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)

Fifteen cases with very advanced and recurrent gastric carcinoma were treated by 5-FU plus cisplatin. Among them, 6 cases were responder (CR + PR) and 9 cases were nonresponder (NC). In order to select the responder, p53 protein status in the tissue obtained by endoscopical biopsy before chemotherapy was studied. The immunohistochemical method was by the avidin-biotin complex method using anti-p53 protein monoclonal antibody. One CR case showed negative p53 staining and 2 of 5 cases of PR cases exhibited positive p53 staining. The staining of all 9 NC cases was positive. Significantly high p53 protein overexpression in the nonresponder cases was indicated. In conclusion, our result suggested that the immunohistochemical method detecting p53 protein in the biopsy specimen may be useful to predict the effect by chemotherapy.
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PMID:[Association between p53 expression and chemosensitivity in advanced and recurrent gastric cancer]. 867 59

Sixteen patients with liver metastases from colorectal cancer were treated by continuous intraarterial chemotherapy of 5-FU and leucovorin. The regimen was that 500 mg/body of 5-FU with 30 mg/ body of leucovorin was administered continuously for 5 days followed by no medication for 16 days. The effect of this therapy was evaluated, and the relationship between this therapy and p53 overexpression was also studied. A complete response was obtained in 3 patients and a partial response in 3 patients; the overall response rate was 38%. The response rate was 56% in patients of more than 6 courses, 57% in patients with positive p53, and 20% in patients with negative p53. The three-year survival rate was 31%, and median survival was 18 months. Duodenal ulcer occurred in 2 patients due to extravascular dislocation of catheter. A high response rate and favorable prognosis were obtained by this therapy. Maintenance of catheter and a short administration period are current issues.
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PMID:[Continuous hepatic arterial infusion of fluorouracil with leucovorin for liver metastases from colorectal cancer]. 938 8

The role of p53 in modulating apoptosis has suggested that it may affect efficacy of anti cancer agents. For this reason, we have evaluated p53 alterations in 282 consecutive patients with infiltrating node-negative breast cancer who underwent primary surgery and were randomized either to CMF (Cyclophosphamide 400 mg/m2, Fluorouracil 400 mg/m2, and Methotrexate 40 mg/m2) or control arm (no adjuvant therapy) from 1980 to 1989. p53 alterations were analyzed by immunohistochemistry using DO7 MoAb, revealed by immunoperoxidase technique, and quantitated in term of percentage of positive cells. We observed a positive staining in 24% of the tumors. Among them, 10% had a positive staining in more than 75% of the cells. There was a highly significant association between the proportion of positive cells and histologic grade of the infiltrating ductal carcinomas (p<0.004). However, there was no association with age, tumor size, hormone receptor content, or vascular embolism. There was a trend but no significant relationship between positive staining and overall survival either in each arm of the trial or in the overall population. Interestingly, we observed a higher relative risk of local relapse after conservative therapy in the boosted area in the group of mutated p53 (RR=4.41; p<0.0005). We conclude that, in this node-negative breast tumor population, alteration of p53 cannot predict the response to the chemotherapy. However, it may represent a useful marker of risk of local relapse and of radio resistance.
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PMID:Is p53 a protein that predicts the response to chemotherapy in node negative breast cancer? 949 75

