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)

Few studies have examined cell proliferation or p53 immunoreactivity in myxopapillary ependymomas. This study retrospectively examines tumor MIB-1 and p53 immunohistochemical features in 14 patients (eight women, six men; age range, 12-69 yr; median, 32 yr) with myxopapillary ependymoma. Their preoperative symptoms lasted from 2 months to 18 years (median, 12 mo) and most commonly involved lower back pain. The tumor was in the lumbar spinal cord region in 12 patients, the sacral cord in 1, and both the lower thoracic and upper lumbar cord in 1. In three patients, cerebrospinal fluid protein levels were markedly elevated, with negative cytologic results. Thirteen patients underwent a gross total resection. All of the tumors demonstrated histologic features diagnostic of myxopapillary ependymoma. Four cases had focal, prominent, nuclear pleomorphism. From 1 to 5 mitotic figures per 10 high power fields were identified in four tumors. There was no vascular proliferation or necrosis. Nine patients are alive at last known follow-up with no evidence of tumor (median, 36 mo); four are alive with residual tumor (median, 40 mo); and one died after 74 months (tumor status unknown). Eleven patients received adjuvant radiation and/or chemotherapy. Six experienced at least one tumor recurrence at intervals of 20 to 132 months. MIB-1 indices on the initial tumor resection ranged from 0 to 5.5 (median, 0.9) in 12 cases. In three patients with recurrent tumor, MIB-1 indices were higher in the initial tumor in two cases and lower in one. p53 Immunostaining of 13 tumors showed rare positive-staining tumor cell nuclei. The conclusions are that myxopapillary ependymomas grow slowly; that MIB-1 labeling indices are unreliable predictors of tumor recurrence; and that the lack of p53 immunostaining in most myxopapillary ependymomas in this series suggests that this gene might not play a significant role in the pathogenesis of these tumors.
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PMID:Myxopapillary ependymomas: a clinicopathologic study of 14 cases including MIB-1 and p53 immunoreactivity. 911 Feb 91

Our purpose was to evaluate the utility of clinicopathological and biological markers prior to treatment in predicting the immediate response to chemotherapy in cervical and endometrial adenocarcinomas. Twelve patients with locally advanced cervical adenocarcinomas and 16 patients with endometrial adenocarcinomas received intraarterial neoadjuvant chemotherapy (NAC) consisting of cisplatin and doxorubicin before surgical resection. The decrease in tumor volume on magnetic resonance imaging (MRI) ([tumor volume before NAC - tumor volume after NAC]/tumor volume before NAC x 100) and the histologic response to NAC were assessed. Five factors prior to NAC (nuclear grade, pretreatment tumor volume, PCNA index, p53 protein expression, and DNA ploidy) were analyzed for correlation with the decrease in tumor volume and histologic response in cervical and endometrial adenocarcinoma, respectively. In cervical adenocarcinoma, patients with higher PCNA index tumor (> or = 40.2%) showed a significantly greater decrease in tumor volume than those with lower PCNA index (P < 0.05). In patients with endometrial adenocarcinoma, those with a smaller tumors (< 30.3 cm3) showed a significantly greater decrease than those with a larger tumors (P < 0.001). Tumors with higher PCNA index (> or = 31.5%) and negative p53 protein expression appeared to respond better than other tumors, but the difference was not statistically significant. Nuclear grade and DNA ploidy were not correlated with decrease in tumor volume either in cervical adenocarcinoma or in endometrial adenocarcinoma. Four cases of effective histologic response (2 complete responses [no microscopic residual tumor] and 2 marked responses [no macroscopic residual tumor]) were noted only in patients with endometrial adenocarcinoma who had a smaller tumor, higher PCNA index, and negative p53 protein expression. Pretreatment tumor volume and PCNA index were the only significant predictive factors (P < 0.05). Results suggest that the PCNA index in cervical and endometrial adenocarcinomas and the pretreatment tumor volume in endometrial adenocarcinoma appeared to be potentially useful in predicting the immediate response to the chemotherapy.
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PMID:Decrease in tumor volume and histologic response to intraarterial neoadjuvant chemotherapy in patients with cervical and endometrial adenocarcinoma. 915 35

