Abstract:
:2',2'-Difluorodeoxycytidine (Gemcitabine, dFdC) is a relatively new deoxycytidine antimetabolite, with established activity against ovarian cancer and non-small-cell lung cancer. dFdC is assumed to exert its antitumour effect mainly by incorporation of the triphosphate dFdCTP into DNA. We determined the sensitivity to dFdC of six cell lines derived from solid tumours; two ovarian carcinoma (A2780 and OVCAR-3), two colon carcinoma (WiDr and C26-10) and two squamous cell carcinoma cell lines (UM-SCC-14C and UM-SCC-22B). In vitro sensitivity to dFdC was strongly time dependent. Under all conditions A2780 was the most sensitive cell line with an IC50 (the concentration of dFdC causing 50% growth inhibition) of 31 and 0.6 nM at 1 and 48 hr exposure, respectively. WiDr and C26-10 cells were relatively insensitive, with IC50s of 468 and 1133 nM, respectively, at 1 hr exposure, but of 11 and 6 nM at 48 hr exposure. Accumulation of the triphosphate dFdCTP was also time dependent. After 4 hr exposure to 10 microM dFdC, A2780, WiDr and C26-10 cells accumulated 223, 136 and 267 pmol/10(6) cells, respectively; after 24 hr exposure they accumulated 1045, 619 and 617 pmol/10(6) cells, respectively. A2780 cells retained the high dFdCTP concentration longer than 24 hr. For comparison purposes we also studied dFdCTP kinetics in the corresponding solid tumours, showing the same sensitivity pattern as the cell lines. In general, sensitivity to dFdC in vitro related with dFdCTP accumulation and retention, but in vivo this relation was less clear. Unexpectedly, remarkable in vitro and in vivo changes were observed in the ribonucleotide pools. The most predominant in vitro cell line dependent changes were a decrease in CTP concentrations, accompanied by an increase in UTP and GTP concentrations. In vivo CTP, UTP and GTP pools increased in all tumours. In conclusion, in this study we demonstrate that dFdCTP is accumulated and retained in solid tumours and cell lines. dFdCTP is not only important as a DNA precursor, but also appears to interfere with normal ribonucleotide metabolism.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Ruiz van Haperen VW,Veerman G,Boven E,Noordhuis P,Vermorken JB,Peters GJdoi
10.1016/0006-2952(94)90554-1subject
Has Abstractpub_date
1994-10-07 00:00:00pages
1327-39issue
7eissn
0006-2952issn
1873-2968pii
0006-2952(94)90554-1journal_volume
48pub_type
杂志文章abstract::One feature that contraindicates the wide therapeutic use of retinoids is their teratogenicity. Synthetic retinoids are distinguishable from each other on the basis of their partial or exclusive preference in binding and activation of all-trans retinoic acid receptors (RARs) or retinoid X receptors (RXRs). Using mouse...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(95)00183-z
更新日期:1995-08-25 00:00:00
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journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.bcp.2020.113862
更新日期:2020-06-01 00:00:00
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(89)90516-9
更新日期:1989-12-01 00:00:00
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(90)90024-f
更新日期:1990-01-15 00:00:00
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(98)00205-6
更新日期:1998-11-15 00:00:00
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(99)00134-3
更新日期:1999-08-15 00:00:00
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2010.06.012
更新日期:2010-10-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/s0006-2952(01)00735-3
更新日期:2001-10-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.bcp.2010.01.028
更新日期:2010-06-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/s0006-2952(98)00219-6
更新日期:1998-10-15 00:00:00
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2004.06.017
更新日期:2004-10-01 00:00:00
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2005.08.018
更新日期:2005-11-25 00:00:00
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pub_type: 杂志文章
doi:10.1016/0006-2952(83)90455-0
更新日期:1983-04-15 00:00:00
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pub_type: 杂志文章
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更新日期:2014-06-15 00:00:00
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pub_type: 杂志文章
doi:10.1016/s0006-2952(97)00075-0
更新日期:1997-05-15 00:00:00
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(90)90585-9
更新日期:1990-12-15 00:00:00
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2006.01.003
更新日期:2006-04-28 00:00:00
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pub_type: 杂志文章
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更新日期:1989-10-01 00:00:00
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pub_type: 杂志文章
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
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更新日期:2012-04-01 00:00:00
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pub_type: 杂志文章
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更新日期:1992-12-15 00:00:00
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2004.11.006
更新日期:2005-02-15 00:00:00
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pub_type: 杂志文章
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更新日期:1988-07-15 00:00:00
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
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更新日期:1997-07-01 00:00:00
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
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更新日期:2001-07-01 00:00:00
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
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更新日期:1987-11-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.bcp.2009.10.011
更新日期:2010-03-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/0006-2952(84)90581-1
更新日期:1984-07-01 00:00:00
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journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(86)90319-9
更新日期:1986-05-15 00:00:00
abstract::There is evidence to suggest that the oxidative metabolism of hydralazine (HP), an antihypertensive drug, may represent a toxic pathway which could account for some of the adverse effects of the drug. Experiments were done to determine whether the hepatic oxidative metabolism of HP is associated with the formation of ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(87)90549-1
更新日期:1987-08-15 00:00:00