UNIPROT:P04637 - FACTA Search

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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the last 50 years, 5-fluorouracil-based therapy has been the mainstay of adjuvant and palliative treatment for colorectal cancer but response rates and median survival have been dismal despite the introduction of thymidylate synthase modulators such as leucovorin. Recently, new therapeutic approaches have been introduced. These include oral 5-fluorouracil analogues, pure thymidylate synthase inhibitors, dihydropyrimidine dehydrogenase inhibitors, and agents with mechanism of action unrelated to thymidylate synthase such as irinotecan, a topoisomerase I inhibitor, and oxaliplatin, the only platinum derivative with significant activity in colorectal cancer. Current treatment strategies involve combination therapies because this approach is the most effective. For instance, responses observed with oxaliplatin and 5-fluorouracil indicate synergy between the two agents and the combination of capecitabine plus oxaliplatin or irinotecan has shown high activity both in chemotherapy-naive and in pretreated patients with advanced colorectal cancer. Additionally, it is likely that future therapeutic management of advanced colorectal cancer may include combination therapy of one of the new oral 5-fluorouracil analogues, because of the convenient oral regimens. The identification of colorectal cancer-specific prognostic factors will undoubtedly influence treatment decisions. For instance, patients overexpressing epidermal growth factor receptor and p53 with thymidylate synthase have a worse prognosis. To target these biomarkers, antibodies such as cetuximab, an anti-EGFR antibody, and angiogenesis inhibitors and tyrosine kinase inhibitors have been introduced and are undergoing clinical evaluation. Over the last 5 years the armamentarium to fight colorectal cancer has increased significantly, giving more hope for effective disease management.
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PMID:The role of oxaliplatin in the treatment of advanced metastatic colorectal cancer: prospects and future directions. 1242 6

NB1011, a phosphoramidate derivative of (E)-5-(2-bromovinyl)-2'-deoxyuridine, is a novel small molecule anticancer agent. NB1011 is selectively active against tumor cells expressing high levels of thymidylate synthase (TS), a critical enzyme in DNA biosynthesis. NB1011 is different from the current TS-targeted drugs, which require inhibition of TS to be effective, because NB1011 cytotoxicity depends upon activation by TS. Here we report a dose-dependent, antitumor activity of NB1011 against established Tomudex-resistant breast cancer (MCF7TDX) xenografts in athymic mice. Against 5-fluorouracil-resistant colon carcinoma (H630R10) xenografts, NB1011 was as efficacious as irinotecan, a drug recently approved for the treatment of 5-fluorouracil-resistant colon cancer. To gain insight into the mechanisms NB1011 uses to suppress cellular growth, we analyzed the downstream molecular events in the high TS-expressing MCF7TDX and RKOTDX cell lines upon NB1011 treatment. NB1011 treatment increased the mRNA levels of p21, Bax, and GADD45. Furthermore, NB1011 induced p53, p21, and Bax proteins specifically in high TS-expressing tumor cells, whereas no induction was observed in low TS-expressing tumor cells (MCF7) or normal cells (WI38). Cell cycle analysis demonstrated that NB1011 treatment of MCF7TDX and RKOTDX cells resulted in an accumulation of cells in the G2-M phase of the cell cycle. Altogether, our data indicate that the induction of the p53 target genes p21, bax, and GADD45, with a concomitant deregulation of the cell cycle, may represent one of the mechanisms by which NB1011 exerts its growth-suppressive effects.
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PMID:Inhibition of cell growth by NB1011 requires high thymidylate synthase levels and correlates with p53, p21, bax, and GADD45 induction. 1247 50

