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A novel approach in the treatment of neuroendocrine gastrointestinal tumours. Targeting the epidermal growth factor receptor by gefitinib (ZD1839).

Höpfner M, Sutter AP, Gerst B, Zeitz M, Scherübl H - Br. J. Cancer (2003)

Bottom Line: Vice versa, the proapoptotic effects of gefitinib, as determined by caspase-3 activation and DNA fragmentation, were most pronounced in the slow-growing STC-1 cells.Using cDNA microarrays, we found extensive changes in the expression of genes involved in the regulation of apoptosis and cell cycle after incubation with gefitinib.Phosphorylation of ERK1/2, which inhibits GADD153 expression, was reduced in a time-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Medical Clinic I, Gastroenterology/Infectious Diseases/Rheumatology, University Hospital Benjamin Franklin, Free University of Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.

ABSTRACT
Therapeutic options to inhibit the growth and spread of neuroendocrine (NE) gastrointestinal tumours are still limited. Since gefitinib (4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline), an inhibitor of epidermal growth factor receptor-sensitive tyrosine kinase (EGFR-TK), had been shown to suppress potently the growth of various non-NE tumour entities, we studied the antineoplastic potency of gefitinib in NE gastrointestinal tumour cells. In human insulinoma (CM) cells, in human pancreatic carcinoid (BON) cells and in NE tumour cells of the gut (STC-1), gefitinib induced a time- and dose-dependent growth inhibition by almost 100%. The antiproliferative potency of gefitinib correlated with the proliferation rate of the tumour cells. So the IC(50) value of gefitinib was 4.7+/-0.6 microM in the fast-growing CM cells, still 16.8+/-0.4 microM in the moderate-growing BON cells, and up to 31.5+/-2.5 microM in the slow-growing STC-1 cells. Similarly, the induction of apoptosis and cell-cycle arrest by gefitinib differed according to growth characteristics: fast-growing CM cells displayed a strong G0/G1 arrest in response to gefitinib, while no significant cell-cycle alterations were seen in the slow-growing STC-1. Vice versa, the proapoptotic effects of gefitinib, as determined by caspase-3 activation and DNA fragmentation, were most pronounced in the slow-growing STC-1 cells. Using cDNA microarrays, we found extensive changes in the expression of genes involved in the regulation of apoptosis and cell cycle after incubation with gefitinib. Among them, an upregulation of the growth arrest and DNA damage-inducible gene GADD153 was observed. Phosphorylation of ERK1/2, which inhibits GADD153 expression, was reduced in a time-dependent manner. However, no gefitinib-induced activation of the GADD153-inducing p38 mitogen-activated protein kinase was detected. Our data demonstrate that the inhibition of EGFR-TK by gefitinib induces growth inhibition, apoptosis and cell-cycle arrest in NE gastrointestinal tumour cells. Thus, EGFR-TK inhibition appears to be a promising novel approach for the treatment of NE tumour disease.

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mRNA and protein expression of EGFR and IGFR in neuroendocrine tumour cells. (A, B) mRNA expression of EGFRvIII (lane 1), EGFR-1 (lane 2) and IGFRβ-1 (lane 3) was evaluated in CM (A) and BON tumour cells (B). β-Actin was used as positive control (lane 4 in A and B), 100 bp DNA ladder. (C–E) Flow cytometric analysis of the expression of EGFR and IGFRβ-1 proteins in CM cells (C), BON cells (D) and STC-1 cells (E). Black lines: cells stained with specific polyclonal antibodies against either EGFR or IGFRβ-1; grey lines: negative controls.
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fig1: mRNA and protein expression of EGFR and IGFR in neuroendocrine tumour cells. (A, B) mRNA expression of EGFRvIII (lane 1), EGFR-1 (lane 2) and IGFRβ-1 (lane 3) was evaluated in CM (A) and BON tumour cells (B). β-Actin was used as positive control (lane 4 in A and B), 100 bp DNA ladder. (C–E) Flow cytometric analysis of the expression of EGFR and IGFRβ-1 proteins in CM cells (C), BON cells (D) and STC-1 cells (E). Black lines: cells stained with specific polyclonal antibodies against either EGFR or IGFRβ-1; grey lines: negative controls.

Mentions: The mRNA expression of EGF receptors (EGFR) and the insulin-like growth factor receptor β-1 (IGFR-β1) was investigated in human BON and in human CM cells. The mRNAs specific for EGFR and IGFRβ-1 were detected in both the cell lines (Figure 1A, BFigure 1


A novel approach in the treatment of neuroendocrine gastrointestinal tumours. Targeting the epidermal growth factor receptor by gefitinib (ZD1839).

