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)

In vivo investigations on oncogenes and onco-suppressor genes may provide new findings on the potential carcinogenic effects of various cytostatic protocols inducing secondary tumours of the head and neck. Further surgeries are often necessary due to regional recurrence after the Cisplatin-supplemented BVM (Bleomycin, Vincristine, Methotrexate) protocol in the treatment of human head and neck tumours. Our earlier studies have illustrated the carcinogenic and mutagenic potential of Cisplatin. The effect of Cisplatin on the alteration of different onco- and suppressor genes has also been proven. Our present study aimed at investigating the early effects of the BVM and the CFu (Cisplatin, 5-Fluorouracil) protocols on early oncogene and tumour suppressor gene expressions in mice. Body weight equivalent amounts of cytostatics were administered intraperitoneally to 6- to 8-week-old, inbred, female CBA/Ca mice. Twenty-four, 48 and 72 hours after the treatment, RNA was isolated from the target organs and the quantitative expression of c-myc, Ha-ras and p53 genes were examined. The protocols caused detectable changes. A "short-term" in vivo test, the 24-hour examination of gene expression, is suitable for detecting early effects of carcinogen exposure. The alterations of gene expression, caused by the Cisplatin-containing protocol, draw attention to the probable role of Cisplatin in the development of regional recurrence and to the possibility of prevention.
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PMID:Early effects of different cytostatic protocols for head and neck cancer on oncogene activation in animal experiments. 1498 32

5-Fluorouracil (5-FU) is the chemotherapeutic drug of choice for the treatment of metastatic colorectal cancer, but resistance to 5-FU remains a major obstacle to successful therapy. We generated 5-FU-resistant derivatives of the HCT116 human colon cancer cell line by serial passage of these cells in the presence of increasing 5-FU concentrations in an attempt to elucidate the biological mechanisms involved in resistance to 5-FU. Two resultant resistant derivatives, HCT116 ResB and ResD, were characterized for resistance phenotypes, genotypes, and gene expression using cells maintained long-term in 5-FU-free media. Compared to parental HCT116 cells that respond to 5-FU challenge by inducing high levels of apoptosis, ResB and ResD derivatives had significantly reduced apoptotic fractions when transiently challenged with 5-FU. ResB and ResD cells were respectively 27- and 121-fold more resistant to 5-FU, had increased doubling times, and significantly increased plating efficiencies compared to the parental cells. Both resistant derivatives retained the wild-type TP53 genotype, TP53 copy number and CGH profile characteristic of the parental line. Alterations in gene expression in the resistant derivatives compared to the parental line were assessed using oligonucleotide microarrays. Overall, the 5-FU-resistant derivatives were characterized by reduced apoptosis and a more aggressive growth phenotype, consistent with the observed up-regulation of apoptosis-inhibitory genes (e.g., IRAK1, MALT1, BIRC5), positive growth-regulatory genes (e.g., CCND3, CCNE2, CCNF, CYR61), and metastasis genes (e.g., LMNB1, F3, TMSNB), and down-regulation of apoptosis-promoting genes (e.g., BNIP3, BNIP3L, FOXO3A) and negative growth-regulatory genes (e.g., AREG, CCNG2, CDKN1A, CDKN1C, GADD45A). 5-FU metabolism-associated genes (e.g., TYMS, DTYMK, UP) and DNA repair genes (e.g., FEN1, FANCG, RAD23B) were also up-regulated in one or both resistant derivatives, suggesting that the resistant derivatives might be able to overcome both 5-FU inhibition of thymidylate synthase and the DNA damage caused by 5-FU, respectively. Development of 5-FU resistance thus appears to encompass deregulation of apoptosis-, proliferation-, DNA repair-, and metastasis-associated regulatory pathways.
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PMID:Molecular characterizations of derivatives of HCT116 colorectal cancer cells that are resistant to the chemotherapeutic agent 5-fluorouracil. 1506 52

