Radiosensitivity of Tumor Cell Lines after Pretreatment with the EGFR Tyrosine Kinase Inhibitor ZD1839 (Iressa®)

Burdak‐Rothkamm, Susanne; Rübe, Claudia E.; Nguyen, Tan Phu; Ludwig, Daniela; Feldmann, Klaus; Wiegel, Thomas; Rübe, Christian

doi:10.1007/s00066-005-1319-5

Cited by 34 publications

(26 citation statements)

References 36 publications

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“…Moreover, a study by Dittmann and colleagues (49) suggested that EGFR translocates to the nucleus in response to radiation-induced DNA damage, and more importantly, the nuclear EGFR shuttling was shown to be involved in the DNA damage repair. Nonetheless, our findings support these and other reports that demonstrated that activation of EGFR enhances overall DSB repair (33)(34)(35).…”

Section: Discussionsupporting

confidence: 93%

“…(31) Moreover, EGFR inhibition was shown to induce cellular senescence in response to radiation and this was attributed to an increase in the levels of nonrepairable DSBs (32), suggesting a link between the EGF:EGFR pathway and the process of DNA damage repair. Finally, a previous study has demonstrated that in tumor cells exposed to ionizing radiation, activation of EGFR by EGF enhances the DSB repair capacity, whereas inhibition of EGFR attenuates DSB rejoining (33)(34)(35).…”

Section: Monocytes Enhance Ddr Via Hb-egf Releasementioning

confidence: 91%

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Macrophages Regulate the Systemic Response to DNA Damage by a Cell Nonautonomous Mechanism

et al. 2015

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The DNA damage response (DDR) is a comprehensive and complex network of phosphorylation-mediated signaling pathways that originates endogenously from the DNA lesion and activates intrinsic DNA repair mechanisms. Here we describe a macrophage-dependent mechanism that regulates the response to DNA damage. We demonstrate that human monocytes, by releasing macrophage-derived HB-EGF, enhance DDR in neighboring cells suffering from DNA damage. Consequently, HB-EGF-treated cells exhibit higher double-strand break (DSB) rejoining and display lower levels of residual DSBs. Diethylnitrosamine (DEN) injection induce DSBs along with elevation in the number of macrophages and HB-EGF expression. Significantly, macrophage depletion or blocking HB-EGF activity results in higher levels of nonrepairable DSBs, suggesting that macrophages play a role in the resolution of DNA damage via HB-EGF. This study establishes that macrophages, acting through the activation of the EGFR cascade, constitute an important cell nonautonomous physiologic component of the DDR and points to a unique role played by immune cells in maintaining genome integrity. Cancer Res; 75(13); 2663-73. Ó2015 AACR.

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Section: Discussionsupporting

confidence: 93%

Section: Monocytes Enhance Ddr Via Hb-egf Releasementioning

confidence: 91%

Macrophages Regulate the Systemic Response to DNA Damage by a Cell Nonautonomous Mechanism

et al. 2015

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“…As importantly, APE1 also functions as a reduction-oxidation activators of several transcription factors thought to be important in carcinogenesis, such as activator protein (Fos/Jun), hypoxia-inducible factor 1, cAMP-responsive element binding protein, and p53 (14,15). Knockout mouse model showed that inactivation of APE1 protein induces embryonic lethality and highlights the importance of its function to the cells (16,17).…”

