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Sequence specific DNA minor groove a...

Shah, Dharini Madhusudan.

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Sequence specific DNA minor groove alkylating agents and their biological activity.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Sequence specific DNA minor groove alkylating agents and their biological activity./
Author:	Shah, Dharini Madhusudan.
Description:	219 p.
Notes:	Source: Dissertation Abstracts International, Volume: 64-06, Section: B, page: 2686.
Contained By:	Dissertation Abstracts International64-06B.
Subject:	Chemistry, Pharmaceutical. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3093287

Sequence specific DNA minor groove alkylating agents and their biological activity.
Shah, Dharini Madhusudan.

Sequence specific DNA minor groove alkylating agents and their biological activity. - 219 p.

Source: Dissertation Abstracts International, Volume: 64-06, Section: B, page: 2686.

Thesis (Ph.D.)--University of Nebraska Medical Center, 2003.

Most carcinogens and anticancer agents show little selectivity in their reactions with duplex DNA and generate a plethora of DNA lesions. This non-specificity makes it difficult to elucidate the biological role(s) of individual DNA lesions; i.e., cytotoxicity and/or mutagenicity. This problem is even more critical in cancer chemotherapy where there is mounting evidence that mutagenic DNA adducts are formed that pose a significant increase in risk for secondary malignancies. Moreover, the role and substrates for specific DNA repair proteins remain obscure due to presence of multiple adducts.Subjects--Topical Terms:

550957
Chemistry, Pharmaceutical.

Sequence specific DNA minor groove alkylating agents and their biological activity.
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035 $a (UnM)AAI3093287
035 $a AAI3093287
040 $a UnM $c UnM
100 1 $a Shah, Dharini Madhusudan. $3 1948133
245 1 0 $a Sequence specific DNA minor groove alkylating agents and their biological activity.
300 $a 219 p.
500 $a Source: Dissertation Abstracts International, Volume: 64-06, Section: B, page: 2686.
500 $a Supervisor: Barry I. Gold.
502 $a Thesis (Ph.D.)--University of Nebraska Medical Center, 2003.
520 $a Most carcinogens and anticancer agents show little selectivity in their reactions with duplex DNA and generate a plethora of DNA lesions. This non-specificity makes it difficult to elucidate the biological role(s) of individual DNA lesions; i.e., cytotoxicity and/or mutagenicity. This problem is even more critical in cancer chemotherapy where there is mounting evidence that mutagenic DNA adducts are formed that pose a significant increase in risk for secondary malignancies. Moreover, the role and substrates for specific DNA repair proteins remain obscure due to presence of multiple adducts.
520 $a To address, this issue we have developed a new DNA alkylating agent, methyl-lexitropsin (Me-lex) that consists of a neutral lex dipeptide (based on N-methylpyrrole carboxamide subunits) appended with an O-methylsulfonate ester functionality. Using sequencing gels, HPLC and ELISA analyses it has been demonstrated that Me-lex equilibrium binds in the DNA minor groove at A•T rich sequences and generates almost exclusively (&sim;99%) 3-methyladenine (3-MeA) both in vitro and in vivo. To determine the toxicity of Me-lex and role of different DNA repair enzymes in repair of 3-MeA, studies of Me-lex were performed in wild type E. coli and mutants that were defective in different DNA repair enzymes. The results demonstrate that the toxicity of Me-lex is due to unrepaired 3-MeA, and that base excision repair is the sole repair system for detoxification of 3-MeA in E. coli. Mutagenesis studies done in wild type and base excision repair deficient yeast indicate that overall Me-lex is relatively non-mutagenic. Mutagenicity of Me-lex, i.e., 3-MeA, is attributed to subsequent formation of abasic sites rather than to 3-MeA. Moreover, the DNA minor groove binding ligand netropsin inhibits DNA alkylation both in vitro and in vivo, and significantly reduces the toxicity of Me-lex in E. coli. Thus, Me-lex because of its high cytotoxicity and low mutagenicity is a model for non-mutagenic anticancer agents. These studies have been extended to the ethyl analog of Me-Lex, Et-Lex. Et-lex shows a DNA alkylation profile that is consistent with sequence-specific binding, but with a reduced level of alkylation that is consistent with the decreased reactivity of the O-ethyl sulfonate ester functionality.
590 $a School code: 0367.
650 4 $a Chemistry, Pharmaceutical. $3 550957
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Biology, Cell. $3 1017686
690 $a 0491
690 $a 0307
690 $a 0379
710 2 0 $a University of Nebraska Medical Center. $3 1021714
773 0 $t Dissertation Abstracts International $g 64-06B.
790 1 0 $a Gold, Barry I., $e advisor
790 $a 0367
791 $a Ph.D.
792 $a 2003
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3093287