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

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

To elucidate mechanisms of resistance to chemotherapies currently used in the first-line treatment of advanced colorectal cancer, we have developed a panel of HCT116 p53 wild-type (p53(+/+)) and null (p53(-/-)) isogenic colorectal cancer cell lines resistant to the antimetabolite 5-fluorouracil (5-FU), topoisomerase I inhibitor irinotecan (CPT-11), and DNA-damaging agent oxaliplatin. These cell lines were generated by repeated exposure to stepwise increasing concentrations of each drug over a period of several months. We have demonstrated a significant decrease in sensitivity to 5-FU, CPT-11, and oxaliplatin in each respective resistant cell line relative to the parental line as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, with increases in IC(50 (72 h)) concentrations ranging from 3- to 65-fold. Using flow cytometry, we have also demonstrated compromised apoptosis and cell cycle arrest in 5-FU-, oxaliplatin-, and CPT-11-resistant cell lines compared with the parental lines after exposure to each drug. In addition, we found that resistance to 5-FU and oxaliplatin was higher in parental p53(-/-) cells compared with parental p53(+/+) cells, with an approximately 5-fold increase in IC(50 (72 h)) for each drug. In contrast, the IC(50 (72 h)) doses for CPT-11 were identical in the p53 wild-type and null cell lines. Furthermore, apoptosis after treatment with 5-FU and oxaliplatin, but not CPT-11, was significantly reduced in parental p53(-/-) cells compared with parental p53(+/+) cells. These data suggest that p53 may be an important determinant of sensitivity to 5-FU and oxaliplatin but not CPT-11. Using semiquantitative reverse transcription-PCR, we have demonstrated down-regulation of thymidine phosphorylase mRNA in both p53(+/+) and p53(-/-) 5-FU-resistant cells, suggesting that decreased production of 5-FU active metabolites may be an important resistance mechanism in these lines. In oxaliplatin-resistant cells, we noted increased mRNA levels of the nucleotide excision repair gene ERCC1 and ATP-binding cassette transporter breast cancer resistance protein. In CPT-11-resistant cells, we found reduced mRNA levels of carboxylesterase, the enzyme responsible for converting CPT-11 to its active metabolite SN-38, and topoisomerase I, the SN-38 target enzyme. In addition, we noted overexpression of breast cancer resistance protein in the CPT-11-resistant lines. These cell lines are ideal tools with which to identify novel determinants of drug resistance in both the presence and absence of wild-type p53.
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PMID:Characterization of p53 wild-type and null isogenic colorectal cancer cell lines resistant to 5-fluorouracil, oxaliplatin, and irinotecan. 1504 37

Recently, we experienced an interesting case of papilla Vater carcinoma. The patient was a 61-year-old woman, who was referred to our department from a private hospital with a chief complaint of high fever. Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography revealed an anomalous arrangement of the pancreaticobiliary duct without a common channel and a tumor, which was detected on the papilla Vater and diagnosed as well-differentiated adenocarcinoma. Pylorus-preserving pancreaticoduodenectomy with lymph node dissection was performed. The immunohistochemical stain showed the strong expression of thymidine phosphorylase in the tumor tissue and also in the normal biliary tract, despite positive p53 cells being undetected in either tumor tissue or epithelium of biliary tract. These findings may suggest important indications to consider some mechanisms of carcinogenesis in the biliary tract.
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PMID:A case report of papilla Vater carcinoma showing positive expression of thymidine phosphorylase. 1508 63

