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Engineering enhanced enzymes for sui...

Willmon, Candice Lynn.

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Engineering enhanced enzymes for suicide gene therapy of cancer.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Engineering enhanced enzymes for suicide gene therapy of cancer./
Author:	Willmon, Candice Lynn.
Description:	131 p.
Notes:	Adviser: Margaret E. Black.
Contained By:	Dissertation Abstracts International67-05B.
Subject:	Biology, Molecular. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3218266
ISBN:	9780542675041

Engineering enhanced enzymes for suicide gene therapy of cancer.
Willmon, Candice Lynn.

Engineering enhanced enzymes for suicide gene therapy of cancer. - 131 p.

Adviser: Margaret E. Black.

Thesis (Ph.D.)--Washington State University, 2006.

Suicide gene therapy of cancer offers a selective approach to eliminating tumor cells. A drawback with suicide gene therapy is the low activity of the enzyme towards prodrug. In an attempt to circumvent this, we sought to optimize three suicide enzymes for increased sensitivity towards their respective prodrugs.

ISBN: 9780542675041Subjects--Topical Terms:

1017719
Biology, Molecular.

Engineering enhanced enzymes for suicide gene therapy of cancer.
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005 20110901
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020 $a 9780542675041
035 $a (UMI)AAI3218266
035 $a AAI3218266
040 $a UMI $c UMI
100 1 $a Willmon, Candice Lynn. $3 1287114
245 1 0 $a Engineering enhanced enzymes for suicide gene therapy of cancer.
300 $a 131 p.
500 $a Adviser: Margaret E. Black.
500 $a Source: Dissertation Abstracts International, Volume: 67-05, Section: B, page: 2496.
502 $a Thesis (Ph.D.)--Washington State University, 2006.
520 $a Suicide gene therapy of cancer offers a selective approach to eliminating tumor cells. A drawback with suicide gene therapy is the low activity of the enzyme towards prodrug. In an attempt to circumvent this, we sought to optimize three suicide enzymes for increased sensitivity towards their respective prodrugs.
520 $a We have altered the sensitivity of herpes simplex virus-1 thymidine kinase (TK) for the prodrugs acyclovir and ganciclovir in two site-directed mutants, A168F and A168Y. While both mutants display increased prodrug specificity, the most noteworthy alteration from wild-type TK is the 763-fold greater relative specificity that A168F displays towards acyclovir. In addition to the A168 mutagenesis study, we have generated a fusion protein of TK and mouse guanylate kinase that displays a greater than 175-fold decreased IC50 for ganciclovir in tumor cells.
520 $a Yeast cytosine deaminase (yCD) activates the anti-fungal agent, 5-fluorocytosine (5FC). From a regio-specific random mutagenesis library, we identified three mutant enzymes (D92E, M93L, and I98L) with enhanced 5FC activities. These three mutant were individually overlayed onto a previously engineered thermostable mutant (triple yCD). Enhanced tumor cell killing was demonstrated with the three 5FC-sensitizing mutants, along with two thermostable (double and triple) and two superimposed variants (triple/M93L and triple/I98L). Interestingly, one superimposed mutant (triple/D92E) displays even greater thermostability than the computationally designed triple yCD variant, but achieves less cell killing.
520 $a Human deoxycytidine kinase (dCK) phosphorylates anti-neoplastic agents, such as gemcitabine. We have performed regio-specific random mutagenesis on an important region of dCK and have identified eight mutant enzymes with the ability to sensitize bacteria to gemcitabine at a level 35,000-fold greater than wild-type dCK. In vitro evaluation of the eight dCK mutants shows no improved cancer cell killing compared to wild-type dCK. Current attempts to elucidate the cause for the observed activities in the tumor cell models evaluation in a dCK-deficient cell line.
520 $a In summary, because of their enhanced activities for their prodrugs, the mutant enzymes we have created should provide the means to use otherwise unfeasible drugs, overcome bottlenecks in pathways, and, overall, demonstrate increased tumor ablation and expanded bystander effects in future suicide gene therapy applications.
590 $a School code: 0251.
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Health Sciences, Pharmacology. $3 1017717
690 $a 0307
690 $a 0419
710 2 0 $a Washington State University. $3 678588
773 0 $t Dissertation Abstracts International $g 67-05B.
790 $a 0251
790 1 0 $a Black, Margaret E., $e advisor
791 $a Ph.D.
792 $a 2006
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3218266