The use of chemotherapy as primary treatment in early and locally advanced breast cancer is rising. As a result, many resected tumors were exposed to cytotoxic drugs in vivo. To study resulting histopathologic changes, we examined 61 patients with locally advanced stage III breast cancer who had been treated with a standardized neoadjuvant polychemotherapy regimen before undergoing surgical resection 3 months later. Matched pairs of pre- and posttherapy breast tissue were evaluated for morphologic changes in the residual malignant and benign breast tissue compartment. A potential correlation between changes and the original p53 immunophenotype was examined as well. In 11 cases (18%), complete pathologic remission with no residual tumor in the mastectomy specimen was achieved. This response was not correlated to the original p53 status. The remaining 50 cases showed residual tumor. The most prominent histologic change was an increase in nuclear atypia of tumor cells (51% of the cases). This effect was independent of the presence or absence of nuclear p53 accumulation in the pre-treatment specimens. Nuclear atypia was frequently accompanied by tumor cell enlargement (in 49% of the cases). Most commonly, a tumor with relatively small cells presented with large epithelioid apocrine features after treatment. In 6 cases (13%), the mitotic rate decreased significantly, while in 12 cases (26%) the mitotic rate increased after chemotherapy. Elston histogrades remained unchanged in 70% of the cases but increased in 17% and decreased in 13%, mainly due to changes in mitotic rates. Extensive tumor cell vacuolization, a common change seen after radiotherapy, was a minor finding but was seen focally. Within the non-malignant compartment, lobular atrophy with hyalinization and minimal epithelial atypia of lobules and ducts were common. We conclude that changes in residual tumor and normal breast are common following systemic cytotoxic therapy. As neoadjuvant chemotherapy becomes mainstream management for locally advanced breast cancer, pathologists are required to recognize treatment induced changes. For correct histopathologic assessment, therapy induced morphologic alterations need to be distinguished from tumor-intrinsic morphologic features.
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PMID:Morphologic effects of neoadjuvant chemotherapy in locally advanced breast cancer. 919 4

Lung cancer is epidemic and lethal throughout the world. Overall survival is estimated to be 13% at 5 years despite treatment. The use of chemotherapy in small-cell lung cancer (SCLC) is established, but it is less active against non-SCLC (NSCLC). Since 98% of SCLC cases are associated with heavy smoking and present at a median age of 60-65 years, the application of dose-intensive therapy to lung cancer patients may be complicated by underlying smoking-related comorbidity and an enhanced risk for secondary smoking-related malignancies. The strategies of intensifying induction therapy, multicycle dose-intensive combination therapies, chest radiotherapy, and stem cell purging for both SCLC and NSCLC are discussed herein. Limited data regarding high-dose therapy for NSCLC have been reported. In SCLC, excellent and immediate palliation is achieved through the use of combination chemotherapy. However, by 2 years, only 20-40% of limited-disease-(LD) and < 5% of extensive-disease stage (ED) patients remain alive. Regimens developed using the many established agents produce similar short- and long-term outcomes, an observation that suggests that many of our systemic agents eradicate the same tumor subpopulation but fail to abolish a central core of tumor stem cells, presumably enriched for heterogeneous in vivo resistance mechanisms. The identification of these minimal residual tumor (MRT) cells and systematic evaluation of their biologic characteristics may guide strategies to target these cells specifically; such strategies may include modification of chemotherapy, tumor vaccination, or other forms of biologic therapy, such as replacement of RB, 3p, and/or p53 function; interference with autocrine or paracrine growth loops; or immunologic therapy [interleukin (IL)-2, IL-12, immunotoxins, and tumor vaccines], which would be most effective in the setting of MRT. To this end the detection of heterogeneity and analysis of patterns of coexpression of various markers form the thrust of our MRT detection program. At the Dana-Farber Cancer Institute and Beth Israel Hospital we performed stem-cell autografts in > 40 patients with LD SCLC and > 25 patients with ED SCLC who were in first response to conventional-dose therapy comprising high-dose combination alkylating agents. Approximately 80% of our patients were in or near complete response after initial chemotherapy. At a minimal follow-up of 23 months (to as long as 10 years) after completion of high-dose chemotherapy in our original trial, 52% of the patients remain disease-free. Of the ED or extrapulmonary patients, approximately 20% remain progression-free at > 2 years after high-dose therapy. Local regional recurrence represents about 50% of all relapses. Thus, the roles of thoracic radiation dose intensity and purification of stem-cell autografts are being evaluated in ongoing trials. It is hoped that a cooperative phase III trial testing the concept of dose intensification will begin soon.
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PMID:Dose-intensive therapy in lung cancer. 927 37

