Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this work was to analyse the ability of p53 and thymidilate synthase (TS) primary tumour expression to retrospectively predict clinical response to chemotherapy and long-term prognosis in patients with advanced colorectal cancers homogeneously treated by methotrexate (MTX)-modulated-5-fluorouracil (5-FU-FA). A total of 108 advanced colorectal cancer patients entered the present retrospective study. Immunohistochemical p53 (pAb 1801 mAb) and TS (TS106 mAb) expression on formalin-fixed paraffin-embedded primary tumour specimens was related to probability of clinical response to chemotherapy, time to progression and overall survival. p53 was expressed in 53/108 (49%) tumours, while 54/108 (50%) showed TS immunostaining. No relationship was demonstrated between p53 positivity and clinical response to chemotherapy (objective response (OR): 20% vs 23%, in p53+ and p53- cases respectively) or overall survival. Percent of OR was significantly higher in TS-negative with respect to TS-positive tumours (30% vs 15% respectively; P < 0.04); simultaneous analysis of TS and p53 indicated 7% OR for p53-positive/TS-positive tumours vs 46% for p53-positive/TS-negative tumours (P < 0.03). Logistic regression analysis confirmed a significant association between TS tumour status and clinical response to chemotherapy (hazard ratio (HR): 2.91; 95% confidence interval (CI) 8.34-1.01; two-sided P < 0.05). A multivariate analysis of overall survival showed that only a small number of metastatic sites was statistically relevant (HR 1.89; 95% CI 2.85-1.26; two-sided P < 0.03). Our study suggests that immunohistochemical expression of p53 and TS could assist the clinician in predicting response of colorectal cancer patients to modulated MTX-5-FU therapy.
 ...
PMID:Thymidilate synthase and p53 primary tumour expression as predictive factors for advanced colorectal cancer patients. 1068 66

5-Fluorouracil (5FU)-based therapy is given to patients with advanced colorectal cancer and as adjuvant treatment. Thymidylate synthase (TS) is the target for 5FU, and may have a prognostic role for the outcome of 5FU-based therapy together with proliferation markers such as p53 and Ki67. Thymidine phosphorylase (TP, also known as platelet-derived endothelial cell growth factor) may be of importance both in the 5FU drug activation pathway and in tumor angiogenesis, similar to vascular endothelial growth factor (VEGF). TS and TP levels were determined biochemically in fresh-frozen tumor specimens of 32 untreated patients with colorectal cancer, whereas in paraffin-embedded tissue samples, immunohistochemistry was performed for TS, TP, and additional prognostic markers such as p53, Ki67, and VEGF as well as microvessel density. All factors were correlated with patient characteristics such as age, gender, Dukes' stage, angio-invasion, and differentiation grade. TS and TP as measured by various assays were correlated with overall and disease-free survival in this patient group. TP enzyme activity and protein expression correlated with each other. A significant correlation was found between TP enzyme activity and 5-fluoro-2'-deoxyuridine-5'-monophosphate binding activity. VEGF expression correlated significantly with TP immunostaining and Ki67 index. Survival analysis revealed a significant relation of TS levels to the overall survival in this small patient group and a significant correlation between TP activity and disease-free survival. TS and TP both were of prognostic significance in these patients with colorectal cancer. The interesting relationship of TS and TP with angiogenesis and proliferation needs further investigation.
 ...
PMID:Prognostic role of thymidylate synthase, thymidine phosphorylase/platelet-derived endothelial cell growth factor, and proliferation markers in colorectal cancer. 1074 35

Response to 5-FU of 5 different human colon cancers (hCC) with a DNA microsatellite instability (MSI), xenografted into nude mice, was analysed according to their p53 status. Two hCC (TC82 and TC71) had a mutated p53 (mutp53), while two others (TC33 and LoVo) had a wild type p53 (wtp53); the fifth tumour (X17LoVo) originated from the stable transfection of LoVo cells with a dominant mutp53 (273his) vector. All tumours were implanted onto the caecum of nude mice to induce orthotopic growth of hCC. 5-FU was administered at 40 mg/kg per day for 5 consecutive days. A significant growth inhibition of TC82 and TC71 tumours (of 68 and 60%, p < 0.05 and < 0.01 respectively) was observed, whereas 5-FU had no effect on TC33 and LoVo. Moreover, the mutp53 transfected tumour, X17LoVo, displayed significant sensitivity to 5-FU (p < 0.05). This suggests that distinct genetic alterations influence differently the response of hCC to this antimetabolite.
 ...
PMID:Response to 5-fluorouracil of orthotopically xenografted human colon cancers with a microsatellite instability: influence of P53 status. 1076 38

