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The in vitro metabolism of three ant...

Fan, Yun.

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The in vitro metabolism of three anticancer drugs.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	The in vitro metabolism of three anticancer drugs./
作者:	Fan, Yun.
面頁冊數:	163 p.
附註:	Source: Dissertation Abstracts International, Volume: 68-06, Section: B, page: 3712.
Contained By:	Dissertation Abstracts International68-06B.
標題:	Health Sciences, Pharmacology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3270104
ISBN:	9780549086512

The in vitro metabolism of three anticancer drugs.
Fan, Yun.

The in vitro metabolism of three anticancer drugs. - 163 p.

Source: Dissertation Abstracts International, Volume: 68-06, Section: B, page: 3712.

Thesis (Ph.D.)--University of Pittsburgh, 2007.

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.

ISBN: 9780549086512Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

The in vitro metabolism of three anticancer drugs.
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520 $a 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.
520 $a 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.
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