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)

We developed a cell system where expression of thymidylate synthase (TS), an enzyme essential for DNA synthesis, can be modulated by a Zn(2+)-inducible promoter in MCF-7 cells. We found that overexpression of TS resulted in downregulation of p21 protein and mRNA levels. Statistical analysis demonstrated a significant downregulation of p21, but not a statistically significant decrease in p53 protein levels following TS induction. Since p21 is known to be transcriptionally activated by p53, these results suggest that TS downregulation of p21 may be occurring through a p53-independent mechanism in this in vitro cell system. In addition, cell cycle analysis demonstrated that downregulation of p21 by TS resulted in a decreased G(1)/S ratio in MCF-7 cells.
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PMID:Downregulation of p21/WAF1 expression by thymidylate synthase. 1144 25

We studied apoptosis and thymidylate synthase (TS) inductions by 5-fluorouracil (5-FU) in gastric cancer cells with wild-type p53 (MKN-45 and MKN-74) and with mutated p53 (MKN-28 and KATO-III). Apoptotic inductions in MKN-45 and MKN-74 were stronger than those in MKN-28 and KATO-III, suggesting that wild-type p53 may contribute to the induction of apoptosis. After continuous exposure to 0.1 microg/ml of 5-FU for 96 h, no TS induction was obtained in KATO-III, while approximately twice the amount of TS was observed compared to non-treatment cells in MKN-45, MKN-74, and MKN-28. The results of immunohistochemical staining for TS and p53 showed no relation between these two protein expressions in endoscopic biopsy specimens of 25 patients with advanced gastric cancer. These results indicated that p53 status may not play a pivotal role in regulating TS expression. We found no significantly different effects of 5-FU between intermittent (repeat of 24-h continuous infusion and 24-h drug-free) and continuous treatments in either MKN-28 or stem cells (CD34+ hematopoietic progenitor cells) when the same area under the time-concentration curve of 5-FU was administered. The TS induction in MKN-28 cells by intermittent treatment was significantly higher than that by continuous treatment; however, most TSs in both types of 5-FU treatment cells were of the inactive form, i.e., TS bound to FdUMP, a 5-FU metabolite. Therefore, neither intermittent nor continuous treatment appears to induce 5-FU resistance related to the level of increment free TS. In conclusion, our observations suggested that p53 mutation may be associated with apoptotic induction by 5-FU; however, p53 status may not strongly affect TS induction by 5-FU. Intermittent treatment can be replaced with continuous treatment without causing 5-FU resistance.
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PMID:Apoptosis and thymidylate synthase inductions by 5-fluorouracil in gastric cancer cells with or without p53 mutation. 1144 54

The role of oral chemotherapy has been getting expanded because of the potential advantage in patients' convenience and better quality of life as well as in cost-effectiveness as compared with intravenous chemotherapy. In this article, the history, mechanism of anti-tumor activity, and clinical use of oral chemotherapy using 5-fluorouracil (5-FU) derivative chemotherapeutic agents are reviewed. Pharmacological analysis has revealed that 5-FU, a basic chemotherapeutic agent widely used against a variety of malignant tumors, shows a time dependent anti-tumor activity, and that continuous maintenance of 5-FU concentration in blood is the optimal method in 5-FU administration. UFT, a combination drug of ftorafur (tetrahydrofuranyl-5-fluorouracil, tegafur, FT) and uracil, has been developed to have potent anti-tumor activity by maintaining higher 5-FU concentration in blood and tumor tissues for a long time. FT is a pro-drug that releases 5-FU continuously, and uracil is added to inhibit degradation of the released 5-FU. Clinically, oral administration of UFT has proved to be effective as an adjuvant therapy after surgery for some malignant tumors such as non-small cell lung cancer. Moreover, UFT has proved to be effective for inoperable advanced malignancies such as colorectal cancer, especially in combination with leucovorin or cisplatin. Recently, S-1, a more active oral 5-FU derivative chemotherapeutic agent has been developed in Japan. Several factors to affect anti-tumor effects and/or toxicities of 5-FU and the derivatives, such as thymidylate synthase activity, dehydropyrimidine dehydrogenase activity and p53 status, are also discussed in the article. In conclusion, oral administration of 5-FU derivatives such as UFT may have several clinical advantages over intravenous 5-FU administration.
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PMID:The history, mechanism and clinical use of oral 5-fluorouracil derivative chemotherapeutic agents. 1146 34