In this study we investigated the relationship between thymidylate synthase (TS) protein expression, evaluated by Western blotting analysis and by immunohistochemistry (IHC), and growth rate in human colon xenograft tumors in nude mice. Human colon cancer cell lines were used to induce xenograft tumors and the tumor mass growth rate was calculated by measuring tumor size variations over time. TS 106 monoclonal antibody was used for both Western blotting and IHC TS detection. Tumor cell growth fraction was measured by Ki67/MIB1 immunolabeling and tumor cell growth rate by evaluating the mean nucleolar size in silver-stained sections. TS Western blotting values were related to tumor mass growth rate (p<0.001) and cell growth rate (p=0.002) but not to cell growth fraction (p=0.676). The degree of the IHC staining showed only a trend to be associated with TS protein expression measured on Western blotting, and was not related either to tumor mass growth or cell proliferation rate. Tumor xenografts were also characterized for TS promoter tandem repeat and p53 status. No relationship was observed between these variables and TS expression evaluated by both Western blotting and IHC analysis. Our results demonstrate that TS expression evaluated by Western blotting analysis is directly related to the tumor mass growth rate and question the use of the IHC approach to obtain precise quantitative information on TS expression in tumor samples.
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PMID:Evaluation of thymidylate synthase protein expression by Western blotting and immunohistochemistry on human colon carcinoma xenografts in nude mice. 1248 85

Esophageal cancer is uncommon, but its incidence is rapidly increasing in the Western countries because of the high incidence of the cardia esophageal adenocarcinoma. Notwithstanding the encouraging results achieved with surgical procedures, esophageal carcinoma has a poor prognosis with 5-year survival in 10% of cases without differences between both squamous and adenocarcinoma histologies. Almost 50% of esophageal cancer patients have unresectable disease at presentation; in the past years combined modality treatments, using chemotherapy and/or radiotherapy with or without surgery, have been evaluated to reduce the risk of local and/or distant recurrences. Ongoing regimens with new agents (Taxanes, Vinorelbine, Irinotecan), in association or not with platinum compounds, show good antitumor efficacy and tolerability, even in the metastatic disease. Preoperative strategies with radiation only did not give any advantage compared to surgery alone, instead, controversial results were obtained, with a minimal advantage, using chemotherapy. Combined chemotherapy and radiation, in suitable candidates for resection has shown an improvement of complete pathological responses, in both the histologies, but with superior toxicities when compared to chemotherapy or radiation therapy alone. Postoperative adjuvant therapies as radiation, chemotherapy or both, have not led to a marked improvement in overall survival and should be performed only in clinical trials. The use of chemoradiotherapy showed a clear advantage versus radiotherapy alone and in many cases equivalent to regimens plus surgery even if control studies haven't been performed. Clinical trials with novel biologic agents, in combination to chemotherapy or alone, against cell growth arrest, neoagiongenesis and tumor metastasis invasion process are currently under evaluation. In the coming years new markers as antigen Ki-67 determination, p53 mutation or high levels activity of thymidylate synthase and novel staging techniques as PET could be precious to identify the better treatment for each patient.
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PMID:[New strategies in the treatment of esophageal cancer]. 1259 16

The benefit of postoperative adjuvant chemotherapy in patients with Dukes' B colorectal cancer is still uncertain and its routine use is not recommended. Prognostic biomarkers may be useful for identifying high-risk patients with resected, node-negative disease, and this stratification may represent an innovative strategy for designing adjuvant chemotherapy trials. Featured prognostic molecular markers can be divided into the following categories: cell proliferation indices (Ki-67, Mib-1, proliferating cell nuclear antigen); oncogenes/tumor suppressor genes [p53, K-ras, Deleted in Colorectal Cancer (DCC), Bcl-2, c-erbB2]; DNA repair (microsatellite instability); markers of angiogenesis (vascular count, vascular endothelial growth factor); markers of invasion/metastasis (plasminogen-related molecules, matrix metalloproteinases); and biochemical markers (thymidylate synthase). Studies that have investigated their prognostic role in Dukes' B colorectal cancer patients are reviewed here. Current data do not provide sufficient evidence for the incorporation of available prognostic biomarkers into clinical practice. However, a biomarker-based approach could be an effective strategy for improving results of postoperative adjuvant treatments in high-risk Dukes' B colorectal cancer patients. Markers of altered DCC function have shown promising prognostic role and sufficient prevalence in retrospective investigations and they deserve further assessment in prospective studies.
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PMID:Prognostic molecular markers for planning adjuvant chemotherapy trials in Dukes' B colorectal cancer patients: how much evidence is enough? 1285 43