Previous studies have indicated that transfer of wild-type (wt) p53 cDNA into cancer cells can suppress the tumor phenotype in vitro and in vivo. In this study we examined the effects of wt p53 transduction in the human cancer cell line H-358 (that bears a homozygous deletion of p53) using a novel recombinant adeno-associated viral vector engineered to express wt p53 (rAAVp53). Western blot analysis demonstrated the expression of wt p53 in H-358 cells following infection with rAAVp53. Furthermore, rAAVp53 inhibited the growth of the neoplastic cells and also mediated cytotoxicity. Cell cycle analysis of rAAVp53-infected cells showed a significant increase in the percentage of cells arrested at the G1-S checkpoint. H-358 cells infected with rAAVp53 underwent apoptosis as demonstrated by the morphological appearance of DAPI-stained nuclei. Direct injection of rAAVp53 into H-358 tumors implanted subcutaneously in immunodeficient nu/nu mice inhibited tumor growth completely in three of the five animals tested. Mock-infected and rAAV control treated tumors showed no growth inhibition. In situ staining in nu/nu mice detected the presence of wild-type p53 protein in residual tumor cells following rAAVp53 administration. The impressive in vivo efficacy of the rAAVp53 suggests a bystander effect. We conclude that rAAV may be effective as a gene transfer vector in the delivery of p53 to cancer cells.
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PMID:Cancer gene therapy using a novel adeno-associated virus vector expressing human wild-type p53. 928 68

Paraffin sections (n = 168, 27 benign, 16 low malignant potential [LMP] and 125 malignant tumours) from epithelial ovarian tumours were evaluated immunohistochemically for expression of retinoblastoma gene product (pRB) and p53 protein, and the relationship among pRB, p53 and cyclin-dependent kinase inhibitor 2 (CDKN2) gene product p16INK4A (p16) was analysed, following our previous study of p16. Forty-one percent of the benign, 50% of the LMP and most (71%) of the malignant tumours showed high pRB expression. High expression of pRB (>50% pRB-positive cells) significantly correlated with non-mucinous histological subtypes. Reduced pRB expression, substage and residual disease were significant predictors for poor prognosis in stage I patients. All the benign and most of the LMP (81%) tumours were in either the p53-negative or low p53-positive category, but nearly half of the malignant tumours had high p53 expression. High p53 accumulation was found in non-mucinous, high grade and late stage tumours. For well-differentiated carcinomas, high p53 expression was a predictor of poor prognosis. However, even though high p53 expression was not associated with histological subtype, stage or the presence of residual disease, high p53 expression was not an independent predictor when all clinical parameters were combined. For all ovarian cancers, a close correlation was found between high p53 and high p16 expression. The relationship between the expression of pRB and p16 depended on tumour stage. In stage I tumours, high pRB was associated with low p16 reactivity. On the other hand, most advanced tumours showed both high pRB and high p16 reactivity.
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PMID:Reduced expression of retinoblastoma gene product (pRB) and high expression of p53 are associated with poor prognosis in ovarian cancer. 929 30

Expression of mdm-2 mRNA was measured in 90 ovarian-cancer tissue specimens using the S1 nuclease assay, to investigate a possible association between MDM2 expression and prognosis. mdm-2 mRNA expression was an independent prognostic factor for patients with primary ovarian cancer, FIGO (International Federation of Gynecology and Obstetrics) stages III and IV (n = 57), who all received chemotherapy with carboplatin or cisplatin and cyclophosphamide. Median survival time for patients (FIGO stages III and IV) with no detectable expression of mdm-2 mRNA (n = 14) was 171 days, as compared with 839 days for patients (n = 43) with detectable mdm-2 mRNA (p = 0.0194; log-rank test). However, no association between mdm-2 mRNA expression and survival was observed for patients with FIGO stages I and II who did not receive chemotherapy. mdm-2 expression was not associated with FIGO stage, residual disease, histologic grade and type. Our results suggest that mdm-2, which is known to disrupt p53 function, sensitizes ovarian-cancer cells to cisplatin/cyclophosphamide, possibly by inhibition of p53-mediated G1 cell-cycle arrest and p53-stimulated nucleotide-excision repair.
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PMID:mdm 2 mRNA expression is associated with survival in ovarian cancer. 929 35

