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  • 1
    Electronic Resource
    Electronic Resource
    Cell-cycle arrest and p53-independent induction of apoptosis in vitro by the new anticancer drugs 5-FdUrd-P-FdCydOct and dCydPam-P-FdUrd in DU-145 human prostate cancer cells (2000)
    Springer
    Journal of cancer research and clinical oncology 126 (2000), S. 247-256 
    Details
    ISSN: 1432-1335
    Keywords: Key words 5-Fluorodeoxyuridine ; Heterodinucleoside dimers ; Prodrugs ; Prostate cancer ; Cytotoxicity ; Cell cycle ; Apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Purpose: Current therapies have limited impact on the progression of metastatic hormone-refractory prostate cancer. Therefore, we investigated the utility of new heterodinucleoside phosphate dimers of 5-fluorodeoxyuridine (5-FdUrd) in p53-mutated and androgen-independent DU-145 human prostate tumour cells. Methods: The effects of the dimers were assessed in vitro by a cell proliferation assay for cytotoxicity, flow cytometry for cell cycle distribution, confocal laser scanning microscopy for the detection of apoptotic bodies, poly(ADP-ribose) polymerase cleavage for caspase 3 activity and by a thymidylate synthetase assay. Results: The new dimers N 4-palmitoyl-2′-deoxycytidylyl-(3′→5′)-5-fluoro-2′-deoxyuridine (dCydPam-P-FdUrd) and 2′-deoxy-5-fluorouridylyl-(3′→5′)-2′-deoxy-5-fluoro-N 4-octadecylcytidine (5-FdUrd-P-FdCydOct) caused marked cytotoxicity with IC50 values of 3–4 μM. 5-FdUrd-P-FdCydOct at 200 μM was capable of eradicating 100% of tumour cells whereas 10% of the cells were resistant to 5-FdUrd. Cytotoxicity was caused by a dramatic S-phase arrest, resulting in an increase of this cell population from 34% to 85% with 5-FdUrd-P-FdCydOct and to 81% with dCydPam-P-FdUrd. S-phase arrest was followed by apoptosis, as shown by 85% of the cells staining positive for Apo 2.7 antibody, a six- to eight-fold increased caspase 3 activity and DNA fragmentation. Thymidylate synthase activity was inhibited by 50% at 0.6–0.7 μM dimer concentration. The dimers were hydrolysed in vitro by phosphodiesterase I and human serum to the corresponding nucleosides and nucleoside monophosphates. Conclusions: The new dimers dCydPam-P-FdUrd and 5-FdUrd-P-FdCydOct are effective prodrugs of 5-FdUrd and have potential value for the treatment of p53-mutated and hormone-independent human prostate carcinomas.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004320050339
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  • 2
    Electronic Resource
    Electronic Resource
    Cytotoxicity, cell-cycle perturbations and apoptosis in human tumor cells by lipophilic N 4-alkyl-1-β-D-arabinofuranosylcytosine derivatives and the new heteronucleoside phosphate dimer arabinocytidylyl-(5′→ 5′)-N 4-octadecyl-1-β-d-arabinofuranosylcytosine (2000)
    Springer
    Journal of cancer research and clinical oncology 126 (2000), S. 311-319 
    Details
    ISSN: 1432-1335
    Keywords: Key wordsN4-Alkyl-AraC derivatives ; NOAC-AraC dimer ; Cytotoxicity ; Apoptosis ; Drug resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The arabinofuranosylcytosine (AraC) derivative N 4-octadecyl-1-β-D-arabinofuranosylcytosine (NOAC) and its (5′ → 5′)-heterodinucleoside phosphate analog NOAC-AraC were compared with AraC for cytotoxicity, cell-cycle dependence, phosphorylation by deoxycytidine (dC) kinase and apoptosis induction in native, AraC- or NOAC-resistant HL-60 cells. NOAC was cytotoxic in all cells with three to seven-fold lower IC50 concentrations than those of NOAC-AraC or AraC. In contrast to NOAC-AraC, the lipophilic monomer NOAC overcame AraC resistance, inducing apoptosis in more than 80% of native and AraC-resistant HL-60 cells. This suggests that NOAC-AraC may be cleaved intracellularly only at very slow rates to AraC and NOAC or to the 5′-monophosphates, whereas NOAC exerts different mechanisms of action from AraC. In vitro the dimer was cleaved by phosphodiesterase or human serum to NOAC, AraC and AraC monophosphate. In contrast to AraC, N 4-alkylated AraC derivatives with alkyl chains ranging from 6–18 C atoms were not substrates for dC kinase. Furthermore, treatment of the multidrug-resistant cell lines KB-ChR-8-5 and KB-V1 with the N 4-hexadecyl-AraC derivative NHAC did not induce P-170 glycoprotein expression, suggesting that the N 4-alkyl-AraC derivatives are able to circumvent MDR1 multidrug resistance. The in vivo activity of liposomal NOAC in a human acute lymphatic leukemia xenograft model confirmed the antitumor activity of this representative of the N 4-alkyl-arabinofuranosylcytosines.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004320050349
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    Paper (German National Licenses)
    Fulltext
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