Abstract:
:Based on the organotropic characteristics of bile acids towards the liver and the intestine, two novel compounds of the Bamet family, containing at least one bile acid moiety bound to platinum(II), have been synthesized and their cytostatic effect compared to their ability to become accumulated in tumor cells of hepato-intestinal origin. Bamet-UD2 [cis-diammine-bis-ursodeoxycholic platinum(II)] induced a marked inhibition of cell growth, which was more marked in human hepatoblastoma HepG2 and mouse hepatoma Hepa 1-6 cells than in rat hepatoma McA-RH7777 and human colon adenocarcinoma LS 174T cells. This effect was similar to that observed for cisplatin and stronger than that previously reported for other members of this family, such as Bamet-H2 and Bamet-R2. By contrast, Bamet-D3 [(N'N'' cis-dichloro N(3-3-amminepropylammine)propyl) glycocholamide platinum (II)] was only effective in reducing growth in human hepatoblastoma HepG2 cells. Because the in vitro DNA-reactivity was approximately 5-fold higher for Bamet-D3 than for Bamet-UD2, an additional cause for the difference in their cytostatic abilities was sought, investigating the relationship between cell load and the cytostatic effect of the drugs. Drug uptake by two cell lines, Hepa 1-6 and HepG2, with different sensitivities to these compounds was measured. The cellular uptake of Bamet-D3 and Bamet-UD2 was several-fold higher than that of cisplatin. No significant difference in the amount of both drugs taken up by these cell types was found. A study on sodium-dependency and substrate specificity indicated that Hepa 1-6 cells take up Bamet-D3 and Bamet-UD2 via similar mechanism(s), whereas these compounds do not seem to share the uptake pathways in HepG2 cells. Measurement of cell viability by formazan formation from tetrazolium salts and by neutral red uptake, after short-term (6 h) exposure to the desired drug, indicated that no acute toxic effect occurs in the presence of cisplatin or Bamet-D3 in either HepG2 or Hepa 1-6 cells. By contrast, in both cell lines Bamet-UD2 induced acute cell toxicity in a dose-dependent fashion. In sum, the results indicate that tumor cells efficiently take up these two novel compounds of the Bamet family. Although the exact uptake mechanism remains unknown, it seems to be dependent on the cell type. However, the cell load does not account for the differences in the anti-proliferative properties of the drugs. The strong and promising cytostatic activity of Bamet-UD2 is additionally related to its ability, absent in Bamet-D3, to acutely alter cellular functions other than proliferation.
journal_name
J Drug Targetjournal_title
Journal of drug targetingauthors
Larena MG,Martinez-Diez MC,Macias RI,Dominguez MF,Serrano MA,Marin JJdoi
10.1080/1061186021000001841keywords:
subject
Has Abstractpub_date
2002-08-01 00:00:00pages
397-404issue
5eissn
1061-186Xissn
1029-2330journal_volume
10pub_type
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
pub_type: 杂志文章,评审
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
pub_type: 杂志文章
doi:10.1080/10611860600648494
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
pub_type: 杂志文章,收录出版
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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更新日期:2016-09-01 00:00:00
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
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journal_title:Journal of drug targeting
pub_type: 杂志文章
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abstract::Notch pathway was found to be activated in most glioblastomas (GBMs), underlining the importance of Notch in formation and recurrence of GBM. In this study, a Notch inhibitory peptide, dominant negative MAML (dnMAML), was conjugated to elastin-like polypeptide (ELP) for tumor targeted delivery. ELP is a thermally resp...
journal_title:Journal of drug targeting
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更新日期:2017-07-01 00:00:00