Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nine human ovarian cancer cell lines that express wild-type (wt) or mutated p53 were used to evaluate the cytotoxicity induced by paclitaxel. The IC50 calculated in the five mutated p53-expressing cell lines was not different from the four wt p53-expressing cell lines. The introduction of wt p53, by using a temperature-sensitive mutant murine p53 or the human p53 under the control of a tetracycline-dependent promoter, did not change the cytotoxicity of paclitaxel as compared to mock-transfected cells. By using for each cell line the paclitaxel IC50, we found that these concentrations were sufficient to induce an increase in p53 levels in all of the four wt p53-expressing cells, whereas in the mutated p53-expressing cells, the levels were unaffected. This increase in p53 levels led to an increase in the mRNA and protein levels of p53 downstream genes (WAF1, GADD45, and bax). In none of the cell lines examined was paclitaxel able to induce apoptosis, evaluated by terminal deoxynucleotidyl transferase-mediated nick end labeling staining and filter binding assay at concentrations closed to the IC50. By increasing the concentration of paclitaxel in the filter binding assay, we could see fragmentation of DNA in the different cell lines. We conclude that the presence of p53 is not a determinant for the cytotoxicity induced by paclitaxel in human ovarian cancer cell lines. Differences in the activation of p53 downstream genes could be observed in wt versus mutated p53-expressing cells, but this does not account either for a differential induction of apoptosis or for a change in cytotoxicity induced by paclitaxel.
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PMID:p53 status does not affect sensitivity of human ovarian cancer cell lines to paclitaxel. 904 Nov 88

Antibodies against the p53 protein were measured with a sandwich-type enzyme-linked immunosorbent assay in blood samples preoperatively collected from 30 patients with ovarian cancer and 30 patients with endometrial cancer. Anti-p53 antibodies were detected in 33.3% of patients with ovarian cancer, comprising 22.2% of the 9 patients with stage I-II disease, 30.8% of the 13 patients with stage III disease, and 50.0% of the 8 patients with stage IV disease. Anti-p53 antibodies were found in none of the 4 patients with well differentiated tumors and in 38.5% of the 26 patients with moderately or poorly differentiated tumors. Among the 21 patients with stage III-IV disease, a complete clinical response to front-line platinum-based chemotherapy was obtained by 46.2% of the 13 patients without anti-p53 antibodies and 25.0% of the 8 patients with anti-p53 antibodies. Antibodies against the p53 protein were detected in only 6.7% of patients with endometrial cancer. The low incidence of anti-p53 antibodies in patients with endometrial cancer seems to suggest that the serum assay of these autoantibodies has a limited clinical relevance in the management of this malignancy. On the other hand in patients with ovarian cancer the incidence of serum anti-p53 antibodies is relatively high, and, moreover, it seems to increase with tumor stage and grade and seems to be associated with a lower response rate to chemotherapy. However, the small number of patients did not allow us to obtain statistically significant differences.
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PMID:Preoperative serum antibodies against the p53 protein in patients with ovarian and endometrial cancer. 904 15

We hypothesize that genomic instability plays an important role in causing specific types of p53 mutations in ovarian cancer. To test this hypothesis, 78 tumors were analyzed for p53 mutations with SSCP analysis of the entire open reading frame. At the same time, alterations in 10 microsatellite loci including di-, tri-, and tetranucleotide repeats were evaluated. Fourteen (26%) of all mutations were insertion/deletion mutations. All insertion/deletion mutations were associated with one of the following features: runs of purines or pyrimidines, repeats of short sequences, or palindromes. There was a strong association of generalized microsatellite instability with p53 in contrast to tumors with other types of mutations or wild-type p53 (P = 0.007). These characteristic p53 mutations appear to be caused by generalized genomic instability rather than to be the direct cause of genomic instability. These findings suggest the existence of additional novel DNA repair genes important to the carcinogenic process.
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PMID:Ovarian cancer genomic instability correlates with p53 frameshift mutations. 906 68