Höpfner M, Sutter AP, Gerst B, Zeitz M, Scherübl H - Br. J. Cancer (2003)

mRNA and protein expression of EGFR and IGFR in neuroendocrine tumour cells. (A, B) mRNA expression of EGFRvIII (lane 1), EGFR-1 (lane 2) and IGFRβ-1 (lane 3) was evaluated in CM (A) and BON tumour cells (B). β-Actin was used as positive control (lane 4 in A and B), 100 bp DNA ladder. (C–E) Flow cytometric analysis of the expression of EGFR and IGFRβ-1 proteins in CM cells (C), BON cells (D) and STC-1 cells (E). Black lines: cells stained with specific polyclonal antibodies against either EGFR or IGFRβ-1; grey lines: negative controls.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2394425&req=5

fig1: mRNA and protein expression of EGFR and IGFR in neuroendocrine tumour cells. (A, B) mRNA expression of EGFRvIII (lane 1), EGFR-1 (lane 2) and IGFRβ-1 (lane 3) was evaluated in CM (A) and BON tumour cells (B). β-Actin was used as positive control (lane 4 in A and B), 100 bp DNA ladder. (C–E) Flow cytometric analysis of the expression of EGFR and IGFRβ-1 proteins in CM cells (C), BON cells (D) and STC-1 cells (E). Black lines: cells stained with specific polyclonal antibodies against either EGFR or IGFRβ-1; grey lines: negative controls.
Mentions: The mRNA expression of EGF receptors (EGFR) and the insulin-like growth factor receptor β-1 (IGFR-β1) was investigated in human BON and in human CM cells. The mRNAs specific for EGFR and IGFRβ-1 were detected in both the cell lines (Figure 1A, BFigure 1

Bottom Line: Vice versa, the proapoptotic effects of gefitinib, as determined by caspase-3 activation and DNA fragmentation, were most pronounced in the slow-growing STC-1 cells.Using cDNA microarrays, we found extensive changes in the expression of genes involved in the regulation of apoptosis and cell cycle after incubation with gefitinib.Phosphorylation of ERK1/2, which inhibits GADD153 expression, was reduced in a time-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Medical Clinic I, Gastroenterology/Infectious Diseases/Rheumatology, University Hospital Benjamin Franklin, Free University of Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.

ABSTRACT
Therapeutic options to inhibit the growth and spread of neuroendocrine (NE) gastrointestinal tumours are still limited. Since gefitinib (4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline), an inhibitor of epidermal growth factor receptor-sensitive tyrosine kinase (EGFR-TK), had been shown to suppress potently the growth of various non-NE tumour entities, we studied the antineoplastic potency of gefitinib in NE gastrointestinal tumour cells. In human insulinoma (CM) cells, in human pancreatic carcinoid (BON) cells and in NE tumour cells of the gut (STC-1), gefitinib induced a time- and dose-dependent growth inhibition by almost 100%. The antiproliferative potency of gefitinib correlated with the proliferation rate of the tumour cells. So the IC(50) value of gefitinib was 4.7+/-0.6 microM in the fast-growing CM cells, still 16.8+/-0.4 microM in the moderate-growing BON cells, and up to 31.5+/-2.5 microM in the slow-growing STC-1 cells. Similarly, the induction of apoptosis and cell-cycle arrest by gefitinib differed according to growth characteristics: fast-growing CM cells displayed a strong G0/G1 arrest in response to gefitinib, while no significant cell-cycle alterations were seen in the slow-growing STC-1. Vice versa, the proapoptotic effects of gefitinib, as determined by caspase-3 activation and DNA fragmentation, were most pronounced in the slow-growing STC-1 cells. Using cDNA microarrays, we found extensive changes in the expression of genes involved in the regulation of apoptosis and cell cycle after incubation with gefitinib. Among them, an upregulation of the growth arrest and DNA damage-inducible gene GADD153 was observed. Phosphorylation of ERK1/2, which inhibits GADD153 expression, was reduced in a time-dependent manner. However, no gefitinib-induced activation of the GADD153-inducing p38 mitogen-activated protein kinase was detected. Our data demonstrate that the inhibition of EGFR-TK by gefitinib induces growth inhibition, apoptosis and cell-cycle arrest in NE gastrointestinal tumour cells. Thus, EGFR-TK inhibition appears to be a promising novel approach for the treatment of NE tumour disease.

Show MeSH
Related in: MedlinePlus