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Titolo:
CYTOTOXICITY AND DNA FRAGMENTATION ASSOCIATED WITH SEQUENTIAL GEMCITABINE AND 5-FLUORO-2'-DEOXYURIDINE IN HT-29 COLON-CANCER CELLS
Autore:
REN QF; KAO V; GREM JL;
Indirizzi:
NCI,NAVY MED BRANCH,NMNC,DEV THERAPEUT DEPT,DIV CLIN SCI,BLDG 8,ROOM 5101,8901 WISCONSIN AVE BETHESDA MD 20889 NCI,NAVY MED BRANCH,NMNC,DEV THERAPEUT DEPT,DIV CLIN SCI BETHESDA MD 20889
Titolo Testata:
Clinical cancer research
fascicolo: 11, volume: 4, anno: 1998,
pagine: 2811 - 2818
SICI:
1078-0432(1998)4:11<2811:CADFAW>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
MOUSE FM3A CELLS; PHASE-II TRIAL; 2',2'-DIFLUORODEOXYCYTIDINE GEMCITABINE; CARCINOMA CELLS; LEUKEMIA-CELLS; STRAND BREAKS; DEATH; MECHANISM; 1-BETA-D-ARABINOFURANOSYLCYTOSINE; FLUOROURACIL;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
34
Recensione:
Indirizzi per estratti:
Citazione:
Q.F. Ren et al., "CYTOTOXICITY AND DNA FRAGMENTATION ASSOCIATED WITH SEQUENTIAL GEMCITABINE AND 5-FLUORO-2'-DEOXYURIDINE IN HT-29 COLON-CANCER CELLS", Clinical cancer research, 4(11), 1998, pp. 2811-2818

Abstract

The combined cytotoxic effects of the antimetabolites gemcitabine (dFdCyd) and 5-fluoro-2'-deoxyuridine (FdUrd) were studied. Cytotoxicity,biochemical perturbations, and DNA damage seen with dFdCyd and FdUrd alone and in combination were evaluated in HT-29 human colon cancer cells. A 4-h exposure to dFdCyd followed by FdUrd for 24 h produced morethan additive cytotoxicity and marked S-phase accumulation. Cells progressed through the cell cycle, however, after a 22-h drug-free interval. [H-3]dFdCyd was rapidly metabolized to the 5'-triphosphate and incorporated into DNA, [H-3]FdUrd was anabolized exclusively to FdUrd monophosphate, and preexposure to dFdCyd did not affect FdUrd monophosphate formation. Thymidylate synthase catalytic activity was inhibited by48% after a 4-h exposure to 10 nM FdUrd and by 80% after exposure to the combination, Sequential 4-h exposures to 15 nM dFdCyd and 10 nM FdUrd led to greater depletion of dTTP pools (29% of control) than with either drug alone. Greater effects on nascent DNA integrity were seen with sequential dFdCyd followed by FdUrd, Although parental DNA damagewas not evident immediately after exposure to 15 nM dFdCyd for 4 h followed by 10 nM FdUrd for 24 h, high molecular mass DNA fragmentation was evident 72-96 h after drug removal. Sequential dFdCyd/FdUrd was associated with prominent disturbance of the cell cycle, dTTP pool depletion, dATP/dTTP imbalance, and nascent DNA damage. Induction of double-strand parental DNA damage and cell death was delayed, consistent with postmitotic apoptosis.

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Documento generato il 01/10/20 alle ore 16:20:58