Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0546837 (esophageal cancer)
 8,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several mechanisms of resistance to chemotherapy have been identified among the agents that are commonly used in the systemic treatment of patients with esophageal cancer: paclitaxel, platinum, and 5-FU. A recent study from our laboratory evaluated the initial endoscopic biopsy material from patients who subsequently underwent trimodality therapy, including chemotherapy with cisplatin and 5-FU, radiation therapy, and surgery. IHC analysis was performed on seven markers of chemotherapy or radiation therapy resistance: P-gp, GST-pi, MT (platinum inhibitors); EGF-R, TGF-alpha, erb-B2 (activation of cell growth cascade); and p53 (interferes with chemotherapy-induced apoptosis). In this study, elevated expression of GST-pi and P-gp were associated with decreased survival and may be markers of treatment resistance. Expression of erb-B2 was associated with enhanced survival and may be a marker of treatment sensitivity. Assessment of the probability of chemoresistance of a particular tumor using the expression of molecular biologic markers may allow for the selection of a more favorable chemotherapeutic agent. Furthermore, understanding the mechanisms of resistance, including the mechanisms of DNA repair, may provide insight into mechanisms to reverse or to inhibit resistance to chemotherapy. DNA repair mechanisms are used by cells to protect themselves against mutagens and carcinogens. DNA repair inhibitors may increase the mutagenicity associated with DNA damage and may prove to be an ineffective oncologic treatment strategy; however, the possibility exists that DNA repair inhibition may improve the efficacy of anticancer agents, and this should be tested. The value of this strategy may be in allowing treatment doses to be decreased and lessening side effects while maintaining therapeutic efficacy.
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PMID:Molecular biology of esophageal cancer. 1096 50

We examined whether antitumor effect could be produced by retrovirally expressed interleukin-2(IL-2) gene, glanulocyte macrophage-colony stimulating factor(GM-CSF) gene, herpes simplex virus-thymidine kinase(HSV-tk) gene and p53 gene in human esophageal cancer cells using nude mice. Loss of tumorigenicity of IL-2 or GM-CSF producing cancer cells were observed. The antitumor effect was also evidenced by the injection of these cells into established tumors of wild-type cells. In suicide gene therapy on esophageal cancer, the growth suppression of esophageal cancer cells transducing HSV-tk gene tumors in nude mice induced by ganciclovir treatment and all the tumors disappeared. The wild-type p53 transduced tumor cells became markedly susceptible to irradiation and anticancer agents. Administration of cisplatine noticeably suppressed the growth of p53 transduced tumors inoculated in nude mice. We established the clinical protocol of gene therapy for esophageal cancer using wild-type p53 gene with adenovirus vector. In this autumn we are going to start this clinical trial.
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PMID:[The protocol of clinical trial and basic experiments for esophageal cancer using gene transduction]. 1100 29

We evaluated the efficacy of chemoradiotherapy (CRT) for advanced esophageal cancer, from the view point of response. The relationship between chemo-radiosensitivity and dihydropyridine dehydrogenase (DPD), thymidylate synthase (TS), and p53 was investigated immunohistochemically. Thirteen patients with inoperable advanced esophageal cancer were involved in this study. CDDP of 10 mg/m2/day and 5-FU of 335 mg/m2/day were infused intravenously (day 1-5, day 15-19). Radiation was delivered concomitantly at a total dose of 30 Gy. Expressions of p53, DPD and TS were detected using immunohistology in the biopsy samples taken before CRT from 8 patients. Partial response was observed in 8 cases, no change in 4 cases, and progressive disease in one case. The overall response rate was 62%. The reduction rate was higher in tumors positive for p53 expression than in negative ones. The same was true for DPD and TS. The Treatment effect was more precisely predicted by combination of p53, DPD and TS. CRT with low-dose CDDP + 5-FU chemotherapy was effective and combination with p53, DPD, and TS might be a predictive marker for CRT in patients with advanced esophageal cancer.
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PMID:[Chemoradiotherapy with low-dose cisplatin and 5-FU for advanced esophageal cancer]. 1108 19

