Cytotoxic effects of novel amphiphilic dimers consisting of 5-fluorodeoxyuridine and arabinofuranosylcytosine in cross-resistant H9 human lymphoma cells

Saiko, Philipp; Horváth, Zsuzsanna; Illmer, Christoph; Madlener, Sibylle; Bauer, Wolfgang; Hoechtl, Thomas; Erlach, Natascha; Grusch, Michael; Krupitza, Georg; Mader, Robert M.; Jaeger, Walter; Schott, Herbert; Agarwal, Rekha; Fritzer‐Szekeres, Monika; Szekeres, Thomas

doi:10.1016/j.leukres.2004.12.015

Cited by 8 publications

(7 citation statements)

References 20 publications

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“…In a previous study, multidrugs were already shown to overcome drug resistance. [13] In the present study, AraC-L-5FdU inhibited cell growth in various cell lines. Cytotoxicity was less in dCK deficient cells, in which also no phosphorylated AraC was detected.…”

Section: Discussionsupporting

confidence: 51%

In Vivo and in Vitro Activity And Mechanism Of Action of the Multidrug Cytarabine-L-Glycerylyl-Fluorodeoxyuridine

Bijnsdorp

Schwendener

Schott

et al. 2007

Nucleosides, Nucleotides and Nucleic Acids

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Multidrugs have the potential to bypass resistance. We investigated the in vitro activity and resistance circumvention of the multidrug cytarabine-L-fluorodeoxyuridine (AraC-L-5FdU), linked via a glycerophospholipid linkage. Cytotoxicity was determined using sensitive (A2780, FM3A/0) and resistant (AG6000, AraC resistant, deoxycytidine kinase deficient; FM3A/TK-, 5FdU resistant, thymidine kinase deficient) cell lines. Circumvention of nucleoside transporter and activating enzymes was determined using specific inhibitors, HPLC analysis and standard radioactivity assays. AraC-L-5FdU was active (IC50: 0.03 microM in both A2780 and FM3A/0), had some activity in AG6000 (IC50: 0.28 microM), but no activity in FM3A/TK(-) (IC50: 18.3 microM). AraC-nucleotides were not detected in AG6000. 5FdU-nucleotides were detected in all cell lines. AraC-L-5FdU did not inhibit TS in FM3A/TK(-) (5%). Since phosphatase/nucleotidase-inhibition reduced cytotoxicity 7-70-fold, cleavage seems to be outside the cell, presumably to nucleotides, and then to nucleosides. The multidrug was orally active in the HT-29 colon carcinoma xenografts which are resistant toward the single drugs.

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Section: Discussionsupporting

confidence: 51%

In Vivo and in Vitro Activity And Mechanism Of Action of the Multidrug Cytarabine-L-Glycerylyl-Fluorodeoxyuridine

Bijnsdorp

Schwendener

Schott

et al. 2007

Nucleosides, Nucleotides and Nucleic Acids

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“…In order to combine the (pharmacologic and therapeutic) advantages of two drugs, new multi- and duplex drugs have been synthesized. The multidrug Ara-C-L-FdUrd has previously shown strong antitumor effects in vitro and could also overcome Ara-C and FdUrd resistance [18]. However, Ara-C-L-FdUrd is cleaved outside the cells to a high extent, limiting its cytotoxic activity [19].…”

Section: Discussionmentioning

confidence: 99%

“…When the drug is inside the cell, specific enzymes can further activate it. For another multidrug, AraC-L-FdUrd, a partial reversal of resistance to one drug was found [18]. However, we previously concluded that the efficacy of the two drugs was too different in order to exert a cytotoxic effect of both drugs [19].…”

Section: Introductionmentioning

confidence: 99%

Cellular pharmacology of multi- and duplex drugsconsisting of ethynylcytidine and 5-fluoro-2′-deoxyuridine