We have developed a novel gene therapy that targets genetic alterations in pancreatic cancer using oncolytic replication-selective adenoviruses in tumor cells. E1B-55kDa-deleted adenovirus (AxE1AdB) can selectively replicate in TP53-deficient human cancer cells but not cells with functional TP53. Consecutive injection with AxE1AdB markedly inhibited the growth of human pancreatic tumors in severe combined immunodeficiency disease mice. Furthermore, AxE1AdB displayed the ability to enhance gene expression as a virus vector. It is reported that uracil phosphoribosyl transferase (UPRT) overcomes 5-FU resistance. The therapeutic advantage of a replication-selective adenovirus that expresses UPRT (AxE1AdB-UPRT) was thus evaluated in an intraperitoneum-disseminated tumor model. Combined treatment with 5-FU and AxE1AdB-UPRT dramatically reduced the disseminated tumor burden without causing toxicity in normal tissues. We also clarified the process of AxE1AdB-inhibited tumor angiogenesis through the preserved E1A region: an adenoviral E1A protein binds to pRB, forcing the quiescent cell into the S phase. We constructed a double-mutant, replication-selective adenovirus (AxdAdB-3) containing a mutation in the RB-binding motif of the E1A region and a deletion of large E1B-55kDa. AxdAdB-3 swiftly induced cancer cell death in vitro and showed a potent antitumor effect in vivo. These results strongly suggest that AxdAdB-3 possesses a wider therapeutic potential than previously believed, given that most pancreatic cancers have abnormalities in both the TP53 and RB pathways.
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PMID:Oncolytic virotherapy as a novel strategy for pancreatic cancer. 1508 81

Consorcial projects focused on 5 cancer types, breast-, colorectal-, head and neck- and pediatric cancers, and malignant melanoma. Breast cancer studies revealed unique splicing mechanisms concerning BRCA1. In sporadic breast cancers the involvement of DNA-repair genes was proved to be dependent on the histological type. Bone-metastatic tumors have been characterized by decreased NM23 and increased c-met and p53 expressions. C-erbB2 genotype of the primary tumor was not maintained frequently in bone metastases. Application of DNA-microarray and quantitative PCR technologies improved the prediction of therapeutic sensitivity of breast cancers. Colorectal cancer studies revealed regional inhomogenities (clusters) in various geographical regions of Hungary, which were distinct in the case of colonic and rectal cancers. To increase the sensitivity of fecal blood test of colorectal cancer screening, a new double-antibody test was developed and tested in a large cohort of patients. Genetic analysis revealed that hypermethylation is a significant factor in microsatellite instability which, and plays a role in silencing of APC and E-cadherin genes as well. The Hungarian pattern of TS polymorphism was also determined and was correlated not only with the efficacy of 5-FU treatment but with the progression of the disease as well. Population-based studies have been carried out in head and neck cancer patients (HNC) and smokers as well to reveal the genetic background of increasing tumor incidence. These studies revealed polymorphism in XRCC1/3 methylation enzyme gene which has preventive role. Other studies found frequent local immunosuppression in HNC patients. Studies indicated that the success of irradiation in this cancer type is dependent on the anti-vascular effects. Pediatric cancer studies determined the parameters of neuroblastoma screening based on VMA measurements. New splice variants of the WT1 gene involved in the monitoring of MRD of ALL patients was also described this year. We also obtained positive experimental data for the retinoic acid therapy of ALL. Melanoma studies extensively used DNA-microarray technology which identified 4 melanoma-specific and 2 melanoma progression-specific genes. In experimental human melanoma xenograft models we have identified 3 anti-metastatic agents: low molecular weight heparin, 2-methoxyestradiol and erythropoietin-alpha, where the later was characterized by specific effects on tumor vasculature.
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PMID:[Report of the National Oncology Research and Developement Consortium, 2003]. 1510

Previous studies by our laboratory have reported that the T cell receptor (TCR) TCR/CD3 complex could mediate activation as well as apoptosis of T lymphocytes. Two tyrosine residues in the ITAM (immuno-receptor tyrosine-based activation motifs) of CD3 epsilon were required for apoptosis signalling of Jurkat T lymphocytes. Stable cell lines TJK and T3JK produced from CD8(-) Jurkat T lymphocytes by transfection with wild-type and mutant CD8 epsilon (fusion of the extracellular and transmembrane domains of human CD8 alpha to the intracellular domain of mouse CD3 epsilon), were used with CD8(-) Jurkat T lymphocytes for studying the role of single intact CD3 epsilon. 5-Fluorouracil (5-FU), a chemotherapeutic drug can induce cell death of many tumour cell lines. In the present experiments, we examined the expression of caspase-3, p53 and Bid in the three cell lines induced by 5-FU and/or anti-CD8 antibody. We found high expression of p53 during activation-induced cell death of TJK cells mediated by anti-CD8 antibody and apoptosis of TJK and T3JK induced by 5-FU, implicating p53 involvement in apoptosis of leukemia cells induced by anti-CD8 antibody and 5-FU. We also detected the active form of caspase-3 and Bid in apoptotic leukemia cells after treatment with 5-FU and/or anti-CD8 antibody, indicating that the drug and antibody induced cell death through caspase-3 and the signal pathway may involve the Bcl-2 protein family. Our results showed that combined treatment with 5-FU and anti-CD8 antibody could enhance the rate of apoptosis induced by 5-FU or anti-CD8 antibody through increased expression of p53 and by promoting activation of caspase-3 and Bid. This suggests that the combination of 5-FU and anti-CD8 antibody may play an important role in inducing apoptosis of leukemia cells.
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PMID:5-Fluorouracil enhances apoptosis sensitivity of T lymphocytes mediated by CD3 epsilon. 1512 84