Mouse lymphoma L5178Ytk+/- (MOLY) cells and human lymphoblastoid TK6 and WTK-1 cells are widely used to detect mutagens in vitro. MOLY and WTK-1 cells have a p53 mutation, while TK6 cells, which were derived from the same parental line as WTK-1 cells, do not. In this study, we tested the clastogen 5-fluorouracil (5-FU) in the Tk assay and the in vitro micronucleus (MN) assay in MOLY, TK6, and WTK-1 cells to clarify whether differential responses were related to p53 gene status. We also determined the effect of 5-FU on the frequency of apoptotic cells and on cell cycle distribution in each cell line. Furthermore, we measured the activity of the 5-FU metabolizing enzymes (thymidylate synthetase (TS), dihydrouracil dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), and thymidine phosphorylase (TP)) in each cell line. We treated MOLY cells with 1.0-8.0 microg/mL 5-FU for 3 h and TK6 and WTK-1 cells with 1.56-25 and 3.13-50 microg/mL, respectively, for 4 h. In MOLY cells, the mutation frequency (MF) and MN frequency increased. In WTK-1 cells, the MN frequency but not the MF increased. In TK6 cells, neither the MF nor the MN frequency increased. Furthermore, the IC50 of 5-FU was lower in MOLY cells than in the human cells. The response to 5-FU treatment differed in other ways as well. At the same level of cytotoxicity, the frequency of apoptotic cell was highest in TK6 cells. The cell cycle was delayed just after treatment in MOLY cells while the delay appeared 24 h later in TK6 and WTK-1 cells. Nothing in our analysis, however, revealed marked differences between the cell lines that could account for the severe cytotoxic and mutagenic responses that 5-FU elicited only in MOLY cells. 5-FU is phosphorylated by OPRT and TP and detoxified by DPD. MOLY cells have higher OPRT activity and markedly lower DPD and TP activity than TK6 and WTK-1 cells. The content of TS, however, the target enzyme of 5-FU, was similar in all cell lines, suggesting that 5-FU was more readily phosphorylated and less readily detoxified in MOLY cells than in TK6 and WTK-1 cells. MOLY cells were more sensitive to 5-FU than WTK-1 cells even though both have a mutated p53 gene, suggesting that the different responses to 5-FU were due to differences in 5-FU metabolism rather than the p53 status.
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PMID:Relationship between p53 status and 5-fluorouracil sensitivity in 3 cell lines. 1658 12

Malignant gastrointestinal tumors are still worldwide a very common cause of death from cancer. Even though the surgical techniques and the neoadjuvant/adjuvant therapies have improved over the last years and multimodal concepts in cancer treatment have been established, these types of tumors remain a challenge. Therefore predictive/prognostic markers need to be established, to be able to tailor chemotherapies and therefore improve efficacy of neoadjuvant/adjuvant treatment. Over the last years potential predictive/prognostic factors have been characterized by molecular-biological technologies: the tumor suppressor gene p53, the cell-cycle regulatory proteins p21 and p27, the marker of proliferation Ki-67, the epidermal growth factor receptor, HER2/neu, angiogenetic factors (the vascular endothelial growth factor, cyclooxygenase 2, thymidine phosphorylase), enzymes involved in the DNA-repair-system (ERCC1), enzymes involved in the 5-fluorouracil-metabolism (thymidylate synthase, dihydropyrimidine dehydrogenase) or other genetic alterations, like the loss of heterozygosity or the microsatellite instability. The results of the mainly retrospective studies are promising but prospective studies are needed to validate those markers in the therapy of gastrointestinal tumors. The goal is that we will be able to predict when and with what to treat.
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PMID:[Predictive and prognostic factors in the neoadjuvant/adjuvant therapy of gastrointestinal tumors: wishful thinking or reality?]. 1661 82

