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Rational search for new anti-cancer ...

Hill, Jason Eric.

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Rational search for new anti-cancer compounds that restorep53 activity in tumor cells.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Rational search for new anti-cancer compounds that restorep53 activity in tumor cells./
Author:	Hill, Jason Eric.
Description:	102 p.
Notes:	Source: Dissertation Abstracts International, Volume: 65-03, Section: B, page: 1133.
Contained By:	Dissertation Abstracts International65-03B.
Subject:	Biology, Genetics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3126818
ISBN:	0496740962

Rational search for new anti-cancer compounds that restorep53 activity in tumor cells.
Hill, Jason Eric.

Rational search for new anti-cancer compounds that restorep53 activity in tumor cells. - 102 p.

Source: Dissertation Abstracts International, Volume: 65-03, Section: B, page: 1133.

Thesis (Ph.D.)--University of Illinois at Chicago, Health Sciences Center, 2004.

p53 mutations are present in half of all human cancers, however, this distribution is not random. Certain tumor types, such as renal cell carcinomas (RCC), often retain wild-type p53. We determined that p53-dependent transactivation is inhibited in RCC, and undertook an extensive molecular analysis of RCC to understand the nature of this inhibition. We found that the components of the p53 pathway were intact in RCC, since very high levels of ectopic p53 overcame the inhibitory effect. This inhibitory effect was dominant when RCC cells were fused to other cell lines capable of activating p53. For these reasons, we concluded that a dominant inhibitory factor was responsible for the non-functional status of p53 in RCC. We developed a RCC-based readout system to screen a library of small molecules for compounds that restored p53-dependent transactivation. Several compounds were identified that, in addition to activating p53, also inhibited NF-kappaB-dependent transactivation. One compound was chosen for further study. This compound, 9-aminoacridine, was more toxic to tumor kidney cells than normal kidney cells and activated p53 in several cell types, including RCC. Interestingly, 9-aminoacridine was more toxic to tumor cells with normal levels of p53 than to cells with suppressed levels of p53, across a broad range of tumor cell types. 9-aminoacridine caused upregulation of a p53 target gene in mouse tissues, and a closely related compound, quinacrine, reduced the size of tumors in nude mice. This effect on tumor growth was dependent on the presence of p53. 9-aminoacridine is neither a topoisomerase II poison nor a proteasome inhibitor, common types of compounds that can activate p53 and inhibit NF-kappaB, respectively. Therefore, 9-aminoacridine may be more specific than current compounds for p53 activation and NF-kappaB inhibition.

ISBN: 0496740962Subjects--Topical Terms:

1017730
Biology, Genetics.

Rational search for new anti-cancer compounds that restorep53 activity in tumor cells.
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520 $a p53 mutations are present in half of all human cancers, however, this distribution is not random. Certain tumor types, such as renal cell carcinomas (RCC), often retain wild-type p53. We determined that p53-dependent transactivation is inhibited in RCC, and undertook an extensive molecular analysis of RCC to understand the nature of this inhibition. We found that the components of the p53 pathway were intact in RCC, since very high levels of ectopic p53 overcame the inhibitory effect. This inhibitory effect was dominant when RCC cells were fused to other cell lines capable of activating p53. For these reasons, we concluded that a dominant inhibitory factor was responsible for the non-functional status of p53 in RCC. We developed a RCC-based readout system to screen a library of small molecules for compounds that restored p53-dependent transactivation. Several compounds were identified that, in addition to activating p53, also inhibited NF-kappaB-dependent transactivation. One compound was chosen for further study. This compound, 9-aminoacridine, was more toxic to tumor kidney cells than normal kidney cells and activated p53 in several cell types, including RCC. Interestingly, 9-aminoacridine was more toxic to tumor cells with normal levels of p53 than to cells with suppressed levels of p53, across a broad range of tumor cell types. 9-aminoacridine caused upregulation of a p53 target gene in mouse tissues, and a closely related compound, quinacrine, reduced the size of tumors in nude mice. This effect on tumor growth was dependent on the presence of p53. 9-aminoacridine is neither a topoisomerase II poison nor a proteasome inhibitor, common types of compounds that can activate p53 and inhibit NF-kappaB, respectively. Therefore, 9-aminoacridine may be more specific than current compounds for p53 activation and NF-kappaB inhibition.
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