Genetic alterations in the p53 tumor suppressor gene are common in human colorectal cancers, occurring in approximately 70% of tumors. In vitro studies have shown that wild-type p53 is involved in controlling cell cycle checkpoint functions and apoptosis involved in the cytotoxic response induced by ionizing radiation and several anticancer chemotherapeutic agents. Wild-type p53 protein can transcriptionally activate the WAF gene, which encodes a cyclin-dependent kinase inhibitory protein, p21WAF1/C1PI protein, and transcriptionally repress the bcl-2 gene, which encodes an inhibitor of apoptosis. To learn more about the in vivo relationship between p53 protein and the expression of p21WAF1/C1PI and bcl-2 proteins in human colorectal cancers treated with radiation therapy, we examined the expression of these proteins by immunohistochemistry in pre-irradiated biopsy specimens and surgical specimens with residual tumor of 27 patients with colorectal carcinoma. Cell proliferation was measured using Ki-67 expression in the tumor cells. The p53 protein was not detected in normal colorectal mucosa, but it was expressed in 21 of 27 (78%) of pre-irradiated tumor samples and in 19 of 27 (70%) of post-irradiated tumors. Expression of the bcl-2 protein in normal colorectal mucosa was confined to the basal epithelial cells of the crypts. Diffuse bcl-2 staining was detected in tumor cells in 13 of 27 (48%) of pre-irradiated samples and in 14 of 27 (52%) of post-irradiated samples. p21WAF1/C1PI expression was detected in 14 of 27 (52%) of pre-irradiated samples but only in 7 of 27 (26%) of post-irradiated samples. No inverse relationship between expression of p53 protein and abnormal bcl-2 expression was apparent. p21WAF1/C1PI was expressed in most nonproliferating Ki-67-negative epithelial cells at the apical tips of the crypts in normal colorectal mucosa, but not in proliferating Ki-67-positive cells of adjacent adenomatous mucosa. An inverse relationship between Ki-67 and p21WAF1/C1PI expression was observed in normal colorectal mucosa and adjacent adenomatous mucosa. After radiation therapy, p53 protein accumulation did not change among residual tumors in 18 cases (three of which were initially negative and remained negative); in four cases there was a significant increase, and five cases had a substantial decrease of p53 expression. Aberrant bcl-2 expression is not correlated with expression of p53 and does not increase significantly in post-irradiated tumor cells. p21WAF1/C1PI expression is markedly reduced in tumor cells that survive radiation therapy.
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PMID:The role of p53, p21WAF1/C1PI, and bcl-2 in radioresistant colorectal carcinoma. 934 26

A decade of advances in understanding of the molecular basis of sporadic and familial cancers has combined with developments in mammalian gene transfer technology to stimulate intensive research into the potential applications of somatic gene therapy for cancer. Somatic gene immunotherapy is already in progress to stimulate and direct the natural targeting capabilities of the immune system against the threat of disseminated residual disease. The association of a plethora of mutated tumor suppressor genes (p53, p16 BRCA1, BRCA2) with diverse cancers has also highlighted the potential of somatic gene therapy with wild-type versions of suppressor genes as an anti-cancer therapeutic modality either in its own right or in synergistic association with traditional anti-cancer therapies. The methodologies for gene transfer technology range from direct intravenous injection of naked modified DNAs to intravenous injection of liposome-encapsulated DNAs or microsphere-bound DNAs. Recombinant retroviral and adenoviral vectors have natural transfection capabilities and display tropism for particular tissues that are of selective advantage against particular cancers. Liposomes display very high efficiencies of gene transfer with the advantages of successful transfer to a wide range of tissue types but their widespread systemic distribution offers problems in relation to selective targeting of tumor cells. The challenges to current gene transfer processes are much the same as that of other anti-cancer therapies: achieving selective targeting of cancer cells whilst optimizing dosages and minimizing the risk of collateral damage to healthy tissues.
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PMID:The basis for somatic gene therapy of cancer. 941 90

Evolving trends in the management of rectal cancer have focused on organ preservation, improved quality of life, and survival of patients. A significant shift is underway in our thinking about what constitutes the true rectum and defining the "proximal" and "distal" segments of the rectum. Tumor mobility remains a dominant prognostic factor in patient selection and choice of surgery. A clinical staging with tumor location in the rectum provides a logical algorithm for treatment decision making with either chemoradiation therapy or surgery as initial treatment of choice. Current rectal cancer management has largely focused on postoperative adjuvant radiation strategies with improvement reported for T3 and N+ cases. Recent data from Europe suggests that preoperative radiation has a significant advantage over surgery alone or postoperative treatment. This appears to be borne out by institutional studies of high-dose preoperative radiation (>45 Gy) in the United States. Aggressive preoperative combined chemoradiation has also led to significant downstaging of cancer with pathological complete response rates of 20% to 30%. This offers new options for surgical management of residual disease with endocavitary radiation or local excision. The development of new agents Gemcitabine, paclitaxel, and CPT-11 may also prove beneficial. New treatment strategies need to be coordinated with evolving knowledge of the biological behavior of the tumor based on its genetic fingerprints. c-Ki-ras and C-myc mutations have been implicated in tumor initiation and progression. A number of other tumor suppressor genes, APC gene, p53, and DCC have also been implicated in colorectal tumor carcigenesis. The modification of biological behavior by mutations in these genes is currently under study. This may guide new treatment strategies significantly reducing the death rates from rectal cancer and improving functional results of treatment.
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PMID:Critical issues in the evolving management of rectal cancer. 942 68


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