Spontaneous and inducible apoptosis in oesophageal adenocarcinoma

Raouf, A. A.; Evoy, Denis; Carton, Eleanor; Mulligan, E.; Griffin, Michael J.; Sweeney, E. C.; Reynolds, John V.

doi:10.1054/bjoc.2001.2084

Cited by 9 publications

(4 citation statements)

References 33 publications

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“…Despite variations in individual mechanisms of action, chemotherapy and radiotherapy ultimately bring about cancer cell death by activation of the apoptotic cascade 14,15 . In esophageal cancer, previous reports from this unit indicate that spontaneous apoptosis occurs in all cases of esophageal adenocarcinoma, that patients with a high apoptotic index have a better response to neoadjuvant therapy, and that apoptosis is significantly induced by chemoradiotherapy 16 . Regulators of apoptosis include p53, the Bcl‐2 protein family, and caspases, and these factors are implicated in the biology of chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic factors predicting complete pathological response to neoadjuvant chemoradiotherapy in esophageal cancer

MacGuill

Mulligan

Ravi

et al. 2006

Diseases of the Esophagus

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Multimodal therapy comprising neoadjuvant chemotherapy and radiation therapy prior to radical resection is increasingly utilized in gastroesophageal cancer. The achievement of a complete pathological response (pCR) or a major response is associated with an improved survival. However, up to 70% of patients show an incomplete or no response to the neoadjuvant regimen, and the identification of factors which predict a response would be of considerable clinical benefit. A retrospective analysis of a prospectively updated esophageal cancer database was performed. The predictive values of the following clinicopathological factors were investigated: age, sex, tobacco, alcohol, weight, clinical history, tumor type, site, length, width, morphology and differentiation. Statistical analysis was performed using Chi-square test with Pearson's test or Kruskal-Wallis test. One hundred and seventy-six patients were identified who had undergone neo-adjuvant chemoradiotherapy at St James's Hospital Dublin, between January 1990 and June 2003. A complete pathological response was seen in 40 cases (23%). There was a significant (P < 0.05) relationship between response to chemoradiotherapy and pretreatment tumor length. The median tumor length in the pCR group was 2 cm (1-5 cm) compared with 3 cm (2-7 cm) in non-responders (P < 0.05). Body weight, sex, tobacco or alcohol usage, tumor site, or differentiation were not predictive of response, although a trend (P = 0.08) was observed for squamous cell cancer compared with adenocarcinoma. Smaller tumor length was predictive of a greater response to chemotherapy and radiation therapy. This may reflect different tumor biology, perhaps with acquired resistance to treatment-induced apoptosis in the larger tumors. A simpler explanation is that the existing dose and treatment schedule for combination chemoradiotherapy is suboptimal in patients with larger tumors.

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Section: Discussionmentioning

confidence: 99%

Clinicopathologic factors predicting complete pathological response to neoadjuvant chemoradiotherapy in esophageal cancer

MacGuill

Mulligan

Ravi

et al. 2006

Diseases of the Esophagus

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“…13,14 In a recent study, we reported that spontaneous apoptosis occurs in all cases of esophageal adenocarcinoma, that patients with a high apoptotic index have a better response to neoadjuvant therapy, and that apoptosis was significantly induced by chemoradiotherapy. 15 Overexpression of p53 had no regulatory role in the apoptotic process, nor did it predict sensitivity to neoadjuvant therapy, suggesting the existence of an alternate pathway that regulates this response. This study is an extension of this work and focuses on bcl-2, bax and bcl-x which are members of a family of genes (bcl-2 family) that function as regulators of apoptosis, with bcl-2 normally associated with an antiapoptotic function.…”

Section: Introductionmentioning

confidence: 97%

“…Apoptosis plays an important role in tumorigenesis and in the cytotoxic effects of chemotherapy and radiation therapy 13,14 . In a recent study, we reported that spontaneous apoptosis occurs in all cases of esophageal adenocarcinoma, that patients with a high apoptotic index have a better response to neoadjuvant therapy, and that apoptosis was significantly induced by chemoradiotherapy 15 . Overexpression of p53 had no regulatory role in the apoptotic process, nor did it predict sensitivity to neoadjuvant therapy, suggesting the existence of an alternate pathway that regulates this response.…”

Section: Introductionmentioning

confidence: 99%

Loss of Bcl-2 expression in Barrett’s dysplasia and adenocarcinoma is associated with tumor progression and worse survival but not with response to neoadjuvant chemoradiation