To evaluate the effect of HPV16 E6/E7 on drug sensitivity, primary human OSE cells were infected with HPV16 E6/E7 expressing retrovirus and then exposed to chemotherapeutic agents. Apoptosis induced by mitomycin C was dose-dependent in both primary OSE and E6E7/OSE cells. E6E7/OSE cells were more sensitive to mitomycin C than parental OSE cells. HPV16 E6/E7 also sensitized OSE cells to 5-FU and its derivative 5-FUdR, but only at low doses. This phenomenon was also observed in cervical cancer cells and was independent of thymidylate synthase, a target of thymine and thymidine analogues. We conclude that HPV16 E6/E7 specifically modulates the activity of 5-FU and 5-FUdR, and confers OSE cells hypersensitivity to low-dose but not high-dose 5-FU and 5-FUdR. Molecular analysis indicates that induction of p53 and p21, and suppression of pRB are associated with apoptosis induced by 5-FUdR and may partly explain the hypersensitivity of E6E7/OSE cells to low-dose 5-FUdR.
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PMID:The HPV16 E6/E7 oncogene sensitizes human ovarian surface epithelial cells to low-dose but not high-dose 5-FU and 5-FUdR. 1520 28

Artemisinin (AR) is a widely used antimalarial drug. Recently, additional uses for AR as an anticancer drug were discovered. Using TUNEL, immunohistochemistry (IHS) markers and flow cytometry techniques, we evaluated the effect of AR and 5-FU on HPV 16 immortalized and transformed human gingival epithelial (IHGK) cells. The results of TUNEL showed that AR-treated IHGK cells consisted of 82% positive cells, while 5-FU-treated cells consisted of 18% positive cells. The IHS markers demonstrated positive staining with Bax p53, CD40 and CD40L in AR-treated cells and negative staining with Bcl-2. 5-FU-treated cells demonstrated a profile similar to AR but with less intensity. Cell cycle by flow cytometry results showed that only 5-FU-treated cells demonstrated a significant S-phase rate increase to 45%. In conclusion, our results indicate that AR is cytotoxic to transformed oral epithelial cells through apoptosis, while 5-FU is cytotoxic primarily through cell toxicity.
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PMID:Artemisinin: an alternative treatment for oral squamous cell carcinoma. 1533 Jan 55

The global effects of 5-fluorouracil (FU) on cervical carcinoma cells were analyzed using an efficient proteomic method. More than 50 proteins showed a significant change in 5-FU-treated cervical carcinoma cells compared to control cells. Among them, 34 proteins have been identified by employing two-dimensional gel electrophoresis and MALDI-TOF-MS using peptide mass fingerprinting. In results, 22 proteins were upregulated (CIDE-B [cell death-inducing DFFA-like effector B], caspase-3, caspase-8, Apo-1/CD95 (Fas), etc.) and 12 proteins were downregulated (mitotic checkpoint protein BUB3, myc proto-oncogene protein [c-myc], src substrate cortactin, transforming protein p21A, etc.) by 5-FU treatment in HeLa cervical carcinoma cells as determined by spot volume (P <0.05). Our experiments showed that 5-FU engaged the mitochondrial apoptotic pathway involving cytosolic cytochrome c release and subsequent activation of caspase-9 and caspase-3 as well as the membrane death receptor (DR)-mediated apoptotic pathway involving activation of caspase-8 with an Apo-1/CD95 (Fas)-dependent fashion. In addition, we could observe reduction of HPV-18 E6/E7 gene expression and activation of p53, pRb, and p21waf1 proteins by 5-FU treatment in HeLa cervical carcinoma cells. In conclusion, we suggest that 5-FU suppresses the growth of cervical cancer cells not only by antiproliferative effect but also antiviral regulation. Our findings may offer new insights into the mechanism of anticancer effect affected by 5-FU treatment in cervical cancer cells and its mode of action.
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PMID:Proteomic analysis of antiproliferative effects by treatment of 5-fluorouracil in cervical cancer cells. 1558 35