NB1011, a phosphoramidate derivative of (E)-5-(2-bromovinyl)-2'-deoxyuridine, is a novel anti-cancer agent that selectively targets tumor cells expressing high levels of thymidylate synthase (TS), an enzyme required for DNA biosynthesis. NB1011 treatment of high-TS-expressing breast carcinoma cells (MCF7TDX) results in the induction of p53 and p21 protein levels, whereas no p53 or p21 induction is observed in the low-TS-expressing MCF7 tumor cells. Furthermore, MCF7TDX cells accumulate in the G(2)/M phase of the cell cycle in response to NB1011. In this study, the effect of NB1011 on the phosphorylation status of p53 was analyzed. We demonstrate that NB1011 treatment of various tumor cell lines expressing high TS results in the phosphorylation of p53 on Ser15, whereas this p53 phosphorylation is not observed in low-TS-expressing tumor cells. Also, we examined the role of several key cell cycle regulators in the growth inhibition observed in response to NB1011. Our results show that the mRNA and protein levels of the G(2)/M regulators cdc2, cyclin B1 and cdc25C are down-regulated in MCF7TDX cells, while unaffected in MCF7 cells. The mRNA and protein levels of 14-3-3sigma, also a direct transcriptional target of p53, are up-regulated in MCF7TDX cells following NB1011 treatment, while unchanged in MCF7 cells. Taken together, our data indicate that the growth inhibition caused by NB1011 in MCF7TDX cells is mediated through phosphorylation of p53 and activation of the G(2)/M checkpoint.
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PMID:NB1011 induces Ser15 phosphorylation of p53 and activates the G2/M checkpoint. 1285 88

To identify factors that influence the clinical response to 5-fluorouracil (5-FU), we studied the correlation between in vitro sensitivity to 5-FU and the expression of seven biological markers. The markers, thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), pyrimidine nucleoside phosphorylase, p53 (wild/mutant), p21, cyclo-oxygenase-2, and inducible nitric oxide synthase were measured in tumour tissues from 32 colorectal cancer patients. The activities of TS and DPD were significantly lower in the tumours sensitive to 5-FU compared with those that were not sensitive to 5-FU. In tumours with TS < 3.7 pmol/min per mg protein and DPD < 98 pmol/min per mg protein, the percentage of cases sensitive to 5-FU (67%) and the mean percentage inhibition of tumour cells by 5-FU (42.8%) were significantly higher than in the other tumours (0% and 13.1%, respectively). The other biological markers did not correlate with in vitro sensitivity to 5-FU. Tumour sensitivity to 5-FU can be more precisely predicted by taking the activities of both TS and DPD into consideration than by using either alone.
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PMID:Intratumoural thymidylate synthase and dihydropyrimidine dehydrogenase activities are good predictors of 5-fluorouracil sensitivity in colorectal cancer. 1287 Mar 70

The purpose of this study was (1) to disclose data from a non-randomized trial of prophylactic hepatic arterial chemotherapy for liver metastases from Dukes'C colorectal cancer, (2) to examine the influence of the expression of dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS), and p53 in the primary lesion on this chemotherapy, and (3) to examine the expression of orotate phosphoribosyl transferase (OPRT) mRNA levels in the cases of recurrence included in this study. Patients who underwent curative resection of Dukes'C colorectal cancer between November 1996 and April 2000 were examined. After curative resection, patients were non-randomly divided into two groups after obtaining their informed consent: Hepatic arterial infusion (HAI) group patients (n = 28) were given 5-FU (500 mg/body for 1 h per week, repeated 50 times) via the hepatic artery and peroral UFT-E after resection of Dukes'C colorectal cancer. Control group patients (n = 21) received UFT-E alone. Liver metastasis-free survival did not differ between the groups. Immunohistochemical examinations revealed that the expression of tumoral DPD or p53 was unlikely to affect the hepatic recurrence, although patients with a low expression of TS tended to have better survival in both groups. However, multivariate analysis by the Cox proportional hazard model revealed that a significant prognostic factor influencing the hepatic recurrence is extensive venous invasion. Expression levels of OPRT mRNA, measured in tumors of patients with recurrence (n = 6 for the HAI group; and n = 4 for the control group) were not significantly different between the groups. These results suggest that (1) intermittent hepatic arterial infusion of 5-FU in addition to oral UFT-E was not more useful than administration of UFT alone, and (2) the expression of DPD, TS, p53, and OPRT in the primary lesion was unlikely to affect the prognosis of patients included in this study.
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PMID:[Results of prophylactic hepatic arterial chemotherapy for liver metastases of Dukes C colorectal cancer--correlation with tumoral expression of dihydropyrimidine dehydrogenase, thymidylate synthase, p53, or orotate phosphoribosyl transferase]. 1461 79