Alteration of the p53 gene product occurs frequently during the progression of colorectal cancer. Recently, mutated p53 protein was found to induce the production of anti-p53 antibodies in the serum of patients. The purpose of this study was to evaluate the relationship between p53 status in serum and chemosensitivity in resectable colorectal cancer patients. A total of 35 patients with primary colorectal cancer who underwent surgical treatment were examined by chemosensitivity test with the viable tumor samples using Histoculture Drug Response Assay (HDRA). Serum samples of these patients to test for p53 antibodies were obtained before tumor resection, and assayed in duplicate by using an enzyme-linked immunosorbent assay (ELISA) kit. The inhibition index of 5-FU and CDDP, determined by the HDRA method, in the sero-positive group was significantly lower than that of the sero-negative group (p < 0.01). Furthermore, significant statistical differences in chemosensitivity to 5-FU and CDDP were revealed depending on the presence of serum p53 antibodies. There was no relationship between chemosensitivity assay and tumor marker positivity or clinicopathological features in these patients. Detection of serum p53 antibodies, which reflects p53 mutations in tumor tissue, is a simple method which correlates with chemosensitivity, and may contribute to the selection of favorable chemotherapeutic strategies of colorectal cancer.
 ...
PMID:[Clinical significance of serum p53 antibody detection in a chemosensitivity assay in cases of human colorectal cancer]. 1089 15

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.
 ...
PMID:Molecular biology of esophageal cancer. 1096 50

Clonogenic survival and early cell death during treatment of human colon carcinoma cells were investigated following X-irradiation (IR) alone, IR followed by 5-FU for 24 h, and Taxol administered 24 h before IR and 5F-U. The investigated cell lines were: HCT116, 40-16 clonally derived from HCT116, and two HCT116 variants: N6CHR3 expressing hMLH1, and TP53 null cells denoted HCT116 p53-/-. The objective was to determine efficacy of the combined treatment and to correlate response with constitutive levels of TP53, WAF1, and hMLH1 proteins, as well as with mRNA levels of the apoptosis-related genes survivin, BNIP3, and MYC. At the end of treatment with 5-FU, the proportion of viable cells was between 0.65 and 0.70 for all cell lines. Additional cell loss occurred in 40-16 and HCT116 p53-/- cells following administration of Taxol before IR and 5-FU. Radiation sensitivity was unaffected by combined treatments, except for Taxol, irradiation, and 5-FU sequence in the HCT116 p53-/- and 40-16 cell lines, where radiation sensitivity determined by clonogenic survival curve slopes was doubled or quadrupled, respectively. Under our present experimental conditions, treatment response did not correlate with TP53 or hMLH1 status, but was associated with apoptosis-related genes, most notably BNIP3. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 175-185 (2000).
 ...
PMID:Survival of colorectal cancer cell lines treated with paclitaxel, radiation, and 5-FU: effect of TP53 or hMLH1 deficiency. 1099 58

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.
 ...
PMID:[Chemoradiotherapy with low-dose cisplatin and 5-FU for advanced esophageal cancer]. 1108 19

In order to develop the new therapeutic intervention for pancreatic cancer, we have examined the effect of gene therapy for this miserable pancreatic disease. The transfection of UPRT, a 5-FU converting enzyme, gene resulted in the significant change in sensitivity of pancreatic cancer cells against 5-FU. Anti-angiogenesis gene therapy has been also demonstrated to be a promising strategy for pancreatic cancer. It has been revealed that replication-competent adenoviruses are not only the strong weapon themselves but also useful carriers of genes possessing anti-tumor activities as virus vectors specific to tumors without normal p53 function nor intact Rb pathway. Whether these experimental results are universally true require the clinical trials in future.
 ...
PMID:[Development of gene therapy for pancreatic cancer]. 1119 71

