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Molecular mechanisms underlying the interaction between ZD1839 ('Iressa') and cisplatin/5-fluorouracil.

Magné N, Fischel JL, Tiffon C, Formento P, Dubreuil A, Renée N, Formento JL, Francoual M, Ciccolini J, Etienne MC, Milano G - Br. J. Cancer (2003)

Bottom Line: ZD1839 alone induced accumulation of cells in the G0/G1 phase of the cell cycle at 24 h accompanied by a concomitant increase in p21, p27 and Bax, a significant decrease in Bcl2 and a decrease in Akt phosphorylation.A decrease in DNA-PK was observed at 48 h.ZD1839 alone had no effect on caspase-3 activity, but addition of ZD1839 to cisplatin-5FU led to a significant increase in caspase-3 activity at 96 h.

View Article: PubMed Central - PubMed

Affiliation: Centre Antoine Lacassagne, Oncopharmacology Unit, 33, Avenue de Valombrose, 06189, Nice cedex 2, France.

ABSTRACT
ZD1839 ('Iressa'), an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is currently being investigated in clinical trials as a treatment for cancer. 'Iressa' is a trademark of the AstraZeneca group of companies. We have previously demonstrated a synergistic interaction between ZD1839 and cisplatin/5-fluorouracil (5FU) in CAL33, a human head and neck cancer cell line that markedly expresses EGFR. This study examined the effects of this drug combination on the cell cycle, cell cycle regulators, apoptosis-related factors, EGFR-related signalling and DNA repair in CAL33 cells. The cells were incubated with ZD1839 alone for 48 h, then cisplatin and 5FU were added. Exposure to the drug combination continued for a further 48 h. ZD1839 alone induced accumulation of cells in the G0/G1 phase of the cell cycle at 24 h accompanied by a concomitant increase in p21, p27 and Bax, a significant decrease in Bcl2 and a decrease in Akt phosphorylation. A decrease in DNA-PK was observed at 48 h. ZD1839 alone had no effect on caspase-3 activity, but addition of ZD1839 to cisplatin-5FU led to a significant increase in caspase-3 activity at 96 h. Thus, ZD1839 affects key cellular pathways controlling cell proliferation, apoptosis and DNA repair. These data provide a rationale to support clinical trials combining ZD1839 and cisplatin-5FU and other protocols that combine EGFR-targeting agents with chemotherapy or radiotherapy.

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Related in: MedlinePlus

Representative Western blots related to Figures 2, 3, 4 and 8. For details on these analyses, see Materials and Methods section.
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fig9: Representative Western blots related to Figures 2, 3, 4 and 8. For details on these analyses, see Materials and Methods section.

Mentions: Differences between the mean values were evaluated using either one-way ANOVA with Tukey's test or one-way ANOVA on ranks with Dunnetts' or Student–Newman–Keuls test, according to data distribution. P=0.05 was regarded as statistically significant. All analyses used SPSS software (Paris, France).


Molecular mechanisms underlying the interaction between ZD1839 ('Iressa') and cisplatin/5-fluorouracil.

Magné N, Fischel JL, Tiffon C, Formento P, Dubreuil A, Renée N, Formento JL, Francoual M, Ciccolini J, Etienne MC, Milano G - Br. J. Cancer (2003)

Representative Western blots related to Figures 2, 3, 4 and 8. For details on these analyses, see Materials and Methods section.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2394392&req=5

fig9: Representative Western blots related to Figures 2, 3, 4 and 8. For details on these analyses, see Materials and Methods section.
Mentions: Differences between the mean values were evaluated using either one-way ANOVA with Tukey's test or one-way ANOVA on ranks with Dunnetts' or Student–Newman–Keuls test, according to data distribution. P=0.05 was regarded as statistically significant. All analyses used SPSS software (Paris, France).

Bottom Line: ZD1839 alone induced accumulation of cells in the G0/G1 phase of the cell cycle at 24 h accompanied by a concomitant increase in p21, p27 and Bax, a significant decrease in Bcl2 and a decrease in Akt phosphorylation.A decrease in DNA-PK was observed at 48 h.ZD1839 alone had no effect on caspase-3 activity, but addition of ZD1839 to cisplatin-5FU led to a significant increase in caspase-3 activity at 96 h.

View Article: PubMed Central - PubMed

Affiliation: Centre Antoine Lacassagne, Oncopharmacology Unit, 33, Avenue de Valombrose, 06189, Nice cedex 2, France.

ABSTRACT
ZD1839 ('Iressa'), an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is currently being investigated in clinical trials as a treatment for cancer. 'Iressa' is a trademark of the AstraZeneca group of companies. We have previously demonstrated a synergistic interaction between ZD1839 and cisplatin/5-fluorouracil (5FU) in CAL33, a human head and neck cancer cell line that markedly expresses EGFR. This study examined the effects of this drug combination on the cell cycle, cell cycle regulators, apoptosis-related factors, EGFR-related signalling and DNA repair in CAL33 cells. The cells were incubated with ZD1839 alone for 48 h, then cisplatin and 5FU were added. Exposure to the drug combination continued for a further 48 h. ZD1839 alone induced accumulation of cells in the G0/G1 phase of the cell cycle at 24 h accompanied by a concomitant increase in p21, p27 and Bax, a significant decrease in Bcl2 and a decrease in Akt phosphorylation. A decrease in DNA-PK was observed at 48 h. ZD1839 alone had no effect on caspase-3 activity, but addition of ZD1839 to cisplatin-5FU led to a significant increase in caspase-3 activity at 96 h. Thus, ZD1839 affects key cellular pathways controlling cell proliferation, apoptosis and DNA repair. These data provide a rationale to support clinical trials combining ZD1839 and cisplatin-5FU and other protocols that combine EGFR-targeting agents with chemotherapy or radiotherapy.

Show MeSH
Related in: MedlinePlus