Cytotoxic chemotherapy has shown little antitumour activity against renal cell carcinoma (RCC). Although immunotherapy is relatively effective against RCC, the response rate is approximately 20%. Therefore, there is an urgent need to increase this response rate. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L) is one member of the tumour necrosis factor ligand family that selectively induces apoptosis of cancer cells. Since several cytotoxic anticancer drugs including 5-fluorouracil (5-FU) also mediate apoptosis, we reasoned that combined treatment of cancer cells with TRAIL and drugs might result in synergy and overcome the resistance of the cancer cell. This study has examined whether TRAIL can synergise with 5-FU in both cytotoxic and apoptotic assays against drug-resistant RCC cells. Cytotoxicity was determined by an 1-day microculture tetrazolium dye assay. Synergy was assessed by isobolographic analysis. Treatment of Caki-1 cells with TRAIL in combination with 5-FU resulted in a synergistic cytotoxic effect. Synergy was also achieved in freshly derived RCC cells from 3 patients. The enhanced cytotoxicity was obtained irrespective of the sequence of the treatment, but the highest cytotoxicity was observed when Caki-1 cells were treated with TRAIL and 5-FU simultaneously. The synergy achieved in cytotoxicity with TRAIL and 5-FU was shown to be due to apoptosis. The mechanisms responsible for the synergistic cytotoxicity and apoptosis were examined. Treatment of Caki-1 cells with 5-FU enhanced the expression of p53 and bax, but had no effect on the expression of bcl-2. Incubation of Caki-1 cells with TRAIL enhanced the intracellular accumulation of 5-FU and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). Treatment of Caki-1 cells with TRAIL downregulated the expression of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) modestly, and upregulated the expression of orotate phosphoribosyltransferase (OPRT). However, the expression level of thymidine phosphorylase (TP) was not affected by TRAIL. This study demonstrates that combined treatment of RCC cells with TRAIL and 5-FU overcomes their resistance. The sensitisation obtained with freshly isolated RCC cells required low subtoxic concentrations of 5-FU. These findings support the potential application in vivo of a combination of TRAIL and 5-FU in the treatment of TRAIL/5-FU-resistant RCC.
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PMID:Potentiation of the sensitivity of renal cell carcinoma cells to TRAIL-mediated apoptosis by subtoxic concentrations of 5-fluorouracil. 1182 14

Cellular drug resistance is one of the principal obstacles to the clinical efficacy of cancer chemotherapy. In this review, we describe the potential role for translational regulation as a novel mechanism for modulating chemosensitivity. The evidence for the translational control of thymidylate synthase, dihydrofolate reductase, and p53 will be presented, as will experimental data showing how disruptions in this important regulatory process can lead to the rapid emergence of cellular drug resistance.
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PMID:Translational regulation as a novel mechanism for the development of cellular drug resistance. 1183 45

Analysis of tumour markers is helping to predict individual patient response to chemotherapy. However, the difficulties in obtaining metastatic disease samples has led to a reliance on assessment of primary tumour, with little data on its predictive ability. This study assessed thymidylate synthase (TS), a target for the commonly used drug 5FU, in 42 paired primary colorectal tumour and lymph node metastasis. High TS staining was seen in 63% of primary colon tumour cells and 81% of the secondary lymph node. Primary tumour did not have significant predictive power for secondary tumour samples (kappa=0.125; p=0.38). There was no significant relationship between TS staining and expression of G1/S cell cycle proteins p21, p27, p53, cyclin D1, proliferating cell nuclear antigen (PCNA) and retinoblastoma protein (Rb) (p>0.05 in all cases). Discordance in TS protein levels between primary and secondary tumours demonstrates the danger of predicting outcome after chemotherapy in metastatic colorectal cancer from the primary tumour.
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PMID:Primary colorectal tumour is not an accurate predictor of thymidylate synthase in lymph node metastasis. 1183 85

Concurrent and pre-exposure of A431 human epidermoid cancer cells to UCN-01, an investigational anticancer drug, with 5-fluoro--2'-deoxyuridine (FdUrd), which targets thymidylate synthase, produced more than additive cytotoxicty. A 24-h exposure to 10 nM FdUrd led to inhibition of TS, a 2.5-fold increase in total thymidylate synthase protein content, profound dTTP depletion and a 6.3-fold increase in the ratio of dATP to dTTP, but did not cause single-strand breaks in DNA. However, FdUrd enhanced UCN-01-associated DNA strand breaks. Concurrent thymidine exposure led to repletion of dTTP pools, and cytoprotection against FdUrd alone and with UCN-01. UCN-01 arrested cells in G1, decreased the percentage of FdUrd-treated cells in S phase and reduced FdUrd-DNA incorporation, suggesting the latter was not important for cytotoxicity. Delayed induction of high molecular mass DNA fragmentation and poly(ADP-ribose) polymerase cleavage was observed with the combination of UCN-01 and FdUrd. These findings suggest that while FdUrd-mediated deoxynucleotide imbalance alone was insufficient to induce apoptosis in this p53-mutant cell line, it magnified UCN-01's effects, most likely by interfering with DNA repair. The clinical evaluation of UCN-01 combined with 5-fluoropyrimidines may be of interest.
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PMID:Biochemical and molecular effects of UCN-01 in combination with 5-fluorodeoxyuridine in A431 human epidermoid cancer cells. 1198 70