Vesnarinone (3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)- quinolinone), a quinolinone derivative, is an orally active inotropic agent used in Japan for the treatment of chronic heart failure. Recently, it has been reported that vesnarinone induces differentiation and apoptosis in certain types of leukaemia and solid tumour cells, and exhibits antitumour effect on several tumours xenografted in nude mice. In the present study, we examined the antitumour effect of vesnarinone in combination with radiation and conventional anticancer agents in nude mice xenografted with human gastric carcinoma, a poorly-differentiated adenocarcinoma, MKN-45 cell line which has a wild-type p53 gene. Vesnarinone treatment combined with radiation resulted in a higher antitumour activity compared with a single treatment with either vesnarinone or radiation alone. Further, vesnarinone treatment together with radiation and conventional anticancer agents including 5-FU and picibanil (an immunopotentiator) produced the highest antitumour effect compared with any other treatment. Additionally, the combination treatment induced marked differentiation and apoptosis of the tumour cells and an increase in the expression of p53 gene in the treated tumour cells. The results suggest that vesnarinone, in combination with radiation and the conventional antitumour agents, may be of clinical interest for treatment of certain types of gastric tumours.
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PMID:Enhancement of anticancer effects of radiation and conventional anticancer agents by a quinolinone derivative, vesnarinone: studies on human gastric cancer tissue xenografts in nude mice. 956 10

A 67-year-old man was diagnosed as having a type 3 advanced esophageal carcinoma by barium swallow and endoscopy. Biopsy specimens showed well-differentiated squamous cell carcinoma with positive immunostaining for p53, C-erb B-2 and negative for bcl-2. Two courses of chemotherapy using 5-FU, leucovorin and CDDP were performed before operation. Because no cancer cells were present in the surgical specimens, the effect was evaluated as grade 3. This neoadjuvant chemotherapy may be effective for esophageal carcinoma with a possible apoptosis mechanism.
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PMID:[A case report of esophageal carcinoma with grade 3 response by preoperative chemotherapy using CDDP/5-FU/LV]. 961 31

One of the most important clinical issues in cancer chemotherapy is the presence of intrinsic resistance or the appearance of acquired resistance against chemotherapy. As for intrinsic resistance, we had to perform direct chemo-sensitivity testing, or had to rely on the knowledge empirically acquired from randomized clinical trials. However, molecular or genetic markers associated with chemo-sensitivity have been reported recently. For example, inactivation of p53 or GML gene has been reported to be associated with chemo-resistance. Overexpression of topo-isomerase I has been reported to be associated with chemo-sensitivity to Topo I inhibitor. Overexpression of Thymidine Phosphorylase has been found to be associated with chemo-sensitivity to prodrug of 5-FU. By checking the status of such chemo-sensitivity markers prior to chemotherapy, it would be possible to predict the chemotherapeutic effect and even the necessity of the chemotherapy in the near future. In this article, we review the chemo-sensitivity markers reported so far, and methodology contributing to the discovery of new chemo-sensitivity markers. As a clinical study, 11 cases of ovarian cancer with high sensitivity to cisplatin-based chemotherapy and 29 cases of ovarian cancer with chemoresistance were analyzed by Comparative Genomic Hybridization (CGH). Copy number decrease in Xp, and copy number increase in 19q were observed in 13, 12 out of 29 resistant cases (45, 41%) and zero, 1 out of 11 sensitive cases (0, 9%), suggesting that -Xp and +19q were likely to be a genetic event associated with intrinsic drug-resistance (p = 0.006, 0.05, respectively). This effort should contribute to the discovery of new chemo-sensitivity and resistance markers.
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PMID:[Cancer-associated gene abnormalities and chemosensitivity]. 979 4

