Phase I study of imatinib, cisplatin and 5-fluoruracil or capecitabine in advanced esophageal and gastric adenocarcinoma

Mayr, Martina; Becker, Karen; Schulte, Nadine; Belle, Sebastian; Hofheinz, Ralf; Krause, Annekatrin; Schmid, Roland M.; Röcken, Christoph; Ebert, Matthias

doi:10.1186/1471-2407-12-587

Cited by 10 publications

(4 citation statements)

References 25 publications

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“…Therefore, it is very important to find a target agent that has synergistic effects while reducing toxicity of cytotoxic agents. Clinical studies on the combination of imatinib, cisplatin and 5-fluoruracil or capecitabine have been reported (42). In one of these clinical trials, the safety and tolerability of combination of imatinib plus 5-fluoruracil was confirmed.…”

Section: Discussionmentioning

confidence: 99%

Imatinib‑induced apoptosis of gastric cancer cells is mediated by endoplasmic reticulum stress

et al. 2018

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Imatinib is a powerful tyrosine kinase inhibitor that specifically targets BCR-ABL, c-KIT, and PDGFR kinases, and is used in the treatment of chronic myelogenous leukemia, gastrointestinal stromal tumors, and other types of cancers. However, the possible anticancer effects of imatinib in gastric cancer have not yet been explored. The present study evaluated the in vitro effects of imatinib on gastric cancer cells and determined the molecular mechanism underlying these effects. We determined that imatinib induced mitochondria-mediated apoptosis of gastric cancer cells by involving endoplasmic reticulum (ER) stress-associated activation of c-Jun NH2-terminal kinase (JNK). We also found that imatinib suppressed cell proliferation in a time- and dose-dependent manner. Cell cycle analysis revealed that imatinib-treated AGS cells were arrested in the G2/M phase of the cell cycle. Moreover, imatinib-treated cells exhibited increased levels of phosphorylated JNK, and of the transcription factor C/EBP homologous protein, an ER stress-associated apoptotic molecule. Results of cell viability assays revealed that treatment with a combination of imatinib and chemotherapy agents irinotecan or 5-Fu synergistically inhibited cell growth, compared with treatment with any of these drugs alone. These data indicated that imatinib exerted cytotoxic effects on gastric cancer cells by inducing apoptosis mediated by reactive oxygen species generation and ER stress-associated JNK activation. Furthermore, we revealed that imatinib induced the apoptosis of gastric cancer cells by inhibiting platelet-derived growth factor receptor signaling. Collectively, our results strongly support the use of imatinib in the treatment of treating gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Imatinib‑induced apoptosis of gastric cancer cells is mediated by endoplasmic reticulum stress

et al. 2018

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“…This hinderance on an otherwise huge success story leaves remaining research into combating BCR-ABL. In recent times, imatinib has been shown to provide synergistic anti-tumour effects when used in combination with cobalt complexes [71] and cisplatin [72][73][74][75]. Due to this, one strategy that has been utilised to circumvent resistance and dose-limiting side effects is to conjugate the BCR-ABL TKi's to metallic moieties in a similar fashion used to target EGFR above.…”

Section: Complexes Targeting Bcr-abl and Pdgfr (Platelet Derived Grow...mentioning

confidence: 99%

Metal-Tyrosine Kinase Inhibitors: Targeted metal-drug conjugates

Beirne

Via

Velasco‐Torrijos

et al. 2022

Coordination Chemistry Reviews

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“…The global incidence rate of EAC is approximately 0.7/100,000 person-years, and the 5-year survival rate is merely less than 20%, although multidisciplinary treatments have been applied, including esophagectomy, radiation, and chemotherapy ( Arnold et al, 2015 ; Markar et al, 2017 ; Smyth et al, 2017 ; Zhao et al, 2019 ). Considering the chemotherapeutic resistance, several targeted agents have been applied in patients with EAC, such as imatinib ( Mayr et al, 2012 ). Unfortunately, the efficacy is still not satisfactory.…”

Section: Introductionmentioning

confidence: 99%

Glycolysis Changes the Microenvironment and Therapeutic Response Under the Driver of Gene Mutation in Esophageal Adenocarcinoma

Zhu

Yang

et al. 2021

Front. Genet.

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Background: Esophageal cancer is one of the most leading and lethal malignancies. Glycolysis and the tumor microenvironment (TME) are responsible for cancer progressions. We aimed to study the relationships between glycolysis, TME, and therapeutic response in esophageal adenocarcinoma (EAC).Materials and Methods: We used the ESTIMATE algorithm to divide EAC patients into ESTIMATE high and ESTIMATE low groups based on the gene expression data downloaded from TCGA. Weighted gene co-expression network analysis (WGCNA) and Gene Set Enrichment Analysis (GSEA) were performed to identify different glycolytic genes in the TME between the two groups. The prognostic gene signature for overall survival (OS) was established through Cox regression analysis. Impacts of glycolytic genes on immune cells were assessed and validated. Next, we conducted the glycolytic gene mutation analysis and drug therapeutic response analysis between the two groups. Finally, the GEO database was employed to validate the impact of glycolysis on TME in patients with EAC.Results: A total of 78 EAC patients with gene expression profiles and clinical information were included for analysis. Functional enrichment results showed that the genes between ESTIMATE high and ESTIMATE low groups (N = 39, respectively) were strongly related with glycolytic and ATP/ADP metabolic pathways. Patients in the low-risk group had probabilities to survive longer than those in the high-risk group (p < 0.001). Glycolytic genes had significant impacts on the components of immune cells in TME, especially on the T-cells and dendritic cells. In the high-risk group, the most common mutant genes were TP53 and TTN, and the most frequent mutation type was missense mutation. Glycolysis significantly influenced drug sensitivity, and high tumor mutation burden (TMB) was associated with better immunotherapeutic response. GEO results confirmed that glycolysis had significant impacts on immune cell contents in TME.Conclusion: We performed a comprehensive study of glycolysis and TME and demonstrated that glycolysis could influence the microenvironment and drug therapeutic response in EAC. Evaluation of the glycolysis pattern could help identify the individualized therapeutic regime.

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Phase I study of imatinib, cisplatin and 5-fluoruracil or capecitabine in advanced esophageal and gastric adenocarcinoma

Cited by 10 publications

References 25 publications

Imatinib‑induced apoptosis of gastric cancer cells is mediated by endoplasmic reticulum stress

Imatinib‑induced apoptosis of gastric cancer cells is mediated by endoplasmic reticulum stress

Metal-Tyrosine Kinase Inhibitors: Targeted metal-drug conjugates

Glycolysis Changes the Microenvironment and Therapeutic Response Under the Driver of Gene Mutation in Esophageal Adenocarcinoma

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