A phase II trial of chemoradiation therapy with weekly oxaliplatin and protracted infusion of 5-fluorouracil for esophageal cancer

Burmeister, Bryan; Walpole, Euan; D’Arcy, Nancy; Burmeister, Elizabeth; Cox, Sharon; Thomson, Damien; Harvey, Jennifer A.; Smithers, B. Mark

doi:10.1007/s10637-008-9178-4

Cited by 13 publications

(11 citation statements)

References 14 publications

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“…2,3 Considerable efforts have been made to identify novel and reliable biomarkers for early diagnosis, more effective combination chemotherapy strategies, and possible mechanisms of chemoresistance. [4][5][6] A recent study indicates that autophagy is a survival mechanism that promotes chemoresistance and that regulators selectively inhibiting autophagy have the potential to improve chemotherapeutic regimes in esophageal cancer cells. 7 Autophagy is an evolutionarily conserved survival response to growth-limiting conditions, in which cytosolic proteins or damaged organelles are sequestered, degraded, and released for recycling.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of autophagosome-lysosome fusion by ginsenoside Ro via the ESR2-NCF1-ROS pathway sensitizes esophageal cancer cells to 5-fluorouracil-induced cell death via the CHEK1-mediated DNA damage checkpoint

Zheng

Wang

et al. 2016

Autophagy

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Modulation of autophagy has been increasingly regarded as a promising cancer therapeutic approach. In this study, we screened several ginsenosides extracted from Panax ginseng and identified ginsenoside Ro (Ro) as a novel autophagy inhibitor. Ro blocked the autophagosome-lysosome fusion process by raising lysosomal pH and attenuating lysosomal cathepsin activity, resulting in the accumulation of the autophagosome marker MAP1LC3B/LC3B and SQSTM1/p62 (sequestosome 1) in various esophageal cancer cell lines. More detailed studies demonstrated that Ro activated ESR2 (estrogen receptor 2), which led to the activation of NCF1/p47(PHOX) (neutrophil cytosolic factor 1), a subunit of NADPH oxidase, and subsequent reactive oxygen species (ROS) production. Treatment with siRNAs or inhibitors of the ESR2-NCF1-ROS axis, such as N-acetyl-L-cysteine (NAC), diphenyleneiodonium chloride (DPI), apocynin (ACN), Tiron, and Fulvestrant apparently decreased Ro-induced LC3B-II, GFP-LC3B puncta, and SQSTM1, indicating that ROS instigates autophagic flux inhibition triggered by Ro. More importantly, suppression of autophagy by Ro sensitized 5-fluorouracil (5-Fu)-induced cell death in chemoresistant esophageal cancer cells. 5-Fu induced prosurvival autophagy, and by inhibiting such autophagy, siRNAs against BECN1/beclin 1, ATG5, ATG7, and LC3B enhanced 5-Fu-induced autophagy-associated and apoptosis-independent cell death. We observed that Ro potentiates 5-Fu cytotoxicity via delaying CHEK1 (checkpoint kinase 1) degradation and downregulating DNA replication process, resulting in the delayed DNA repair and the accumulation of DNA damage. In summary, these data suggest that Ro is a novel autophagy inhibitor and could function as a potent anticancer agent in combination therapy to overcome chemoresistance.

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Section: Introductionmentioning

confidence: 99%

Inhibition of autophagosome-lysosome fusion by ginsenoside Ro via the ESR2-NCF1-ROS pathway sensitizes esophageal cancer cells to 5-fluorouracil-induced cell death via the CHEK1-mediated DNA damage checkpoint

Zheng

Wang

et al. 2016

Autophagy

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“…However, single-agent chemotherapy is not effective for esophageal cancer because of natural resistance and the development of resistance (4). In esophageal cancer, many studies have demonstrated that combination therapy is more effective than single-drug therapy (3,5,6).…”

Section: Introductionmentioning

confidence: 99%

Combination of SNX-2112 with 5-FU exhibits antagonistic effect in esophageal cancer cells

