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Characterization of the interaction of the chemotherapeutic drug mitomycin C with DNA in vitro and in vivo and effects on specific DNA-protein interactions.

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Call No.	RC271.M53 W37 1996
Author	Warren, Amy J.
Title	Characterization of the interaction of the chemotherapeutic drug mitomycin C with DNA in vitro and in vivo and effects on specific DNA-protein interactions.
Date	1996
Abstract	Mitomycin C (MMC) is a chemotherapeutic drug that reacts with the N$\sp2$ of guanine to form monoadducts, interstrand and intrastrand crosslinks. These lesions, especially the interstrand crosslink, are believed to be responsible for the potent anti-tumor properties of MMC in vivo. Previous work demonstrated that MMC also has significant, preferential effects on inducible gene expression at low, non-cytotoxic doses. The goal of these studies was to use chemical and biochemical techniques to add a further understanding regarding the structures of the MMC-DNA adducts, particularly the interstrand crosslink, and to determine how these MMC-induced changes in DNA structure may relate to the mechanism of MMC action in vivo. The specific hypothesis of this work is that MMC-induced alterations in gene expression are a result of MMC binding to critical regions of the promoter of a gene, causing perturbations in DNA structure and alterations in specific DNA-protein interactions. Specific MMC-DNA adducts were quantified in the chick embryo in vivo by $\sp{32}$P-postlabeling, and the formation and removal of these lesions were correlated with the previously observed alterations in inducible gene expression. To address the molecular basis for these effects, a model 23 bp duplex oligonucleotide containing a single MMC interstrand crosslink was synthesized, purified and characterized, and MMC-induced alterations in DNA structure were determined by circular dichroism, chemical footprinting, and other techniques. Electrophoretic mobility shift analysis (EMSA) was used to examine the effects of MMC adducts on DNA-protein interactions. The interstrand crosslink was specifically recognized by nuclear protein complexes which may involve the damage-recognition and repair proteins ERCC-1 and XPA. Finally, by means of EMSA, it was demonstrated that MMC-DNA adducts significantly alter transcription factor binding within important regulatory sequences of an inducible gene whose expression is altered by MMC in vivo. These studies provide further insight into the mechanism of MMC action in vivo, and may lead to a better understanding of how MMC and other crosslinking agents can either initiate the multistep process of carcinogenesis or be used as more effective cancer chemotherapy agents.
Description	xvii, 342 leaves : ill. (some col.) 28 cm
Format	application/pdf
Advisor	Hamilton, Joshua W.
Subject	Mitomycin C -- Mechanism of action. ; DNA -- Effect of mitomycin C on. ; Genetic expression -- Effect of mitomycin C on. ; DNA-protein interactions -- Effect of mitomycin C on.
College	Dartmouth College -- Department of Chemistry.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.1804

Title	Page 1
Full Text	Characterization of the Interaction of the Chemotherapeutic Drug Mitomycin C with DNA In Vitro and In Vivo and Effects on Specific DNA-Protein Interactions A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry by Amy J. Warren DARTMOUTH COLLEGE Hanover, New Hampshire May 17,1996

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Characterization of the interaction of the chemotherapeutic drug mitomycin C with DNA in vitro and in vivo and effects on specific DNA-protein interactions.

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