Hypoxia-inducible factors (HIF-1alpha and HIF-2alpha) are closely related protein complexes that activate transcription of target genes in response to hypoxia. The immunohistochemical expression of these two proteins was investigated in 144 bladder cancer tissue samples and correlated with standard clinicopathological features, in order to elucidate their prognostic significance. We also evaluated their possible associations with other angiogenesis related markers such as microvessel density (MVD), vascular endothelial growth factor, thymidine phosphorylase, tenascin, fibronectin, p53 and bcl-2 to further clarify their implication in tumor stroma vascularization. Nuclear HIF-1alpha expression in tumor cells was detected in 57.1% of the cases. A trend of correlation of this expression with poorly differentiated tumors was observed. In addition, HIF-1alpha expression was positively correlated with stromal cells thymidine phosphorylase expression. Tumors that were progressed in muscle-infiltrating disease showed a higher HIF-1alpha expression. A higher HIF-1alpha expression was also observed in tumors with an in situ component. In tumor cells, low HIF-2alpha expression was observed in 6.3%, moderate in 31.9% and high in 61.8% of the cases. A trend of correlation of this expression with MVD was observed. In addition, HIF-2alpha expression was positively correlated with thymidine phosphorylase and fibronectin expression. A lower HIF-2alpha expression was detected in tumors that recurred earlier in univariate methods of analysis. HIF-2alpha was expressed in tumor stroma associated cells in 53.5% of specimens and was correlated with advance tumor stage, thymidine phosphorylase and tenascin expression. There was no statistically significant difference in the expression of both HIF-1alpha and HIF-2alpha between primary and recurrent tumors. In multivariate analysis including T stage, T grade, multifocality and T size, both HIF-1alpha and HIF-2alpha expression were not considered dependent in the prediction of recurrence or progression. In conclusion, the results of the present study indicate that HIF-1alpha and HIF-2alpha expression may help to predict recurrence or progression to muscle invasive disease but not as independent prognostic factors. In addition, the expression of HIF-1alpha and HIF-2alpha, appear to play a role in bladder cancer, vascularization possibly and in cooperation with other angiogenic factors.
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PMID:Hypoxia-inducible factors HIF-1alpha and HIF-2alpha expression in bladder cancer and their associations with other angiogenesis-related proteins. 1703 15

Recent studies have demonstrated that tegafur-uracil (UFT) is useful for the adjuvant treatment of various types of cancers. To determine whether nucleoside metabolizing enzymes could be used to predict the response to UFT treatment in women with primary breast cancer, we retrospectively analyzed archived tumor tissue samples obtained from the 3rd Adjuvant Chemo-Endocrine Therapy for Breast Cancer (ACETBC) study, in which adjuvant treatment with tamoxifen (TAM) plus UFT for 2 years was compared with TAM alone for 2 years. Samples of tumor tissue were obtained from 192 premenopausal women with node-positive invasive breast cancer. The tissue samples were examined immunohistochemically to study the expression of thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD), as well as the expression of Her2 and p53. In patients with TS-positive tumors, the risk of relapse was significantly lower in the tamoxifen plus UFT group than in the tamoxifen alone group. After 2 years, however, there was a trend towards a decrease in the relative predictive value (RPV) of TS with time. No relationship to outcome was detected for TP or DPD. Expression of Her2 or p53 was a significant prognostic indicator in the tamoxifen alone group. TS, but not TP or DPD, may be a useful predictor of response to UFT therapy. After 2 years, the RPV of TS decreased with time, suggesting that 2 years of treatment with oral fluorouracil derivatives may be inadequate. Further studies are required to investigate this possibility.
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PMID:Predictive implications of nucleoside metabolizing enzymes in premenopausal women with node-positive primary breast cancer who were randomly assigned to receive tamoxifen alone or tamoxifen plus tegafur-uracil as adjuvant therapy. 1778 23

Tumor suppressor gene p53, the most commonly mutated gene in human cancers has been shown to play an important role in the biology of gynaecological carcinomas. Thymidine phosphorylase is one of the most important angiogenic factors, which is connected with tumor expansion and invasiveness. The aim of the study was an evaluation of thymidine phosphorylase and p-53 tissue protein expression in human endometrial cancer cells by immunohistochemistry and comparison obtained data with clinicopathological factors as FIGO stage of disease and histopathologic grade. Endometrial cancer specimens were obtained from 55 postmenopausal patients (aged 52 to 74 years) operated by total abdominal hysterectomy with bilateral salpingo-oophorectomy. None of patients received preoperative pelvic irradiation. Histopathological typing and grading of the endometrial tumors (G-1, G-2, G-3) as well as myometrial invasion (<1/2, >1/2) were assessed using standard criteria, on hematoxylin-eosin sections. FIGO clinical stage of disease was determined. at the surgery. Thymidine phosphorylase overexpression was observed in 23 (41,8 %) cases. Although we found no statistically significant differences in TP expression between histopathologic grades, particular FIGO stages showed a significant trend of increase TP tumor overexpression. P53 protein overexpression was observed in tumor tissue in 21 cases (35,2%). It tended to be more frequent in cases of advanced disease as well as in low differentiated tumors. Although we found no statistically significant differences in p53 gene expression between groups of FIGO stage and histopathologic grade, we obtained a significant trend of increasing the P53 positive rate with both FIGO and tumour differentiation grading Joint assessment of thymidine phosphorylase and tumor suppressor genes expression may be of additional value in determining the biology of endometrial carcinoma. Key words: endometrial cancer, thymidine phosphorylase, p-53.
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PMID:A role of thymidine phosphorylase and P53 tissue protein expression in biology of endometrial cancer. 1834 59