It was the objective to determine in this retrospective study whether thymidylate synthase (TS), p53, bcl-2, Ki-67 and p27 in Dukes' stage B and stage C (AJCC/UICC stage II and III) colorectal adenocarcinoma were predictive of disease-free survival (DFS) and overall survival (OS). Paraffin-embedded specimens from 103 patients with colorectal cancer, treated with surgery between October 1994 and September 1999, were examined for TS expression, p53, bcl-2, Ki-67 and p27 using immunohistochemistry; 51 cases were Dukes' stage B and 52 cases were Dukes' stage C disease. Adjuvant 5-FU-based chemotherapy was given to all patients, while 31 having rectal malignancy also received pelvic radiotherapy. Data were associated with the recurrence rate and survival. With a median follow-up of 5 years, 38 patients (36.8%) developed recurrence and as many patients (36.8%) died. TS was overexpressed in 16 cases (15.6%), p53 nuclear oncoprotein accumulation in >10% of cells occurred more frequently [61 of 103 cases (59.3%)], positive expression of bcl-2 protein in >10% of cells was observed in 41 of 103 cases (39.9%), 57 patients (55.4%) showed immunohistochemical expression of Ki-67 and there were 75 cases (72.9%) with p27 accumulation. The pathological stage was the only independent prognostic factor for DFS (p = 0.042). Sex, as well as age and biological prognostic factors, had no significant impact value on DFS and OS. A multivariate analysis of OS demonstrated that stage C, p53 negative and Ki-67 positive were associated significantly with an unfavorable outcome and a worse median OS (p = 0.035 and t ratio = 2.48). Some biological characteristics such as p53 and Ki-67 status may provide useful prognostic information in addition to the classical clinicopathological parameters. However, further studies are needed to clarify the value of adopting biological prognostic factors into clinical practice.
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PMID:Thymidylate synthase expression, p53, bcl-2, Ki-67 and p27 in colorectal cancer: relationships with tumor recurrence and survival. 1562 89

5-Fluorouracil (5-FU) and capecitabine alone and in combination with irinotecan/oxaliplatin are clinically active in the treatment of colorectal and other solid tumors. Studies of the antitumor activity and toxicity of capecitabine or irinotecan alone and in combination with each other, were compared with 5-FU and raltitrexed in human tumor xenografts of colorectal and squamous cell carcinoma of the head and neck using clinically relevant schedules. Antitumor activity and toxicity were evaluated in nude mice bearing human colon carcinomas of HCT-8 and HT-29 and in head and neck squamous cell carcinomas of A253 and FaDu xenografts using the maximum tolerable dose of single-agent capecitabine, 5-FU, or raltitrexed, or each of the drugs in combination with irinotecan. Mice were treated with capecitabine and irinotecan alone or in combination using 2 different schedules: (1) capecitabine orally once a day for 7 days and a single dose of irinotecan (50 mg/kg intravenously [I.V.]), with each drug alone or in combination, and (2) capecitabine orally 5 days a week for 3 weeks and irinotecan 50 mg/kg (I.V. injection) once a week for 3 weeks, with each drug alone or in combination. For comparative purposes, the antitumor activity of single-agent capecitabine, 5-FU, or raltitrexed, or each drug in combination with irinotecan was carried out at its maximum tolerated dose (MTD) using a 3-week schedule. Results indicated that HT-29 and A253 xenografts were de novo resistant (no cure) to capecitabine and irinotecan alone at the MTD, whereas HCT-8 and FaDu xenografts were relatively more sensitive, yielding 10%-20% cures. The combination of irinotecan/capecitabine was much more active than either drug alone against all 4 tumor models. The cure rates were increased from 0 to 20% in A253 and HT-29 xenografts and from 10%-20% to 80%-100% in HCT-8 and FaDu tumor xenografts, respectively. Irinotecan/capecitabine had clear advantage over irinotecan/5-FU and irinotecan/raltitrexed in efficacy and selectivity in that they were more active and less toxic. The extent of synergy with irinotecan/capecitabine appears to be tumor-dependent and independent of the status of p53 expression. The potential impact of the preclinical results on clinical practice for the use of these drugs in combination needs clinical validation.
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PMID:Synergistic antitumor activity of capecitabine in combination with irinotecan. 1566 39


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