Loss of heterozygosity (LOH) on chromosome 17 is a frequent genetic alteration in breast cancer. To assess whether the location of potential tumor suppressor genes is compatible with the LOH pattern in individual tumors, we analyzed allele loss on chromosome 17 in 121 invasive ductal breast carcinomas and 16 benign breast tumors with 14 polymorphic microsatellite markers (4 on 17p and 10 on 17q). Fluorescent polymerase chain reaction (PCR) for typing microsatellites coupled with DNA fragment analysis in an automated DNA sequencer was applied. Frequencies of LOH varied from 29.4% (D17S1322) to 57.4% (TP53-Alu). No LOH could be detected in benign breast tumors. In 54 tumors the deletion patterns were consistent with the complete loss of 17p (n = 28), 17q (n = 9) or the whole chromosome 17 (n = 17). Five smallest regions of overlap (SROs) were identified in tumors with interstial deletion patterns. On 17p, two foci were detected affecting the TP53 locus and the hypermethylated in cancer I (HICI) region (17p13.3). On 17q, SRO1 was localized between markers THRAI and D17S855, centromeric to the breast/ovarian cancer gene BRCAI; SRO2 was flanked by markers AFM234 and NMEI, and SRO3 was centered between markers MPO and GH. Associations between LOH and histopathological characteristics were determined. Significant correlations were found between higher grade and loss of the TP53 gene (marker TP53, P = 0.019), loss of the BRCAI region (P < 0.009), LOH of marker AFM155 (P = 0.003) and marker NMEI (P = 0.026). For positive estrogen receptor status, only LOH of the THRAI marker correlated significantly, whereas highly significant correlations were determined between positive progesterone receptor and markers centromeric to the BRCAI region D17S250 (P = 0.00002), THRAI (P = 0.0006), and the intragenic BRCAI markers [D17S1322 (P = 0.021), D17S855 (P = 0.029)]. Results presented in this study identify five independent regions of chromosome 17 which are likely to contain potential tumor suppressor genes involved in the carcinogenesis of sporadic breast cancer.
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PMID:Patterns of allelic loss on chromosome 17 in sporadic breast carcinomas detected by fluorescent-labeled microsatellite analysis. 907 71

Antibodies against the P53 tumour suppressor gene product are present in the serum of many cancer patients, but with varying frequencies ranging from 0 to 30%. Approximately 15-20% of patients with ovarian carcinoma develop auto-antibodies against p53 that circulate in the serum. Since many ovarian cancer patients develop ascites during their disease, we speculated that p53 antigen and/or p53 auto-antibodies may be present in this biological fluid. Ninety-six ascites fluids from women with primary ovarian cancer and one from a patient with cancer of the breast, which metastasised to the ovaries, were analysed for p53 auto-antibodies. Seventeen ascites fluids (18%) contained auto-antibodies. For 30 of these patients, serum was also available. Auto-antibodies were present in both serum and ascites in 6/30 patients; 22 patients were negative in both ascites and serum; and 2 patients had auto-antibodies only in their serum. All 97 ascites fluids were also analysed for p53 antigen and 7 (7%) were positive. None of the 17 p53 auto-antibodies-positive ascites fluids were positive for p53 antigen suggesting that p53 auto-antibodies may interfere with p53 antigen detection by capturing the antigen. In total, 24 patients (25%) had either p53 auto-antibodies or p53 protein in their ascites fluid. These data demonstrate that p53 auto-antibodies and/or p53 protein are present in ascites and may have some value for tumour diagnosis, prognosis or monitoring.
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PMID:Detection of the TP53 tumour suppressor gene product and p53 auto-antibodies in the ascites of women with ovarian cancer. 907 10

The usefulness of adjuvant therapy in early ovarian cancer is a matter of controversy and there is a need for predictive methods to distinguish between low and high risk patients. Specimens from 95 early-stage ovarian cancer patients have been analysed for conventional clinical variables as well as for the biological markers--DNA content, MIB-1, p53, WAF-1--and correlated to survival. Prognostic significance achieved in univariate analysis could be improved by using a score based on several biological markers. Using a score based on DNA content, MIB-1, p53 and WAF-1, a significant predictor could be achieved with the aim of determining the postsurgical therapy. By using this tool, it is hoped that adjuvant therapy can be avoided for one-third of the patients with early-stage ovarian cancer.
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PMID:Biological malignancy grading in early-stage ovarian carcinoma. 907 54