Potent thymidine phosphorylase (TP) inhibitors with anti-angiogenic activity are required to improve the prognosis of patients with TP-positive tumors. We have designed and developed novel structural and functional classes of TP inhibitors that also inhibit TP-induced angiogenesis, i.e. (i) the first purine analogue inhibitor of TP (7DX), (ii) the first multifunctional TP inhibitor (TP65), and (iii) the purine riboside analogue KIN59, which inhibits TP without interacting with the substrate-binding sites. The latter finding indicates that a, yet unidentified, allosteric site in TP contributes to its biological activities. In order to identify the amino acid residues in TP that interact with KIN59, we performed co-crystallograpy of the KIN59-TP complex. Our preliminary data suggest the existence of a putative KIN59 binding site. Identification of the allosteric site(s) in TP is important to gain more insight into the different biological activities of TP and may aid in the design of novel TP inhibitors. The nucleotide analogue cidofovir, which is being used clinically for the treatment of cytomegalovirus-induced retinitis in AIDS patients, emerged as a promising antitumor agent. So far, cidofovir has only been evaluated clinically for the treatment of HPV-associated tumors. Our results demonstrate the potent activity of cidofovir against tumors that are not associated with a virus. Cidofovir inhibits the growth of strongly vascularized tumors via inhibition of the growth factor FGF2, and by increasing the expression of the tumor suppressor p53, leading to apoptosis. These exciting results open new perspectives for the use of cidofovir as an anti-tumor agent in the therapy of tumors that are not associated with an oncogenic virus.
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PMID:Regulation of cancer progression by inhibition of angiogenesis and induction of apoptosis. 1866 59

We evaluated the expression of molecular markers in colorectal adenocarcinoma in relation to p53 protein expression. Tissue samples of 54 patients with colorectal adenocarcinoma were obtained at surgery at university hospitals in the years 2000-2003. These were analyzed by immunohistochemical techniques using primary antibodies for p53, Bcl-2, P-gp, topoisomerase II alpha and Thymidylate Synthase (TS), thymidine phosphorylase/PD- ECGF (TP) and LSAB detection kit. The highest prevalence of expression among six analyzed markers were P-gp and p53 with 77% expression and the lowest one was Topo II with 35% expression. No clinicopathological significance was recorded in colorectal cancer patients. Several immunophenotypes were observed between p53 and other molecular markers. Additionally the prevalence of lack of expression of Bcl-2, Topo II and TS was higher in p53+ tumors than in p53-tumors. A significant association (p = 0.021) existed between p53/Bcl-2 coexpression and mean age of patients (63.5 [10.1]y vs. 52.3 [15.2] y) and between p53/TP coexpression and sex (66.7% male; (p = 0.022). Overexpression of mutated p53 seen in tumor samples may alter the expression pattern of other molecular markers that are predictors of tumor response to chemotherapy regimens. Age and sex of patients could also affect the p53 related proteins such as Bcl-2 and TP, which can affect therapeutic outcome and disease prognosis. These findings emphasize the importance of tumor immunophenotypes as valuable prognostic or predictive markers in clinical settings.
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PMID:Association between p53 expression and Bcl-2, P-glycoprotein, topoisomerase II alpha, thymidylate synthase and thymidine phosphorylase as potential therapeutic targets in colorectal cancer patients. 1909 Jan 49


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