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MODULATION OF 6-THIOGUANINE INDUCED CELL TOXICITY AND DIFFERENTIATION BY GUANINE IN S-49 AND HL-60 CELLS.

Record Type:	Electronic resources : Monograph/item
Title/Author:	MODULATION OF 6-THIOGUANINE INDUCED CELL TOXICITY AND DIFFERENTIATION BY GUANINE IN S-49 AND HL-60 CELLS./
Author:	CHENG, HUI-WEN.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 1985,
Description:	109 p.
Notes:	Source: Dissertations Abstracts International, Volume: 46-07, Section: B.
Contained By:	Dissertations Abstracts International46-07B.
Subject:	Pharmaceuticals. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=8608571
ISBN:	9798204877726

MODULATION OF 6-THIOGUANINE INDUCED CELL TOXICITY AND DIFFERENTIATION BY GUANINE IN S-49 AND HL-60 CELLS.
CHENG, HUI-WEN.

MODULATION OF 6-THIOGUANINE INDUCED CELL TOXICITY AND DIFFERENTIATION BY GUANINE IN S-49 AND HL-60 CELLS. - Ann Arbor : ProQuest Dissertations & Theses, 1985 - 109 p.

Source: Dissertations Abstracts International, Volume: 46-07, Section: B.

Thesis (Ph.D.)--University of California, San Francisco, 1985.

This item must not be added to any third party search indexes.

The mechanism of 6-TG toxicity has been attributed to its incorporation into DNA. The presence of guanine in vivo is expected to modify the action of 6-TG by either interfering with 6-TG metabolism or its incorporation into nucleic acids. The effects of guanine on 6-TG metabolism and cell toxicity were therefore studied in mouse lymphoma S-49 cells. The results showed that while guanine does not affect the accumulation of 6-TGMP, it does eliminate the formation of 6-dTGTP. Guanine also competes effectively with 6-TG for incorporation into DNA and RNA, but fails to prevent the growth inhibitory effect of 6-TG. Therefore, mechanisms other than 6-TG incorporate into DNA and RNA contribute to 6-TG toxicity in S-49 cells. 6-TG is able to induce cell differentiation in human promyelocytic HL-60 cells at low concentrations. Coadministration of guanine with 6-TG decreases the accumulation of 6-TGMP and suppresses of cell differentiation; therefore, differentiation apparently depends on 6-TGMP formation at low 6-TG concentrations. 6-TGMP is a poor substrate of GMP kinase with a low V(,max) value and k(,m) = 384 (mu)M. It also behaves as a noncompetitive inhibitor of GMP for 5'-nucleotidase, acid phosphatase, and alkaline phosphatase and again represents a poor substrate for these enzymes studied. Thus, high concentrations of 6-TGMP can be reached in cells that in turn inhibit several other enzymes involved in guanosine nucleotide biosynthesis, such as PRPP amidotransferase, HGPRTase, and IMP dehydrogenase, thus causing guanine starvation. Therefore, guanine starvation induced by 6-TG treatment may play an important role in regulating cell differentiation.

ISBN: 9798204877726Subjects--Topical Terms:

3562593
Pharmaceuticals.

MODULATION OF 6-THIOGUANINE INDUCED CELL TOXICITY AND DIFFERENTIATION BY GUANINE IN S-49 AND HL-60 CELLS.
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020 $a 9798204877726
035 $a (MiAaPQ)AAI8608571
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100 1 $a CHENG, HUI-WEN. $3 3680583
245 1 0 $a MODULATION OF 6-THIOGUANINE INDUCED CELL TOXICITY AND DIFFERENTIATION BY GUANINE IN S-49 AND HL-60 CELLS.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 1985
300 $a 109 p.
500 $a Source: Dissertations Abstracts International, Volume: 46-07, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
502 $a Thesis (Ph.D.)--University of California, San Francisco, 1985.
506 $a This item must not be added to any third party search indexes.
506 $a This item must not be sold to any third party vendors.
520 $a The mechanism of 6-TG toxicity has been attributed to its incorporation into DNA. The presence of guanine in vivo is expected to modify the action of 6-TG by either interfering with 6-TG metabolism or its incorporation into nucleic acids. The effects of guanine on 6-TG metabolism and cell toxicity were therefore studied in mouse lymphoma S-49 cells. The results showed that while guanine does not affect the accumulation of 6-TGMP, it does eliminate the formation of 6-dTGTP. Guanine also competes effectively with 6-TG for incorporation into DNA and RNA, but fails to prevent the growth inhibitory effect of 6-TG. Therefore, mechanisms other than 6-TG incorporate into DNA and RNA contribute to 6-TG toxicity in S-49 cells. 6-TG is able to induce cell differentiation in human promyelocytic HL-60 cells at low concentrations. Coadministration of guanine with 6-TG decreases the accumulation of 6-TGMP and suppresses of cell differentiation; therefore, differentiation apparently depends on 6-TGMP formation at low 6-TG concentrations. 6-TGMP is a poor substrate of GMP kinase with a low V(,max) value and k(,m) = 384 (mu)M. It also behaves as a noncompetitive inhibitor of GMP for 5'-nucleotidase, acid phosphatase, and alkaline phosphatase and again represents a poor substrate for these enzymes studied. Thus, high concentrations of 6-TGMP can be reached in cells that in turn inhibit several other enzymes involved in guanosine nucleotide biosynthesis, such as PRPP amidotransferase, HGPRTase, and IMP dehydrogenase, thus causing guanine starvation. Therefore, guanine starvation induced by 6-TG treatment may play an important role in regulating cell differentiation.
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650 4 $a Pharmaceuticals. $3 3562593
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773 0 $t Dissertations Abstracts International $g 46-07B.
790 $a 0034
791 $a Ph.D.
792 $a 1985
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=8608571