et al. 2009

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SummaryProdrugs can have the advantage over parent drugs in increased activation and cellular uptake. The multidrug ETC-L-FdUrd and the duplex drug ETC-FdUrd are composed of two different monophosphate-nucleosides, 5-fluoro-2′deoxyuridine (FdUrd) and ethynylcytidine (ETC), coupled via a glycerolipid or phosphodiester, respectively. The aim of the study was to determine cytotoxicity levels and mode of drug cleavage. Moreover, we determined whether a liposomal formulation of ETC-L-FdUrd would improve cytotoxic activity and/or cleavage. Drug effects/cleavage were studied with standard radioactivity assays, HPLC and LC-MS/MS in FM3A/0 mammary cancer cells and their FdUrd resistant variants FM3A/TK−. ETC-FdUrd was active (IC50 of 2.2 and 79 nM) in FM3A/0 and TK− cells, respectively. ETC-L-FdUrd was less active (IC50: 7 nM in FM3A/0 vs 4500 nM in FM3A/TK−). Although the liposomal formulation was less active than ETC-L-FdUrd in FM3A/0 cells (IC50:19.3 nM), resistance due to thymidine kinase (TK) deficiency was greatly reduced. The prodrugs inhibited thymidylate synthase (TS) in FM3A/0 cells (80–90%), but to a lower extent in FM3A/TK− (10–50%). FdUMP was hardly detected in FM3A/TK− cells. Inhibition of the transporters and nucleotidases/phosphatases resulted in a reduction of cytotoxicity of ETC-FdUrd, indicating that this drug was cleaved outside the cells to the monophosphates, which was verified by the presence of FdUrd and ETC in the medium. ETC-L-FdUrd and the liposomal formulation were neither affected by transporter nor nucleotidase/phosphatase inhibition, indicating circumvention of active transporters. In vivo, ETC-FdUrd and ETC-L-FdURd were orally active. ETC nucleotides accumulated in both tumor and liver tissues. These formulations seem to be effective when a lipophilic linker is used combined with a liposomal formulation.

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“…After application as monotherapeutic either orally or intravenously the molecule should be metabolized in vivo into several cytostatic metabolites possessing different activities with additive or synergistic effects. Cytostatic nucleoside analoges such as 5-fluoro-2′-deoxyuridine (5FdU) that are used as standard chemotherapeutic in gastrointestinal malignancies, can principally be linked via a natural phosphodiesterbonding into dinucleoside phosphate analogues resulting in highly potent cytostatic duplex drugs [5][6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Cytostatic activity of the duplex drug linking 2′-deoxy-5-fluorouridine (5FdU) with 3′-C-ethynylcytidine (ECyd) against gastric adenocarcinoma cell lines

et al. 2010

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The cytostatic potential of the new duplex drug 2'-deoxy-5-fluorouridylyl-(5'5')-3'-C-ethynylcytidine (5FdU(5'-5')ECyd) was evaluated in comparison to those of 5-fluorouracil (5FU), 2'-deoxy-5-fluorourindine (5FdU), 3'-C-ethynylycytidine (ECyd), cisplatin, an equimolar mixture of 5FdU + ECyd and a three component-mixture of 0.75 μM epirubicin/0.90 μM cisplatin/3.0 μM 5FU (ECF) by incubation of the two human gastric adenocarcinoma cell lines 23132/87 and MKN-45. The molar composition of ECF was taken from data of a triple combination chemotherapy for human gastric cancer. Time and dose depending inhibition of cell growth was determinated using the CASY technology. A growth decrease of both cell lines from 100% to about 20% was observed by treatment with ECF over a course of 14 days. This result provided basis to estimate the cytostatic potential of all tested drugs and combinations thereof. Corresponding high activities in respect to ECF were achieved by incubation of 23132/87 cells with single drugs 49 μM 5FU, 10 μM cisplatin, 3.4 μM 5FdU, 0.65 μM ECyd, the mixture 0.32 μM 5FdU + 0.32 μM ECyd and 0.32 μM 5FdU(5'-5')ECyd. The less sensitive MKN-45 cells require a 1.5-4 fold higher dose of the standard chemotherapeutics in order to achieve an equivalent cytostatic effect, in respect to the 23132/87 cell line,. However, the effect of the duplex drugs on MKN-45 cells was gained with a 5-fold lower dose than ECF. Due to its high cytostatic potential the duplex drug, which covalently links two active anticancer compounds, could be a new therapeutic alternative for chemotherapy in gastric cancer, currently treated with different combinations.

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Cytotoxic effects of novel amphiphilic dimers consisting of 5-fluorodeoxyuridine and arabinofuranosylcytosine in cross-resistant H9 human lymphoma cells

Cited by 8 publications

References 20 publications

In Vivo and in Vitro Activity And Mechanism Of Action of the Multidrug Cytarabine-L-Glycerylyl-Fluorodeoxyuridine

In Vivo and in Vitro Activity And Mechanism Of Action of the Multidrug Cytarabine-L-Glycerylyl-Fluorodeoxyuridine

Cellular pharmacology of multi- and duplex drugsconsisting of ethynylcytidine and 5-fluoro-2′-deoxyuridine

Cytostatic activity of the duplex drug linking 2′-deoxy-5-fluorouridine (5FdU) with 3′-C-ethynylcytidine (ECyd) against gastric adenocarcinoma cell lines

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