Although micrometastatic cancer cells in lymph nodes can be detected by monoclonal antibodies against epithelial or tumor-associated antigens, it remains unclear whether these cells are precursors of overt metastases or shedded tumor cells with a limited life span. Here we used esophageal cancer as a model to evaluate the prognostic significance and biological characteristics of such micrometastases. In lymph nodes classified as tumor free by conventional histopathological staging, tumor cells were identified with monoclonal antibody Ber-EP4 in 89 of 126 patients (71%) with completely resected (R0) esophageal carcinomas. Multivariate survival analysis underlined the strong and independent prognostic significance of Ber-EP4-positive cells in "node-negative" (pN0) patients. To assess the biology of Ber-EP4-positive cells, we established tumor cell lines from an immunohistochemically positive lymph node and the autologous primary tumor. p53 mutational analysis and multiplex-fluorescence in situ hybridization revealed common aberrations shared between both cell lines, whereas an insertion of chromosome 13 material in the short arm of chromosome 1 was only observed in micrometastatic cells. The tumorigenicity and metastatic potential of both cell lines were demonstrated in severe combined immunodeficient mice. In conclusion, our data provide first direct evidence for the malignant potential of micrometastatic cancer cells.
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PMID:Malignant potential and cytogenetic characteristics of occult disseminated tumor cells in esophageal cancer. 1115 75

Despite improvements in perioperative treatment and surgical techniques, rapid recurrence led to death of many patients with advanced esophageal cancer. Since surgical resection alone rarely results in long term survival, efforts now are focused on combined multi modality treatment in an attempt to improve local control and eliminate micro metastasis present at time of surgery. We have reported that the importance of alteration of p53 gene in progression and prognosis of esophageal cancer. P53 molecule of solid tumors has been shown to play an important role in the response to DNA damage induced by chemotherapeutic agents and radiation therapy, including induction of apoptosis. Based on the research of p53 gene therapy for esophageal cancer, we applied clinical study in 1997. After intensive reference, phase study was accepted in May, 2000. Phase I/II study will start on October 2000.
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PMID:[Perspectives on postgenome medicine: Gene therapy for esophageal cancer]. 1119 68

Over 15,000 human tumor p53 mutations have been recorded in the scientific literature, including over 700 mutations in esophageal tumors. There are no data on p53 mutations in esophageal cancer patients from Iran yet; however, this country experiences one of the highest cancer mortality rates in the world for esophageal squamous cell carcinomas (ESCCs). The causes of this high cancer burden in Iran remain obscure and do not appear to be related to tobacco and alcohol consumption, the two major risk factors identified in Europe and North America. Because molecular analysis of tumors can provide clues to endogenous or environmental factors contributing to high cancer risk, we examined 74 Iranian ESCCs for the presence of mutations in exons 5-8 of the p53 gene by PCR and direct sequencing. Forty-eight of the 74 tumors (65%) had one or more p53 gene point mutations, including 5 patients with two or more mutations and one with a tandem mutation in codon 242. Surprisingly, over one-third of the 54 mutations we identified were transitions at CpG sites (20 of a total of 54 mutations, or 37%), a class of mutation that is significantly less common (16% of mutations) in the compilation of ESCC mutations from other countries (chi2 statistic, P < 0.0002), whereas transversions, which the literature shows to be common in ESCCs from non-Iranian patients, were infrequent in the tumors we examined here. Elevated levels of cyclooxygenase-2 and inducible nitric oxide synthase were observed in 74 and 91%, respectively, of tumors from Tehran as determined by immunohistochemistry, and high COX-2 expression correlated significantly with the presence of a p53 mutation in the tumor. Mediators of the inflammatory response in esophageal mucosa, perhaps in conjunction with specific dietary or cultural practices in Iran, may contribute importantly to the p53 mutation load in Iranian ESCC patients.
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PMID:Unusual profile and high prevalence of p53 mutations in esophageal squamous cell carcinomas from northern Iran. 1130 96

Preoperative chemotherapy combined with radiotherapy (chemrad) is a common type of neoadjuvant treatment for esophageal adenocarcinoma or squamous cell carcinoma. The purpose of this study was to describe the clinical, histologic, proliferative (MIB-1), and oncogenetic (p53) features of 15 patients with gastric dysplasia-like epithelial atypical changes associated with preoperative chemrad for esophageal cancer. Two of these cases were initially misinterpreted as dysplasia, which led to partial gastrectomy. The findings were compared with 12 age- and sex-matched patients with known gastric dysplasia. Cases with gastric dysplasia-like epithelial atypia were significantly associated with a flat gross appearance, a patchy distribution, foveolar and gland involvement, surface maturation, an open nuclear chromatin pattern with prominent nucleoli, retention of nuclear polarity, mitoses confined to the pits, lack of atypical mitoses, cytoplasmic hypereosinophila and/or vacuolization, a lack of association with intestinal metaplasia, and finally, irregular glandular microcystic change, in comparison to the dysplasia controls. Furthermore, the study cases showed MIB-1 positivity restricted to the deep foveolar epithelium and an absence of p53 staining in 14 of 15 cases, in contrast to the dysplasia controls, in which MIB-1 stained both the deep and superficial foveolar epithelium and surface epithelium, and p53 was positive in all cases (100%). In summary, a number of histologic and immunohistochemical features may distinguish gastric dysplasia-like epithelial atypia associated with chemrad for esophageal cancer from true dysplasia. Pathologists should be aware of this entity and its histologic and immunohistochemical features to avoid misinterpretation and prevent unnecessary treatment.
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PMID:Gastric dysplasia-like epithelial atypia associated with chemoradiotherapy for esophageal cancer: a clinicopathologic and immunohistochemical study of 15 cases. 1135 47

