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