Section: Introductionmentioning

confidence: 99%

A Polymorphism in the APE1 Gene Promoter is Associated with Lung Cancer Risk

Jou

Hsiao

et al. 2009

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential enzyme in the base excision repair pathway, which is the primary mechanism for the repair of DNA damage caused by oxidation and alkylation. We hypothesized that polymorphisms of APE1 are associated with risk for lung cancer. In the hospital-based matched case-control study, a total of 730 lung cancer cases and 730 cancer-free controls were genotyped for four APE1 haplotype-tagging polymorphisms (that is, -656T>G, 400A>G, 630T>C, and 1350T>G). Among them, the single-nucleotide polymorphism -656T>G located in the promoter region of APE1 was significantly associated with risk for lung cancer. We found that, compared with -656 TT homozygotes, the variant genotypes were associated with a significantly decreased risk [adjusted odds ratio, 0.51; 95% confidence interval (95% CI), 0.33-0.79 for -656 TG; adjusted odds ratio, 0.43; 95% CI, 0.25-0.76 for -656 GG, respectively]. Furthermore, we found a statistically significant reduced risk of -656T>G variants among heavy smokers (adjusted odds ratio, 0.52; 95% CI, 0.30-0.93 for -656 TG; adjusted odds ratio, 0.27; 95% CI, 0.13-0.57 for -656 GG, respectively), with a significant gene-smoking interaction (P = 0.013). A similar gene-smoking interaction in the context of APE1 haplotypes was also observed. The in vitro promoter assay revealed that the -656 G allele had a significantly higher transcriptional activity than that of the -656 T allele. Together, our results suggest that polymorphisms of the APE1 gene possibly interact with smoking and may contribute to the development of lung cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(1):223 -9)

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“…In addition to the well-known differences in radioresponse between SCLC and NSCLC, great differences in response exist between NSCLCs with the same histology. Expression and activity of EGFR are important determinants of radioresponse in several neoplasias, including NSCLCs, and loss of function mutations in the EGFR or anti-EGFR therapy has been shown to sensitize tumor cells to radiation (17)(18)(19). The discovery of activating mutations in the EGFR raises important questions about the response of mutant EGFR NSCLC to ionizing radiation (IR).…”

Section: Introductionmentioning

confidence: 99%

Non–Small Cell Lung Cancers with Kinase Domain Mutations in the Epidermal Growth Factor Receptor Are Sensitive to Ionizing Radiation

Das¹,

Sato

Story³

et al. 2006

Cancer Research

197

172

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Non-small cell lung cancers (NSCLCs) bearing mutations in the tyrosine kinase domain (TKD) of the epidermal growth factor receptor (EGFR) often exhibit dramatic sensitivity to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Ionizing radiation (IR) is frequently used in the treatment of NSCLC, but little is known how lung tumor-acquired EGFR mutations affect responses to IR. Because this is of great clinical importance, we investigated and found that clonogenic survival of mutant EGFR NSCLCs in response to IR was reduced 500-to 1,000-fold compared with wild-type (WT) EGFR NSCLCs. Exogenous expression of either the L858R point mutant or the #E746-E750 deletion mutant form of EGFR in immortalized human bronchial epithelial cells, p53 WT NSCLC (A549), or p53-null NSCLC (NCI-H1299) resulted in dramatically increased sensitivity to IR. We show that the majority of mutant EGFR NSCLCs, including those that contain the secondary gefitinib resistance T790M mutation, exhibit characteristics consistent with a radiosensitive phenotype, which include delayed DNA repair kinetics, defective IR-induced arrest in DNA synthesis or mitosis, and pronounced increases in apoptosis or micronuclei. Thus, understanding how activating mutations in the TKD domain of EGFR contribute to radiosensitivity should provide new insight into effective treatment of NSCLC with radiotherapy and perhaps avoid emergence of single agent drug resistance.

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Radiosensitivity of Tumor Cell Lines after Pretreatment with the EGFR Tyrosine Kinase Inhibitor ZD1839 (Iressa®)

Abstract: The sensitivity to ZD1839 correlated with the EGFR expression level, an inhibition of cell proliferation, and induction of apoptosis in the cell lines analyzed. A radiosensitizing effect of ZD1839 was associated with downregulation of EGFR mRNA expression.

Cited by 34 publications

References 36 publications

Macrophages Regulate the Systemic Response to DNA Damage by a Cell Nonautonomous Mechanism

Macrophages Regulate the Systemic Response to DNA Damage by a Cell Nonautonomous Mechanism

A Polymorphism in the APE1 Gene Promoter is Associated with Lung Cancer Risk

Non–Small Cell Lung Cancers with Kinase Domain Mutations in the Epidermal Growth Factor Receptor Are Sensitive to Ionizing Radiation

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