Mechanism of the antineoplastic action of farnesyltransferase inhibitors (FTIs) / Wei Du.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Du, Wei.

Contributor:

Prendergast, George C., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Biology.

Biology--Penn dissertations.

Biology.

Academic Dissertations as Topic.

Medical Subjects:

Biology.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Biology.

Biology--Penn dissertations.

Physical Description:

vii, 132 pages : illustrations ; 29 cm

Production:

1999.

Summary:

Farnesyltransferase inhibitors (FTIs) are a novel class of anti-cancer therapeutics that were developed to block the localization and thereby the activity of oncogenic Ras protein. Preclinical studies have established that FTIs are non-toxic yet capable of reversing malignant phenotypes. However, there is growing evidence that inhibition of Ras may not be critical and that the antitransforming properties of FTIs are based, at least in part, upon alteration of Rho, a small GTPase, which is involved in cell adhesion and cytoskeletal regulation. Our work is to identify the mechanisms of FTI action. In the first part of the study, I provide strong evidence that gain of geranylgeranylated RhoB function is sufficient to mediate FTI cellular response in both Ras-transformed cells and human tumor models. In the second part of this study, I attempt to identify the mechanisms that distinguished FTI cytostatic versus cytotoxic in Ras-transformed cells. I found activation of PI3'K-AKT pathway marks the proapoptotic effects of FTI. Lastly, I identified a gene, type 1 alpha (2) collagen, which is required not only to initiate but also to maintain FTI-induced long lasting phenotypic reversion.

Notes:

Supervisor: George C. Prendergast.

Thesis (Ph.D. in Biology) -- University of Pennsylvania, 1999.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 99-53524.

OCLC:

187483686