We have demonstrated previously a Fas-dependent component in thymineless death of human colon carcinoma cells. Importantly, the cytotoxic effects of thymidine deprivation induced by 5-fluorouracil (FUra) combined with leucovorin (LV) was enhanced by IFN-gamma, and the synergism was shown to be dependent on Fas, FUra-induced DNA damage, and independent of p53. Subsequently we examined the potential for synergistic interactions between IFN-gamma and the specific thymidylate synthase inhibitor, ZD9331. IFN-gamma sensitized colon carcinomas to ZD9331-induced apoptosis and loss in clonogenic survival, also dependent on ZD9331-induced DNA damage, independent of p53. Synergism occurred in HCT116, demonstrating previously RNA-mediated FUra/LV cytotoxicity that could not be potentiated by IFN-gamma. Manipulation of the Fas death receptor pathway from the level of the receptor (Nok1/Nok2, Fas overexpression, and DN-FADD) to the mitochondria (Bcl-xL and Bcl-2) did not modulate ZD9331 +/- IFN-gamma-induced cytotoxicity in HT29, with the exception that Nok1/Nok2-blocking antibodies partially protected HT29 from the cytotoxic activity of ZD9331 alone. However, IFN-gamma alone (but not ZD9331) up-regulated the expression of caspases -3, -4, -7, and -8, and in combination with ZD9331 demonstrated enhanced caspase activation and cleavage of poly(ADP-ribose) polymerase that was not prevented by overexpression of Bcl-2. Additionally, IFN-gamma increased the activity of the proteasome in HT29, leading to selective down-regulation of the antiapoptotic protein survivin, whereas simultaneously increasing Fas expression. However, reduction in the survivin:Fas ratio by transfection of survivin small interfering RNA and/or overexpression of Fas did not affect sensitivity of HT29 to ZD9331 +/- IFN-gamma. Data demonstrate that IFN-gamma combined with ZD9331 is synergistic in additional cell lines that demonstrate RNA-mediated FUra/LV cytotoxicity, and that a major target of interaction is at the level of caspases, downstream of Fas, and independent of involvement of either the mitochondria or survivin.
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PMID:Interferon-gamma-induced sensitization of colon carcinomas to ZD9331 targets caspases, downstream of Fas, independent of mitochondrial signaling and the inhibitor of apoptosis survivin. 1469 55

5-Fluorouracil (5-FU) is the most common chemotherapeutic agent used in the treatment of colorectal cancer, yet objective response rates are low. Recently, camptothecin (CPT) has emerged as an effective alternative therapy. Decisive means to determine treatment, based on the likelihood of response to each of these agents, could greatly enhance the management of this disease. Here, the ability of cDNA microarray-generated basal gene expression profiles to predict apoptotic response to 5-FU and CPT was determined in a panel of 30 colon carcinoma cell lines. Genes whose basal level of expression correlated significantly with 5-FU- and CPT-induced apoptosis were selected, and their predictive power was assessed using a "leave one out" jackknife cross-validation strategy. Selection of the 50 genes best correlated with 5-FU-induced apoptosis, but not 50 randomly selected genes, significantly predicted response to this agent. Importantly, this gene expression profiling approach predicted response more effectively than four previously established determinants of 5-FU response: thymidylate synthase and thymidine phosphorylase activity; and p53 and mismatch repair status. Furthermore, reanalysis of the database demonstrated that selection of the 149 genes best correlated with CPT-induced apoptosis maximally and significantly predicted response to this agent. These studies demonstrate that the basal gene expression profile of colon cancer cells can be used to predict and distinguish response to multiple chemotherapeutic agents and establish the potential of this methodology as a means by which rational decisions regarding choice of therapy can be approached.
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PMID:Gene expression profiling-based prediction of response of colon carcinoma cells to 5-fluorouracil and camptothecin. 1469 96

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