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Titolo:
Radiosensitivity of thymidylate synthase-deficient human tumor cells is affected by progression through the G(1) restriction point into S-phase: Implications for fluoropyrimidine radiosensitization
Autore:
Hwang, HS; Davis, TW; Houghton, JA; Kinsella, TJ;
Indirizzi:
Case Western Reserve Univ, Sch Med, Dept Radiat Oncol, Cleveland, OH 44106USA Case Western Reserve Univ Cleveland OH USA 44106 , Cleveland, OH 44106USA Univ Hosp Cleveland Ireland Canc Ctr, Cleveland, OH 44106 USA Univ Hosp Cleveland Ireland Canc Ctr Cleveland OH USA 44106 OH 44106 USA St Jude Childrens Res Hosp, Dept Mol Pharmacol, Memphis, TN 38101 USA St Jude Childrens Res Hosp Memphis TN USA 38101 ol, Memphis, TN 38101 USA
Titolo Testata:
CANCER RESEARCH
fascicolo: 1, volume: 60, anno: 2000,
pagine: 92 - 100
SICI:
0008-5472(20000101)60:1<92:ROTSHT>2.0.ZU;2-X
Fonte:
ISI
Lingua:
ENG
Soggetto:
COLON-CARCINOMA CELLS; WILD-TYPE P53; DOUBLE-STRAND BREAKS; MOUSE FM3A CELLS; CANCER-CELLS; MEDIATED RADIOSENSITIZATION; THYMINELESS DEATH; DEOXYRIBONUCLEOSIDE TRIPHOSPHATES; MIMOSINE ARRESTS; ADJUVANT THERAPY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
62
Recensione:
Indirizzi per estratti:
Indirizzo: Kinsella, TJ Univ Hosp Cleveland, Dept Radiat Oncol, Lerner Tower 6068,11100 Euclid Ave, Cleveland, OH 44106 USA Univ Hosp Cleveland Lerner Tower 6068,11100 Euclid Ave Cleveland OH USA 44106
Citazione:
H.S. Hwang et al., "Radiosensitivity of thymidylate synthase-deficient human tumor cells is affected by progression through the G(1) restriction point into S-phase: Implications for fluoropyrimidine radiosensitization", CANCER RES, 60(1), 2000, pp. 92-100

Abstract

Recent studies of fluoropyrimidine (FP)-mediated radiosensitization (RS) have focused on the molecular mechanisms underlying regulation of the cell cycle, particularly at the G(1)-S transition. Although thymidylate synthase (TS) inhibition by FP is necessary, we hypothesize that FP-RS is temporallydependent on progression of cells into S-phase under conditions of altereddeoxynucleotide triphosphate pools, particularly an increased dATP:dTTP ratio, which subsequently results in enhanced DNA fragmentation and cell death. To better understand the mechanism of FP-RS, me characterized the cellular and biochemical responses to ionizing radiation (IR) alone, using different synchronization techniques in two isogenic, TS-deficient mutant cell lines, JH-1 (TS-) and JH-2 (Thy4), derived previously from a human colon cancer cell line. After G(0) synchronization by leucine deprivation, these clones differ under subsequent growth conditions and dThd withdrawal: JH-2 cells have an intact G(1) arrest (>72 h) and delayed cell death (>96 h), whereas JH-1 cells progress rapidly into early S-phase and undergo acute cell death (<24 h). No difference in the late S-phase and G(2)-M cell populations were noted between these growth-stimulated, G(0)-synchronized TS-deficient cell lines with dThd withdrawal. Biochemically, the intracellular ratio of dATP: dTTP increased substantially in JH-l cells as cells progressed into early S-phase compared with JH-2 cells, which remained in G(1) phase. Synchronized JH-l cells showed significantly decreased clonogenic survival and an increase in DNA fragmentation after IR when compared with JH-2 cells. RS was demonstrated by an increase in alpha and decrease in beta, using linear quadratic analyses. An alternative synchronization technique used mimosine to induce a block in late G(1), close to G(1)-S border. Both JH-1 and JH-2 cells, synchronized in late G(1) and following growth stimulation, now progressed into S-phase identically (<24 h), with similarly increased dATP:dTTP ratios under dThd withdrawal conditions. These late G(1)-synchronized JH-l and JH-2 cells also showed a comparable reduction in clonogenic survival and similar patterns of increased DNA fragmentation following IR, We suggest,based on the cellular and biochemical differences in response to IR between G(0)- and late G(1)-synchronized cells, that S-phase progression through the G(1) restriction point under an altered (increased) dATP:dTTP ratio is a major determinant of FP-RS.

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Documento generato il 27/09/20 alle ore 20:14:30