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Biological mass spectrometry of sphi...

Pruett, Sarah Trotman.

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Biological mass spectrometry of sphingolipids in drug discovery and development.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Biological mass spectrometry of sphingolipids in drug discovery and development./
Author:	Pruett, Sarah Trotman.
Description:	169 p.
Notes:	Source: Dissertation Abstracts International, Volume: 67-09, Section: B, page: 5044.
Contained By:	Dissertation Abstracts International67-09B.
Subject:	Chemistry, Analytical. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3234044
ISBN:	9780542876882

Biological mass spectrometry of sphingolipids in drug discovery and development.
Pruett, Sarah Trotman.

Biological mass spectrometry of sphingolipids in drug discovery and development. - 169 p.

Source: Dissertation Abstracts International, Volume: 67-09, Section: B, page: 5044.

Thesis (Ph.D.)--Emory University, 2006.

Prostate cancer (PC) is a disease of advancing age that progresses from prostatic intraepithelial neoplasia (PIN) to adenocarcinoma and finally to metastatic disease. While many treatment options are available for androgen dependent forms of the disease, once it transforms into androgen independent PC there is no cure. A 1-deoxy, 5-hydroxy sphinganine analog (Enigmol) was developed to treat this hormone refractory form of PC. This molecule was developed to resemble the fungal sphingolipid Fumonisin B1 (FB1), a pro-apoptotic sphingolipid with the ability to inhibit ceramide synthase. One of the hallmarks of FB1 exposure is the dramatic accumulation of sphinganine, a proapoptotic sphingolipid. FB1 is also extremely toxic causing a variety of veterinary illnesses. Moreover, exposure to FB1 has been linked to increased incidence of birth defects in Guatemala. Here we developed LC-MS/MS methods to follow Enigmol, an analog to this extremely powerful sphingolipid, its potential metabolites in vivo, and its effects on endogenous sphingolipids. This method was then applied to the evaluation of Enigmol in cell culture with the DU145 cell line. This cell line served as a model to predict the behavior of Enigmol and to investigate its metabolism. Based on positive cell culture results, Enigmol was tested in Lewis rats to rigorously determine its pharmacokinetic profile and subsequent tissue distribution. This molecule was also evaluated for toxicity due to prolonged exposure in TRAMP mice (transgene adenocarcinoma mouse prostate) a PC mouse model. Finally, DU145 xenografted nude mice were examined after intraperitoneal injections of Enigmol, for tumor growth suppression.

ISBN: 9780542876882Subjects--Topical Terms:

586156
Chemistry, Analytical.

Biological mass spectrometry of sphingolipids in drug discovery and development.
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520 $a Prostate cancer (PC) is a disease of advancing age that progresses from prostatic intraepithelial neoplasia (PIN) to adenocarcinoma and finally to metastatic disease. While many treatment options are available for androgen dependent forms of the disease, once it transforms into androgen independent PC there is no cure. A 1-deoxy, 5-hydroxy sphinganine analog (Enigmol) was developed to treat this hormone refractory form of PC. This molecule was developed to resemble the fungal sphingolipid Fumonisin B1 (FB1), a pro-apoptotic sphingolipid with the ability to inhibit ceramide synthase. One of the hallmarks of FB1 exposure is the dramatic accumulation of sphinganine, a proapoptotic sphingolipid. FB1 is also extremely toxic causing a variety of veterinary illnesses. Moreover, exposure to FB1 has been linked to increased incidence of birth defects in Guatemala. Here we developed LC-MS/MS methods to follow Enigmol, an analog to this extremely powerful sphingolipid, its potential metabolites in vivo, and its effects on endogenous sphingolipids. This method was then applied to the evaluation of Enigmol in cell culture with the DU145 cell line. This cell line served as a model to predict the behavior of Enigmol and to investigate its metabolism. Based on positive cell culture results, Enigmol was tested in Lewis rats to rigorously determine its pharmacokinetic profile and subsequent tissue distribution. This molecule was also evaluated for toxicity due to prolonged exposure in TRAMP mice (transgene adenocarcinoma mouse prostate) a PC mouse model. Finally, DU145 xenografted nude mice were examined after intraperitoneal injections of Enigmol, for tumor growth suppression.
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