Resistance to chemotherapy remains a serious problem inhibiting the successful treatment of advanced esophageal cancer. A number of studies have revealed that p53 genetic alteration and protein overexpression can predict chemosensitivity. Furthermore, p53 protein overexpression in cancer tissues has been found to induce serum p53 antibodies (p53-Abs). This study was conducted to examine whether analysis of serum p53 Abs could predict the chemosensitivity of esophageal cancer. Serum analysis of p53 antibodies was performed by enzyme-linked immunosorbent assay in 19 patients with esophageal squamous cell carcinoma preoperatively, then surgically resected specimens were stained immunohistochemically for p53 protein expression. Tumor tissues were also analyzed for chemosensitivity by the histoculture drug response assay (HDRA) using cis-dichlorodiammineplatinum(II) (CDDP), 5-fluorouracil (5-FU), and adriamycin (ADM). Serum p53-Abs were present in 47% (9/19) of the patients and immunohistochemical analysis revealed overexpression of p53 protein in 42% (8/19) of the tumors. The presence of serum p53 antibodies was significantly correlated with p53 immunoreactivity (P = 0.005). The inhibition index of patients positive for p53-Abs was significantly lower than that of patients negative for p53-Abs (P < 0.001). This tendency was also observed in the inhibition index to 5-FU. The presence of serum p53-Abs was associated with decreased in vitro chemosensitivity to CDDP and 5-FU. Thus, the detection of serum p53-Abs is suggested to be useful for predicting chemosensitivity in patients with esophageal cancer.
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PMID:Presence of serum p53 antibodies is associated with decreased in vitro chemosensitivity in patients with esophageal cancer. 1149 53

An alteration of the p53 gene function is a major factor in the development of esophageal cancer. Recently, p53 gene therapy has been applied for clinical studies in lung cancer and head and neck cancer. However, no preclinical studies have yet demonstrated an anticancer effect of adenoviral-mediated wild-type p53 gene therapy on esophageal cancer. We herein evaluated the effect of p53 adenoviral gene therapy on human esophageal squamous cell carcinoma to test the ability of clinical application. A normal esophageal epithelial cell line (EN53F) and two human esophageal cancer cell lines (ECGI-10 and T.Tn) with a p53 alteration were used. The transduction efficiency, p53 protein expression, p21 protein expression, the induction of apoptosis, and growth suppression were assessed by using the recombinant adenoviral vector Ad5CMV-p53. The transduction efficiency was 60%-80% at 100 plaque-forming units (PFU)/cell and 80%-100% at 300PFU/cell. A significant growth suppression following an Ad5CMV-p53 infection was observed in both cancer cell lines. A Western blot analysis confirmed the presence of both exogenous p53 protein expression and p21 protein induction. Apoptotic cell death was observed with TUNEL staining. T.Tn xenografts in nude mice transduced with Ad5CMV-p53 demonstrated significant growth suppression. These data suggest that Ad5CMV-p53 may thus be a potentially effective therapeutic agent for locally advanced esophageal cancer.
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PMID:Preclinical study of adenoviral p53 gene therapy for esophageal cancer. 1149 54

Recently, neoadjuvant chemotherapy combined with radiation (NAT) has been used in the active treatment of progressive esophageal cancer (T4). However, many patients are resistant to supplemental therapy, and it is necessary to to be aware that side-effects may occur. Accordingly, to minimize adverse reactions and cost, it is important to determine the indications for NAT. We investigated 34 patients with T4 esophageal squamous cell carcinoma and examined the relation between the effects of NAT and immunohistochemical or additional clinicopathologic factors. There was no relation between clinicopathologic factors and immunohistochemical findings (p53 or hsp27 expression), and no clinicopathologic factors showed a relation to a supplemental therapeutic effect. In addition, there was no correlation between p53 staining and therapeutic effects (P=0.734). In contrast, there was a correlation (P=0.0058) between hsp27 staining and therapeutic effect. In conclusion, the usefulness of hsp27 immunostaining in predicting the therapeutic effect of NAT was confirmed in T4 esophageal squamous cell carcinoma.
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PMID:Immunohistochemical and clinicopathologic analysis of response to neoadjuvant therapy for esophageal squamous cell carcinoma. 1155 27


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