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

Magné, Nicolas; Fischel, Jean‐Louis; Tiffon, Céline; Formento, Patricia; A, Dubreuil; Renée, Nicole; Jl, Formento; Francoual, M; Ciccolini, Joseph; Etienne, Marie‐Christine; Milano, Gérard

doi:10.1038/sj.bjc.6601131

Cited by 77 publications

(55 citation statements)

References 21 publications

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“…All the experiments of gefitinib-induced cytotoxicity were evaluated after 3 days of continuous exposure, therefore the use of FCS in the in vitro culture system was required to ensure cell vitality; this is consistent with other studies (Magne et al, 2003;Tortora et al, 2003;Xu et al, 2003b). Furthermore, we have previously shown the stability of the drug in the presence of serum in the HPLC system .…”

Section: Resultssupporting

confidence: 86%

Laminin-5 offsets the efficacy of gefitinib (‘Iressa’) in hepatocellular carcinoma cells

Giannelli

Azzariti²,

Fransvea

et al. 2004

Br J Cancer

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Prognosis and survival of patients with hepatocellular carcinoma (HCC) is still very poor, and no therapies are currently available to inhibit tumour growth and metastases. Recently, we reported that the expression of an extracellular matrix component (ECM), namely , is directly related to poor prognosis in HCC patients. The aim of our study is to investigate the preclinical effect of gefitinib in an in vitro HCC model. We found that the IC 50 of gefitinib in HCC cells ranged from 0.7 to 10.0 mM, whereas Ln-5 inhibited the activity of gefitinib in a dose-dependent manner. Complete inhibition of phosphorylated (p)-EGFR (epidermal growth factor receptor) was obtained within 6 h exposure to gefitinib and complete restoration of the receptor status was obtained after 24 h. A downstream effect yields a decrease in p-Akt and p-Erk 1/2. The addition of exogenous Ln-5 has no effect on p-EGFR, whereas it restores p-Erk 1/2 and p-Akt. Consistently, Ln-5 induces recovery of HCC cells from Gefitinib-induced apoptosis. In conclusion, gefitinib inhibits HCC cell growth and we report for the first time that Ln-5, but not other ECM molecules, reduces the ability of gefitinib to inhibit cell growth via Akt. As patients with HCC have different Ln-5 expression levels, these results may help to better understand which patients might benefit from gefitinib treatment.

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Section: Resultssupporting

confidence: 86%

Laminin-5 offsets the efficacy of gefitinib (‘Iressa’) in hepatocellular carcinoma cells

Giannelli

Azzariti²,

Fransvea

et al. 2004

Br J Cancer

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“…4,5 Some phase I and II clinical trials have reported that gefitinib monotherapy does not show any benefit for the treatment of advanced breast cancer patients. 5,6 In addition, although some studies of combination therapies involving gefitinib and other cytotoxic drugs have been reported, [7][8][9][10][11] the clinical benefits remain unclear, and little information has been obtained. On the other hand, taxane shows excellent efficacy for breast cancer either as a monotherapy or in combination with other cytotoxic drugs, such as anthracycline agents.…”

mentioning

confidence: 99%

“…8,9 For breast cancer in particular, Giardiello et al reported that gefitinib enhances the taxane activity on bcl-2-overexpressing MCF7/ADR cells. 7 They demonstrated the combination effect of gefitinib and taxane, 7 but it remains unclear whether the effect is an additive or synergistic one.…”

mentioning

confidence: 99%

“…Several reports have shown that gefitinib accelerates the activity of some cytotoxic drugs and may be able to reverse drug-resistance. [7][8][9][10] To obtain more preclinical information about combination therapies with gefitinib and other cytotoxic drugs, we examined the tumor inhibitory effect of a combination treatment with gefitinib and taxane on breast cancer cell lines overexpressing EGFR both in vitro and in vivo. Although a similar study on a gefitinib and taxane combination was reported by Caldiello et al in 2002, 7 we investigated the mechanism of the effect of the combination in more detail and from a different viewpoint.…”

mentioning

confidence: 99%

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Tumor inhibitory effect of gefitinib (ZD1839, Iressa) and taxane combination therapy in EGFR‐overexpressing breast cancer cell lines (MCF7/ADR, MDA‐MB‐231)