Raouf¹,

Evoy²,

Carton³

et al. 2003

Diseases of the Esophagus

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Esophageal adenocarcinoma arising on a background of Barrett's esophagus is increasing in incidence. A molecular understanding of both the progression of Barrett's esophagus and the factors determining the response of adenocarcinoma to neoadjuvant therapy is required, and this study focused on the role of proteins regulated by the bcl-2 family of genes, which are important regulators of programmed cell death (apoptosis). In total, 48 patients (36 men, 12 women) with Barrett's adenocarcinoma were studied. All patients received preoperative chemoradiotherapy followed by surgery. Bcl-2, bax and bcl-x protein expression were detected by standard avidin-biotin peroxidase method. Bcl-2, bax and bcl-x expression were detected in 84%, 80%, and 76%, respectively, of normal squamous mucosa. An increasing degree of dysplasia in Barrett's mucosa both before and after chemoradiotherapy was significantly associated with a reduction of bcl-2 expression (P = 0.03 and 0.009, respectively). Bcl-2 expression was significantly associated with tumor differentiation (P = 0.03) and a trend towards earlier T stage (P = 0.08), but not with nodal status. Pre-therapeutic bcl-2, bax and bcl-x protein expression (27%, 75%, and 87.5%, respectively) were not associated with tumor response or resistance to therapy. Bcl-2-positive patients had a significantly improved survival compared with bcl-2-negative tumors. A significant reduction of bcl-2 expression is associated with the progression of Barrett's mucosa to adenocarcinoma. Bcl-2 expression was associated with improved survival. Preoperative chemoradiotherapy induces expression of bax and bcl-x protein. The pretreatment expression of bcl-2 and related proteins did not predict response or resistance to neoadjuvant chemoradiotherapy, suggesting that regulators of apoptosis alone do not determine the response of Barrett's adenocarcinoma to neoadjuvant therapy.

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“…Apoptosis is an important pathway of cell death following radiotherapy, chemotherapy, and apoptotic gene therapy in cancers, including esophageal cancer (6)(7)(8). A major mode of resistance to antitumor therapy, including radiotherapy and chemotherapy, is insensitivity to apoptosis induction (9).…”

Section: Introductionmentioning

confidence: 99%

Tumor-specific apoptotic gene targeting overcomes radiation resistance in esophageal adenocarcinoma

Chang

Zhang

Komaki

et al. 2006

International Journal of Radiation Oncology*Biology*Physics

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Purpose-To overcome radiation resistance in esophageal adenocarcinoma by tumor-specific apoptotic gene targeting using tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).Methods and Materials-Adenoviral vector Ad/TRAIL-F/RGD with a tumor specific human telomerase reverse transcription promoter was used to transfer TRAIL gene to human esophageal adenocarcinoma and normal human lung fibroblastic cells (NHLF). Activation of apoptosis was analyzed using western blot, FACS, and TUNEL assay. A human esophageal adenocarcinoma mice model was treated with intratumoral injections of Ad/TRAIL-F/RGD plus local radiotherapy.Results-The combination of Ad/TRAIL-F/RGD and radiotherapy increased cell-killing effect in all esophageal adenocarcinoma cell lines but not in NHLF cells. This combination also significantly reduced clonogenic formation (p < 0.05) and increased sub-G1 DNA accumulation in cancer cells (p < 0.05). Activation of apoptosis by Ad/TRAIL-F/RGD plus radiotherapy was demonstrated by activation of caspase-9, -8, -3 and cleaved PARP in vitro and TUNEL assay in vivo. Combined Ad/ TRAIL-F/RGD and radiotherapy dramatically inhibited tumor growth and prolonged mean survival in esophageal adenocarcinoma model to 31.6 days from 16.7 days for radiotherapy alone and 21.5 days for Ad/TRAIL-F/RGD alone (p< 0.05).Conclusions-The combination of tumor-specific TRAIL-gene targeting and radiotherapy enhances the effect of suppressing esophageal adenocarcinoma growth and prolonging survival.

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Spontaneous and inducible apoptosis in oesophageal adenocarcinoma

Cited by 9 publications

References 33 publications

Clinicopathologic factors predicting complete pathological response to neoadjuvant chemoradiotherapy in esophageal cancer

Clinicopathologic factors predicting complete pathological response to neoadjuvant chemoradiotherapy in esophageal cancer

Loss of Bcl-2 expression in Barrett’s dysplasia and adenocarcinoma is associated with tumor progression and worse survival but not with response to neoadjuvant chemoradiation

Tumor-specific apoptotic gene targeting overcomes radiation resistance in esophageal adenocarcinoma

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