The authors carried out immunohistochemical and genetic research on the tumor suppressor protein p53 and H-RAS oncogene in oromaxillofacial neoplasms. The purpose was to verify, genetically, the presence of correlations between the degree of histopathological overexpression (per cent) of oncogenes and chemoresistance. The study was carried out on 15 patients with squamous cell carcinoma of the oromaxillofacial region, of equal histopathological grade (G2), who underwent neoadjuvant chemotherapy: cis-diaminodichloroplatinum (CDDP, 20 mg/m2 i.v. days 1-5) and 5-fluorouracil (5-FU 1000 mg/m2 continuous infusion, volumetric pump 2 ml/h, for 5 days). Restaging was carried out after three cycles of chemotherapy to evaluate clinical response. The p53 immunohistochemical study (clone DO-7) showed a pathological overexpression in 9/15 cases; whereas the genetic exam (PCR method, wild DNA) showed mutations in 5/15 cases, with individual corresponding percentages of 95%, 80%, 70%, 45% and 95%. The H-RAS immunohistochemical study (AB-1) (clone 235-1.7.1) showed a pathological overexpression in 12/15 cases; the genetic exam showed mutations in 9/15 cases, corresponding to, respectively, 90%, 35%, 10%, 20%, 77%, 90%, 85%, 25%, 75%. The response to the neoadjuvant chemotherapy was as follows: 2 partial responses (PR) (90%) in 1 tumor of the cheek and in 1 tumor of the soft palate, with global survival (GS) of, respectively, 18 and 15 months. 1 PR (75%) and 4 PR (55%) in 5 tumors of the gum, with GS of, respectively, 10, 6, 8 , 9 and 8 months. Two objective improvements (OI) in, respectively, 1 tumor of the floor of the mouth and 1 tumor of the gum, with GS of, respectively, 5 and 6 months. Three patients had stable disease (S) in 2 tumors of the tongue and 1 tumor of the gum, with GS of, respectively, 10, 7 and 7 months. Three patients had progression (P) in 2 tumors of the floor of the mouth and in 1 tumor of the cheek, with GS of, respectively, 8, 8 and 6 months. This study showed some correlation between genetic analysis and immunohistochemical investigation of 73.3% of cases for p53 and of 80% of cases for H-RAS (Chi-Square Test: p=0.3089). These data do not permit definition of the range of oncogene overexpression which corresponds to mutation, thus serving as a marker of chemoresistance. However, the cases studied confirm that, in regard to p53, there is a certain degree of correlation between absence of mutations and sensitivity to neoadjuvant chemotherapy.
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PMID:p53 tumor suppressor protein and H-RAS oncogene in maxillofacial tumors: immunohistochemical and genetic investigation, induction chemotherapy response and prognosis evaluation. 982 61

The prognostic value of tumoural epidermal growth factor receptor (EGFR), p53, thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) was analysed on 82 advanced head and neck cancer patients (71 men, 11 women; mean age 59). Induction treatment was cisplatin-5-FU +/- folinic acid (61 patients, Chem group) or concomitant cisplatin-5-FU-radiotherapy (21 patients, RChem group). EGFR (binding assay), p53 protein (Sangtec immunoluminometric assay), TS and DPD activities (radioenzymatic assays) were measured on biopsies obtained at time of diagnosis. Significant positive correlation was demonstrated between p53 and EGFR. In the RChem group, p53 was higher in non-complete responders (median 1.03 ng mg(-1)) than in complete responders (median 0.08 ng mg(-1)) (P = 0.057). Univariate Cox analyses stratified on treatment group showed that specific survival (33 events) was significantly related to T staging, p53 taken as continuous or categorial (below vs over 0.80 ng mg(-1)) variable, and EGFR (below vs over 220 fmol mg(-1)); survival increased when EGFR and p53 were below thresholds. Multivariate stepwise analysis including T staging, EGFR and p53 revealed that T staging and EGFR were independent predictors of survival; relative risks were 3.68 for T staging and 2.65 for EGFR. Overall, EGFR remained an independent prognostic factor when response to treatment and T staging were considered in the multivariate analysis.
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PMID:A multifactorial approach including tumoural epidermal growth factor receptor, p53, thymidylate synthase and dihydropyrimidine dehydrogenase to predict treatment outcome in head and neck cancer patients receiving 5-fluorouracil. 1020 6