5-Fluorouracil (5-FU) is one of the most widely used anticancer agents for advanced colorectal carcinoma, but its response rate is only 15%. The "pharmacokinetic modulating chemotherapy" (PMC) regimen that we have advocated has proved to be highly effective in treating colorectal carcinoma. PMC consists of a continuous i.v. infusion of 5-FU over 24 h for 1day a week at 600 mg/m2/day, and an oral dose of uracil-tegafur (UFT), a 5-FU derivative, at 400 mg/day for 5-7 days per week, repeated every week for more than 6 months. Assays of 5-FU in 23 patients receiving this treatment showed serum concentrations ranging from 88 to 1,323 ng/ml. We then analyzed the effects of clinically relevant concentrations of 5-FU found in colorectal cancer patients treated with the PMC regimen on the growth of three human colorectal adenocarcinoma cell lines, SW480 and COLO320DM (mutant p53) and HCT116 (wild-type p53). Exposure of these three cell lines to 5-FU resulted in growth inhibition in a dose-dependent manner. Exposure to 100 ng/ml of 5-FU in SW480 and COLO320DM caused G1 arrest after 24 h and G2 arrest after 72-144 h, and only a minority of the cell population showed apoptotic features, which indicated that most of the cells were killed through mitotic catastrophe, nonapoptotic cell death. On the contrary, exposure to 1000 ng/ml of 5-FU in SW480 and COLO320DM resulted in G1-S-phase arrest and the induction of apoptosis throughout the experimental period. Nuclear cyclin B1 expression was markedly induced with exposure to 100 ng/ml of 5-FU in SW480 and COLO320DM; and expression of 14-3-3sigma protein, a cell cycle inhibitor in the GG phase, was induced in SW480. ICT116 responded to lower concentrations of 5-FU more rapidly: G2 arrest was seen after 24-72 h of exposure to 10 ng/ml of 5-FU, and G,1rrest was seen after 12-24 h of exposure to 100 ng/ml. These results show that 5-FU acts via two different pathways, depending on dose: (a) G,1S-phase cell cycle arrest and apoptosis at 1,000 ng/ml in SW480 and COLO320DM, and 100 ng/ml in HCT116; and (b) G2-M-phase cell cycle arrest and mitotic catastrophe at 100 ng/ll in SW480 and COLO320DM, and 10 ng/ml in HCT116. These results suggest that the efficacy of our PMC regimen is based on targeting at least two different phases of the cell cycle. In our clinical trial, we showed efficacy independent of p53 status, ascertained by cell kinetic analysis in vitro, which may lead to a novel concept of schedule-oriented biochemical modulation of this drug.
 ...
PMID:Dual antitumor effects of 5-fluorouracil on the cell cycle in colorectal carcinoma cells: a novel target mechanism concept for pharmacokinetic modulating chemotherapy. 1122 29

To determine whether the expression of p53, p21, bcl-2 or Ki-67 in cancer cells is predictive of chemosensitivity, immunohistochemical examination of these factors and chemosensitivity assays were performed on colon and gastric cancer specimens. Chemosensitivity tests were performed using CDDP, 5-FU, MMC, or ADR and inhibition rate (IR) was calculated by MTT assay. Before exposure to anticancer drugs, the samples were investigated immunohistochemically for expression of the above factors and after anticancer drug exposure by TUNNEL staining, for the presence of apoptotic cells. With 5-FU and MMC, the apoptotic index was well correlated with IR, so their effects were related to apoptosis. Moreover, with these two agents, the p53 labeling index (LI) was inversely correlated with IR and p21-LI showed a good correlation with IR. We therefore concluded that immunohistochemical studies for p53 and p21 were useful for predicting the chemosensitivities of colon and gastric cancer to MMC and 5-FU.
 ...
PMID:Correlation of immunohistochemical p53 labeling index with inhibition rate in chemosensitivity test in gastric and colon cancer. 1129 39


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>