Drug resistance is often a limiting factor in successful chemotherapy. Our laboratory has been interested in studying mechanisms of resistance to drugs that are targeted to the thymidylate biosynthesis pathway especially those that target thymidylate synthase (TS) and dihydrofolate reductase (DHFR). We have used leukemia as a model system to study resistance to methotrexate (MTX) and colorectal cancer as the model system to study 5-fluorouracil (5-FU) resistance. In leukemias, we and others have shown that transport, efflux, polyglutamylation and hydrolase activities are major determinants of MTX resistance. We have further reported that some leukemic cells have an increase in DHFR gene copy number possibly contributing to the resistant phenotype. Recently, we have begun to study in detail the molecular mechanisms that govern translational regulation of DHFR in response to MTX as an additional resistance mechanism. Studies thus far involving colorectal tumors obtained from patients have focused predominantly on the predictive value of levels of TS expression and p53 mutations in determining response to 5-FU. Although the predictive value of these two measures appears to be significant, given the variety of resistance to 5-FU observed in cell lines, it is not likely that these are the only measures predictive of response or responsible for acquired resistance to this drug. The enzyme uridine-cytidine monophosphate kinase (UMPK) is an essential and rate-limiting enzyme in 5-FU activation while dihydropyrimidine dehydrogenase (DPD) is a catabolic enzyme that inactivates 5-FU. Alterations in UMPK and DPD may therefore explain failure of 5-FU response in the absence of alterations in TS or p53. Transcription factors that regulate TS may also influence drug sensitivity. We have found that mRNA levels of the E2F family of transcription factors correlates with TS message levels and are higher in lung metastases than in liver metastases of colorectal cancers. Moreover, gene copy number of the E2F-1 gene appears to be increased in a significant number of samples obtained from metastases of colorectal cancer. We have also generated mutants of both DHFR and TS that confer resistance to MTX as well as 5-FU by random as well as site-directed mutagenesis. These mutants used alone or as fusion cDNAs of the mutants have proven to be useful in transplant studies where transfer of these mutant cDNAs to bone marrow cells have been shown to confer drug resistance to recipients. The fusion cDNAs of DHFR such as the DHFR-herpes simplex virus type 1 thymidine kinase (HSVTK) are also useful for regulation of gene expression in vivo using MTX as the small molecule regulator that can be monitored by positron emission tomography (PET) scanning or by optical imaging using a fusion construct such as DHFR-EGFP.
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PMID:Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase. 1208 58

Studies from our laboratory have shown that the folate-dependent enzyme, thymidylate synthase (TS), functions as an RNA binding protein. There is evidence that TS, in addition to interacting with its own TS mRNA, forms a ribonucleoprotein complex with a number of other cellular mRNAs, including those corresponding to the p53 tumor suppressor gene and the myc family of transcription factors. Using both in vitro and in vivo model systems, we have demonstrated that the functional consequence of binding of TS protein to its own cognate mRNA, as well as binding of TS to the p53 mRNA, is translational repression. Herein, we review current work on the translational autoregulatory control of TS expression and discuss the molecular elements that are required for the TS protein-TS mRNA interaction. TS may play a critical role in regulating the cell cycle and the process of apoptosis through its regulatory effects on expression of p53 and perhaps other cell cycle related proteins. Finally, the ability of TS to function as a translational regulator may have important consequences with regard to the development of cellular resistance to various anticancer drugs.
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PMID:Thymidylate synthase as a translational regulator of cellular gene expression. 1208 59

Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a novel antifolate/antimetabolite with activity in breast cancer and has well-defined molecular targets, including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. In a phase II trial in patients with T3-4, N0-2 breast cancer, expression of thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, p53, and c-erb-B2 (at the mRNA or protein level) is being examined before and 24 hours after the first dose of neoadjuvant pemetrexed and after three cycles of single-agent treatment to establish correlations of biomarker levels and changes with clinical outcome and toxicity. Full biomarker and clinical data are not yet available from this study; however, clinical responses to pemetrexed treatment have been observed in patients. Results of this trial should provide both an idea of the activity of neoadjuvant pemetrexed in breast cancer and information on biomarker association with clinical performance that can be used in the design of additional clinical studies to assess the predictive value of these markers.
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PMID:Pemetrexed: translational research in breast cancer. 1209 37


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