Liu

Xiao

Wang

et al. 2014

International Journal of Oncology

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The low efficacy of single-drug chemotherapy forms the basis for combination therapy in esophageal squamous cell carcinoma. SNX-2112, a selective heat shock protein 90 (Hsp90) inhibitor, was recently reported as being effective in combination with cisplatin and paclitaxel. In this study, we investigated the effect of SNX-2112 in combination with 5-fluorouracil (5-FU), another first-line anticancer drug, in esophageal cancer. Unexpectedly, tetrazolium assay revealed that the combination of SNX-2112 with 5-FU exhibited antagonistic effect. Flow cytometry revealed that the SNX-2112 and 5-FU combination greatly decreased the number of G2/M cells compared to SNX-2112-only treatment in Eca‑109 cells. This effect might be related to the altered mRNA level of cyclin-related genes including cyclin D1, Chk2 and Cdk4. Further, 5-FU attenuated SNX-2112-induced apoptosis by decreasing poly(ADP-ribose) polymerase (PARP) cleavage and inactivating caspase-3, -8 and -9. Additionally, 5-FU suppressed the SNX-2112-induced decrease of mitochondrial membrane potential. Moreover, 5-FU partly recovered Hsp90 client proteins, including Akt, p-Akt, inhibitor of κB kinase (IKK)α, extracellular signal-regulated kinase (ERK)1/2, and glycogen synthase kinase (GSK)-3β, which SNX-2112 had downregulated. Taken together, this is the first report that the combination of SNX-2112 with 5-FU exhibited antagonistic effect in esophageal cancer cells by affecting growth inhibition, cell cycle, apoptosis, and Hsp90 client proteins, suggesting that care is required in the clinical application of combined SNX-2112 and 5-FU.

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“…The cord dose described in other studies is: 42 Gy [13]; 41 Gy [16]. The reduction in cord dose could be of significance, as new evidence suggests that cord dose should not exceed 40 Gy in cases of combined modality with oxaliplatin [38,39].…”

Section: Volumetric Modulated Arc Therapy For Oesophageal Malignanciesmentioning

confidence: 91%

Volumetric modulated arc therapy planning for distal oesophageal malignancies

Hawkins

Bedford²,

Warrington³

et al. 2012

BJR

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Objectives: Volumetric modulated arc therapy (VMAT) is a novel form of intensitymodulated radiation therapy that allows the radiation dose to be delivered in a single gantry rotation using conformal or modulated fields. The capability of VMAT to reduce heart and cord dose, while maintaining lung receiving 20 Gy ,20%, was evaluated for chemoradiation for oesophageal cancer. Methods: An optimised forward-planned four-field arrangement was compared with inverse-planned coplanar VMAT arcs with 35 control points for 10 patients with lower gastro-oesophageal tumours prescribed 54 Gy in 30 fractions. Conformal (cARC) and intensity-modulated (VMATi) arcs were considered. Plans were assessed and compared using the planning target volume (PTV) irradiated to 95% of the prescription dose (V95), volumes of lung irradiated to 20 Gy (V20), heart irradiated to 30 Gy (V30), spinal cord maximum dose and van't Riet conformation number (CN). The monitor units per fraction and delivery time were recorded for a single representative plan. Results: VMATi provided a significant reduction in the heart V30 (31% vs 55%; p50.02) with better CN (0.72 vs 0.65; p50.01) than the conformal plan. The treatment delivery was 1 min 28 s for VMAT compared with 3 min 15 s. Conclusion: For similar PTV coverage, VMATi delivers a lower dose to organs at risk than conformal plans in a shorter time, and this has warranted clinical implementation.

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A phase II trial of chemoradiation therapy with weekly oxaliplatin and protracted infusion of 5-fluorouracil for esophageal cancer

Abstract: Although weekly oxaliplatin in combination with infusional 5 fluorouracil produces durable remissions in esophageal cancer, the regimen used in this trial was not acceptable for routine use. Future protocols should incorporate lower chemotherapy doses.

Cited by 13 publications

References 14 publications

Inhibition of autophagosome-lysosome fusion by ginsenoside Ro via the ESR2-NCF1-ROS pathway sensitizes esophageal cancer cells to 5-fluorouracil-induced cell death via the CHEK1-mediated DNA damage checkpoint

Inhibition of autophagosome-lysosome fusion by ginsenoside Ro via the ESR2-NCF1-ROS pathway sensitizes esophageal cancer cells to 5-fluorouracil-induced cell death via the CHEK1-mediated DNA damage checkpoint

Combination of SNX-2112 with 5-FU exhibits antagonistic effect in esophageal cancer cells

Volumetric modulated arc therapy planning for distal oesophageal malignancies

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