Etoposide is a widely used topoisomerase II inhibitor particularly useful in the clinic for treatment of disseminated tumors, including childhood leukemia. However, its use is associated with the increased risk of development of secondary acute myelogenous leukemias. The mechanism behind this is still unclear. It was hypothesized that etoposide ortho-quinone, a reactive metabolite previously shown to be generated in vitro by myeloperoxidase, the major oxidative enzyme in the bone marrow cells from which the secondary leukemias arise, might be a contributor to the development of treatment-related secondary leukemias. Experiments showed that the glutathione adduct of etoposide ortho-quinone was formed in myeloperoxidase-expressing human myeloid leukemia HL60 cells treated with etoposide, that its formation was enhanced by addition of the myeloperoxidase substrate hydrogen peroxide, and that the glutathione adduct level was dependent on myeloperoxidase. Both the normoisotopic and a stable isotope-labeled version of the glutathione adduct were synthesized. The latter was used for liquid chromatography-mass spectrometry-based quantitative analyses of the adduct formed by the cells.
Discodermolide and dictyostatin are two strucuturally related natural products that possess potent microtubule stabilizing activity. Discodermolide advanced to Phase II clinical trials, but the trials were halted for unannounced reasons. Here, both agents were found to be extensively metabolized by human liver microsomes in vitro. In order to determine the metabolic soft spots in the molecules, the chemical structures of the metabolites of discodermolide and dictyostatin were elucidated by liquid chromatography-mass spectrometry. At least eight metabolites of discodermolide and six metabolites of dictyostatin were formed in human liver microsomes in vitro. The terminal diene groups on discodermolide and dictyostatin were found to be the metabolic soft spots. Results from these studies can be used in future medicinal chemistry design and synthesis work to decrease metabolic rate and improve drug metabolism and pharmacokinetic properties, therefore decreasing the doses needed and perhaps even the toxicity.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-03292007-222254 |
| Date | 17 April 2007 |
| Creators | Fan, Yun |
| Contributors | Michael A. Zemaitis, Jack C. Yalowich, Samuel M. Poloyac, Raman Venkataramanan, Billy W. Day |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-03292007-222254/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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