Human head and neck squamous cell carcinoma A253 cells, which do not express p53 and p21 proteins, were engineered to stably express about 50-fold higher level of Bax protein (A253/Bax) than the mock-transfected (A253/vec) or parental cells. Using these cell lines, studies were carried out to evaluate the role of Bax in response to anticancer drugs and to study the associated mechanisms. A253/Bax cells exhibited a significant increase in in vitro sensitivity to various anticancer drugs, including tomudex (9.5-fold), SN-38 (13.8-fold), doxorubicin (7.9-fold), taxol (3.1-fold), 5-FU (2.7-fold), and 5-FU/LV (4.5-fold). Increased level of drug-induced apoptosis was observed in A253/Bax cells in a drug concentration-dependent manner. In untreated A253/Bax cells, Bax was expressed in a monomeric state. Treatment with tomudex induced the formation of Bax dimer in a drug concentration-dependent manner. Dimerization of Bax occurred only in mitochondria, while the cytosolic Bax was retained in the monomeric state. Low level of Bax dimerization was also detected in parental A253 cells following tomudex exposure. In addition, Bax dimer formation was associated with mitochondrial cytochrome c release and activation of caspases in A253/Bax cells. The data suggest that Bax overexpression increases drug response by enhancing drug-induced apoptosis. Furthermore, dimerization of mitochondrial Bax and downstream mechanisms are associated with drug-induced apoptotic cell death and increased drug sensitivity.
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PMID:Dimerization of mitochondrial Bax is associated with increased drug response in Bax-transfected A253 cells. 1048 65

Squamous cell carcinoma of the skin and melanoma are the rare progeny of precancerous lesions that usually remain stable or regress. For SCC the sequence appears to include TP53 mutant clones in normal skin; dysplasia; carcinoma in situ; and SCC. When such lesions are contiguous, their TP53 mutations are consistent with a single clonal lineage. The set of TP53 mutations in tumours is more restricted than in precancers, suggesting additional selection. Melanoma lies at the end of a continuum including mole, dysplastic naevus, radial growth melanoma and vertical growth. The genetics of melanoma is less clear. Basal cell carcinomas seem to arise without a precancer and contain mutations in TP53 and PTCH. Childhood sunlight exposure directs the location and frequency of precancers. For melanoma, its effects on intermittently exposed body sites are superimposed on the effect at sites chronically exposed. SCC precancers and tumours, BCC tumours and melanoma cell lines contain UV induced mutations. Sun exposed skin of normal individuals contains thousands of small clones of TP53 mutated cells. Predisposition to sunlight induced precancer is a multigenic trait involving factors such as hair and skin color, DNA repair proficiency and mole type and number. These each contribute a relative risk on the order of two to four. Familial predisposition to dysplastic naevi carries a larger risk. The cell of origin for melanoma is uncontroversial, and the proposed hair follicle origin of BCC is consistent with the presence of stem cells in the bulge region. The origin of SCCs and the arrangement of interfollicular stem cell compartments are less clear. Clonal expansion of the initial mutated cell may also be driven by sunlight. When a mutation confers apoptosis resistance, as TP53 mutations do, subsequent UV exposure will be more likely to kill normal cells than mutants. The latter can expand into a clone, only one cell of which need be mutated again. Immunosuppressant drugs may have the same effect as UV, facilitating the clonal expansion of precancers. In the absence of exogenous influences, mutant clones and precancers tend to regress. There is little evidence that regression of precancers is immunological, though regression of melanoma appears to be. The chemotherapeutic agent 5-FU causes regression of dysplasias by removing initiated cells, perhaps by enhancing apoptosis. In contrast, retinoic acid temporarily suppresses clonal expansion. Most sunscreens are mutagenic, with as yet unknown consequences. Mice develop dysplasias and SCCs after UV irradiation. Initiation and clonal expansion of dysplasias is UV driven, but conversion to SCC and subsequent growth involve spontaneous events. With chemical carcinogens mice develop papillomas that usually regress and thus are precancers. Tumour promotion yields abundant low risk papillomas that contain Hras1 mutations but rarely progress to SCC. High risk papillomas are infrequent but do convert to SCC, particularly if re-treated with mutagens. Conversion to SCC is associated with TP53 mutations. The mechanisms of multiple mutation and clonal expansion observed in human and mouse systems, respectively, are beginning to converge into a coherent understanding of precancerous events in skin.
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PMID:Skin precancer. 1048 24


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