Over the past 20 years ovarian cancer has provided a vivid illustration of the successes, failures and challenges for the medical oncologist. During that time the results of treatment have substantially improved; in the West of Scotland for example, for women aged under 55, 3-year survival rates have increased from 36% to 50%. One reason for this was probably the introduction of effective agents such as cisplatin in the mid-1970s and then carboplatin in the mid-1980s. The recent introduction of taxoids promises further improvement in the future. It is important to remember, however, that the best results will be obtained by an optimal organization for the delivery of treatment; national audit studies have shown that factors such as management in integrated clinics can have a major impact on outcome. Nevertheless, the majority of patients still die from the disease; when relapse occurs, clinical drug resistance eventually proves fatal despite further treatment. What are the fundamental mechanisms by which this resistance develops, and what means are available to attempt its circumvention? Factors involved could be described as pharmacological or cellular. Pharmacological resistance might best be addressed by increasing the doses of the drugs used, particularly, cis- or carboplatin. Three years ago we published the results of a randomized trial of 2 doses of cisplatin in 191 patients. At that stage a highly significant median survival advantage for the higher dose (100 mg/m2) of cisplatin was seen. However, a recent updated analysis with a median follow-up of 4 1/2 years shows a reduction in the survival benefit, with 4-year overall survival rates for high- and low-dose cisplatin of 32.4% and 26.6%, respectively. This suggests that a population of drug resistant ovarian cancer cells will eventually emerge despite the use of initial higher doses of cisplatin. A more dose-intensive approach is being pursued with carboplatin, and it seems clear that dose-increments over standard therapy of at least 4-fold will be necessary, to justify further randomized trials. Meanwhile, the alternative approach to delivering high drug concentrations, i.e. intraperitoneal (i.p.) chemotherapy, clearly merits further study, particularly in the light of a recently reported study in patients with minimal disease, which showed a significant survival benefit for i.p. cisplatin treatment. Cellular factors will probably prove to be crucial; studies using various cell lines suggest that multiple mechanisms are likely to be involved and these will need to be examined in relevant clinical material. After DNA damage induced by a range of cytotoxic agents has taken place in ovarian cancer cells, the key to sensitivity/resistance may well be the ability of these cells to engage the process of apoptosis. Several genes are involved in control of this process; these include the p53 gene, mutations of which have been linked to cisplatin resistance in our laboratory studies, as well as in clinical trials with carboplatin. We have also demonstrated an association in ovarian cancer cell lines between cisplatin resistance and microsatellite instability (indicative of defective mismatch repair) and the clinical relevance of this link is also being pursued. A thorough understanding of underlying mechanisms may lead to the rational development of therapeutic means for circumventing cisplatin-resistance in ovarian cancer; the emergence of new classes of drug such as taxoids as topoisomerase I inhibitors offers further promise of improvement in outcome in the next few years.
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PMID:Ovarian cancer, from the laboratory to the clinic: challenges for the future. 908 99

Ovarian cancer has been described in association with three autosomal dominant syndromes: familial site-specific ovarian cancer, familial breast and ovarian cancer, and the hereditary nonpolyposis colon cancer syndrome. It appears that most breast-ovarian and site-specific ovarian cancer families are explained by mutations in the BRCA1 tumor suppressor gene. Other genes associated with inherited susceptibility to ovarian cancer include BRCA2, p53, and the DNA mismatch repair genes.
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PMID:Hereditary ovarian cancer. 909 Apr 74

We tested the ability of synthetic peptides derived from p21(WAF1), fused to the internalization peptide sequence derived from Antennapedia, to inhibit the growth of cancer cells in two human ovarian cancer cell lines expressing wild-type p53 or not. Two fused peptides corresponding to p21(WAF1) regions 17-33 and 63-77 inhibited cell growth in both cell lines while the same peptides without the internalization sequence were inactive. The fused peptides prevented growth at concentrations which inhibited cyclin-dependent kinase 2 and cdc2 activity, thus demonstrating that the peptides act by mimicking the action of p21(WAF1) on kinases. This study illustrates the potential pharmacological use of small peptides fused with the Antennapedia internalization sequence in proliferative disorders. The approach may be extended to other diseases in which cell penetration of a peptide may be of therapeutic benefit. More stable drug-like molecules with better pharmacological properties could be designed based on the results obtained with peptides.
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PMID:p21WAF1-derived peptides linked to an internalization peptide inhibit human cancer cell growth. 910 43

We performed a mutational analysis of the p53 gene in matched samples of solid tumors and ascites from patients with ovarian cancer using the single-strand conformation polymorphism technique on exons 5-9 of the p53 gene on fresh and cultured material. We observed a discordance in the pattern of p53 mutations between the ascites and their solid tumor counterpart. In two cases, cancer cells from ascites carried a p53 mutation and the corresponding solid tumor cells retained the wild-type allele, while the opposite pattern was observed in two other patients samples. These results suggest that ovarian tumor cells within the ascites may not simply represent cells shed from the ovarian solid tumor and bear directly on gene therapy strategies in ovarian cancer.
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PMID:Discordance in p53 mutations when comparing ascites and solid tumors from patients with serous ovarian cancer. 914 13


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