Takabatake

Fujita

Shien

et al. 2006

Intl Journal of Cancer

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Some kinds of breast cancer cell lines, similar to several types of solid tumors, express epidermal growth factor receptor (EGFR). However, gefitinib, an EGFR tyrosine kinase inhibitor, is not effective for all these cell lines. Similarly, taxane is effective for many of the cell lines, although some, such as the multidrug-resistant MCF7/ADR cell line, show taxane-resistance. Here, we examined the growth inhibitory effect of combination treatment with gefitinib and taxane on the breast cancer cell lines MDA-MB-231 (EGFR-positive) and MCF7/ADR (EGFR-and HER2-positive). To estimate the combined effect, a Combination Index was calculated for each cell line. The combination of gefitinib and taxane showed a strong synergistic effect on MCF7/ADR cells, but an in vitro additive-antagonistic effect on MDA-MB-231 cells. Similarly, the combination treatment showed a significantly increased tumor inhibitory effect on MCF7/ADR xenografts, but not on MDA-MB-231 xenografts. Regarding the mechanism of the synergistic effect, Western blotting analysis revealed that taxane activated the EGFR-Akt pathway in MCF7/ADR cells but not in MDA-MB-231. To determine the optimal sequential administration of gefitinib and taxane for MCF7/ADR cells, we used flow cytometry to analyze the cell cycle and apoptosis; finding that taxane treatment followed by gefitinib produced a higher rate of G2 arrest and apoptosis than gefitinib treatment followed by taxane. These results suggest gefitinib overcomes the drug-resistance of these cells, thereby increasing the effects of taxane on MCF7/ADR cells. Further, activation of the EGFR-Akt pathway by taxane is related to this synergistic effect. ' 2006 Wiley-Liss, Inc.

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“…5 Gefitinib is a well-known molecular targeting agent for epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase, associated with its ligand, EGF, as well as transforming growth factor-alpha (TGF-a). Gefitinib has demonstrated antitumor activity through the effects on proliferation, apoptosis-induction [6][7][8][9] and neovascularization. 10 Intermittent NK4-expressing gene therapy rather than continuous administration of the NK4 recombinant protein has the advantage of reducing both the patient burden and medical costs.…”

mentioning

confidence: 99%

Preclinical study of a “tailor-made” combination of NK4-expressing gene therapy and gefitinib (ZD1839, Iressa™) for disseminated peritoneal scirrhous gastric cancer

Namiki¹,

Namiki²,

Yoshida³

et al. 2005

Int. J. Cancer

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We evaluated the effect of a ''tailor-made'' chemo-gene therapy in scirrhous gastric cancer (SGC)-bearing nude mice. For this tailormade approach, we first selected gefitinib (epidermal growth factor receptor-tyrosine kinase inhibitor)-sensitive SGC cell lines, and 5/8 cell lines demonstrated various degrees of gefitinib-sensitivity. In the highly gefitinib-sensitive NUGC-4, the biological response to NK4 (HGF antagonist/angiogenesis inhibitor) was examined. Subsequently, the composition of an NK4-expressing ternary complex (cationic lipid/nucleic acid/HMG-1, 2 protein) was optimized for maximum transfection activity in NUGC-4. Finally, mice were peritoneally coinoculated with NUGC-4 and scirrhous-associated gastric fibroblasts, NF22, on day 0. Animal models were orally administrated gefitinib (50 mg/kg/day, on days 7-28), and peritoneally NK4-expressing ternary complex (on days 14, 21 and 28). NK4-expression suppressed the gefitinib-resistance induced by the interaction between fibroblasts and SGC, and eventually, this tailor-made combination synergistically decelerated the disease progression by inhibiting proliferative, angiogenic and antiapoptotic effects in tumor tissues. On day 28, both the hemoglobin concentration (g/dl) (control (n 5 8), 11.9; treated (n 5 8), 17.3; p 5 0.0014) and the numbers of mice in good condition (control, 2; treated, 8; p 5 0.0012) were significantly greater, and the abdominal girth (mm) (control, 81.1; treated, 70.3; p 5 0.0036) was significantly reduced. The median points of bloody ascite-free survival time (days) (control, 22; treated, 44; p < 0.0001) and time to euthanasia (days) (control, 36.5; treated, 56; p < 0.0001) were also significantly prolonged. This combination is a potentially useful approach to the treatment of peritoneal gefitinib-sensitive SGC dissemination. ' 2005 Wiley-Liss, Inc.

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

Cited by 77 publications

References 21 publications

Laminin-5 offsets the efficacy of gefitinib (‘Iressa’) in hepatocellular carcinoma cells

Laminin-5 offsets the efficacy of gefitinib (‘Iressa’) in hepatocellular carcinoma cells

Tumor inhibitory effect of gefitinib (ZD1839, Iressa) and taxane combination therapy in EGFR‐overexpressing breast cancer cell lines (MCF7/ADR, MDA‐MB‐231)

Preclinical study of a “tailor-made” combination of NK4-expressing gene therapy and gefitinib (ZD1839, Iressa™) for disseminated peritoneal scirrhous gastric cancer

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