Combinations of 5‐Fluorouracil with UCN‐01 or Staurosporine

Sigmond, J.; Comijn, E. M.; Kamphuis, J.A.E.; Peters, Godefridus J.

doi:10.1081/ncn-200027718

Cited by 6 publications

(3 citation statements)

References 5 publications

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“…Shao et al (2004) have previously shown that cytotoxicity was enhanced in human colon carcinoma HT‐29 cells when UCN‐01 was added after treatment with ara‐C. For 5‐fluorouracil we also showed a sequence‐dependent interaction in colon cancer cell lines (Sigmond et al , 2004).…”

Section: Drug Interaction Between Ara‐c and Six Potential Modulators supporting

confidence: 55%

“…Furthermore, it is able to abrogate checkpoints induced by genotoxic stress due to modulation in chk1 kinase (Senderowicz, 2001). Shao et al (2004) have previously shown that cytotoxicity was enhanced in human colon carcinoma HT-29 cells when UCN-01 was added after treatment with ara-C. For 5-fluorouracil we also showed a sequence-dependent interaction in colon cancer cell lines (Sigmond et al, 2004).…”

supporting

confidence: 62%

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Potentiation of in vitro ara‐C cytotoxicity by ribonucleotide reductase inhibitors, cyclin‐dependent kinase modulators and the DNA repair inhibitor aphidicolin in paediatric acute myeloid leukaemia

et al. 2005

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Summary To modulate in vitro cytarabine (ara‐C) resistance we combined ara‐C with six potential resistance modifiers in 10 paediatric acute myeloid leukaemia (AML) patient samples (methyl thiazol tetrazolium assay). Drug interactions were determined by median drug effect analysis. Co‐incubation of ara‐C/aphidicolin showed strong synergism. The combinations of ara‐C/cladribine and ara‐C/gemcitabine were synergistic. Nearly additive and moderately synergistic interactions were observed between ara‐C/flavopiridol and ara‐C/UCN‐01. The combination of ara‐C/decitabine was antagonistic. In conclusion, favourable interactions were observed between ara‐C and aphidicolin, cladribine, gemcitabine and also with flavopiridol and UCN‐01, supporting the evaluation of these combinations in clinical trials with AML patients.

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Section: Drug Interaction Between Ara‐c and Six Potential Modulators supporting

confidence: 55%

supporting

confidence: 62%

Potentiation of in vitro ara‐C cytotoxicity by ribonucleotide reductase inhibitors, cyclin‐dependent kinase modulators and the DNA repair inhibitor aphidicolin in paediatric acute myeloid leukaemia

et al. 2005

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“…In mut-p53 cells this regulation is abrogated, so that UCN-01 by inhibition of the G2/M checkpoint regulators, will increase DNA damage. Moreover UCN-01 will further prevent DNA repair and enhance the effect of deoxynucleoside analogues ara-C, dFdC, 5-FU [26][27][28][29][30][31], the purine analogue fludarabine [26,32] and DNA binding agents such as cisplatin, thiotepa, mitomycin C, cisplatin, melphalan and topotecan [26]. Treatment with a DNA damaging drug (cisplatin, 5FU, nucleoside analogs or radiation) prior to UCN-01 or a novel ChK1 inhibitor (SCH00766) was synergistic and induced more cell death than vice versa through abrogation of the G2/M checkpoint and was associated by reduced expression of cyclins A and B and activation of Cdk1 [33,34].…”

Section: Discussionmentioning

confidence: 99%

Effect of staurosporine and ucn-01 on gemcitabine cytotoxicity in relation to cell cycle effects and p53 status

Sigmond¹,

León²,

Kamphuis³

et al. 2012

J Cancer Ther Res

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Gemcitabine (dFdC) is an anti-cancer agent that is affected by cell cycle modulation. Staurosporine and 7-hydroxystaurosporine (UCN-01) are potent protein kinase C (PKC) inhibitors as well as inhibitors of cyclin dependent kinase 2 (cdk2) and were therefore investigated for potential synergism, cell cycle modulation, cell death induction, and the role of the p53 protein. Lovo colon cancer cell line variants with wild type and mutant p53 (Lovo 175x2) or inactive (Lovo Li) were used for this purpose. Combinations of dFdC with staurosporine were most synergistic when cells were exposed to dFdC prior to staurosporine, while for UCN-01 the simultaneous exposure was most synergistic. This synergism appeared to be related with abrogation of the cell cycle and cell cycle proteins. For dFdC (1.0 μM), a gradual time dependent increase of cells in S phase (up to 40%) was observed in all Lovo variants. Staurosporine (0.05 μM) initially induced accumulation of cells in the G 2 /M phase (after 24 hr), while 48 hr exposure showed accumulation in the S-phase. UCN-01 (0.5 μM) caused an arrest in G 0 /G 1 after 24 hr exposure, while after 48 hr cells accumulated in the S phase. Simultaneous exposure to dFdC combinations showed an average cell cycle distribution of both drugs when used alone. In sequential addition of dFdC combinations, the first drug dominated the cell cycle distribution. Synergism of gemcitabine combinations was associated with induction of cell death by UCN-01, which was 2-fold higher in Lovo 175x2 (mutant p53) compared to other Lovo variants. Additive effects in induction of cell death were observed at the simultaneous addition of dFdC and UCN-01, but exposure to dFdC prior to UCN-01 caused a 2-fold higher induction of cell death than the sum of each compound alone in Lovo 175x2 cells, in contrast to the other lines. Accumulation of cells in the G2/M phase prevented repair of DNA damage, resulting in increased apoptosis. These data demonstrate that staurosporine and UCN-01 affect dFdC cytotoxicity via modulation of the cell cycle.

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