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)

Drug resistance is a major problem in patients with small cell lung cancer; in fact, most die of resistant disease, despite an initial response. Several markers of drug resistance have been described in preclinical models, but the mechanism of drug resistance in lung cancer patients remains unknown. The objective of this study was to evaluate the role of the expression of a number of markers of drug resistance, proliferation, and apoptosis in relation to response to chemotherapy and survival in patients with small cell lung cancer. Tumor samples were derived from 93 previously untreated patients who were randomized in a Phase III study to receive cyclophosphamide, epirubicine, and etoposide or cyclophosphamide, epirubicine and vincristine alternating with carboplatin and etoposide. Paraffin-embedded samples, derived from the primary tumor site prior to chemotherapy, were analyzed by immunohistochemistry for expression of markers implicated in drug resistance [topoisomerase (topo) IIalpha, topo IIbeta, and multidrug resistance-associated protein], apoptosis (p53, p21, and bcl-2), or proliferation (Ki67). Response prediction was analyzed by chi2 test and logistic regression analysis; overall and disease-free survival curves were compared by log-rank test and Cox regression analysis. Shorter survival was observed in patients with extensive disease (P = 0.037) and poorer performance status (P = 0.028) and in patients whose tumors expressed high topo IIalpha levels (P = 0.01) and high Ki67 (P = 0.024). By multivariate analysis, the following factors were found to be predictive for worse survival: high expression levels of topo IIalpha, Ki67, and bcl-2; male sex; and extensive disease. High topo IIbeta expression was found to be predictive for lower overall and complete response rate. No relationship between apoptotic pathway markers or MRP and response to chemotherapy was observed. In conclusion, high expression of topo IIalpha was predictive of worse survival, and high expression of topo IIbeta was predictive of lower response rates. Furthermore, lower survival probability was observed in patients with bcl-2-positive tumors. Immunohistochemical assessment of these markers in diagnostic biopsies may give important prognostic information and may help selecting patients in the worse prognostic categories for new therapeutic strategies.
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PMID:Expression of DNA topoisomerase IIalpha and topoisomerase IIbeta genes predicts survival and response to chemotherapy in patients with small cell lung cancer. 1047 85

Mutations in the p53 tumor suppressor gene have been demonstrated to be one of the most frequent genetic abnormalities in human cancers. Previous studies have shown that the frequency of p53 mutations is significantly higher in small cell lung cancer than in non-small cell lung cancer. However, this conclusion was based in large part on data derived from tumor cell lines and from studies with relatively small sample sizes and biased gender populations. To determine the mutational frequency in the p53 tumor suppressor gene and a potential difference in gender, we analyzed primary small cell lung cancer tumors from 65 patients (37 males and 28 females) for p53 mutations between exons 5 and 9. Mutations were found in 37 of 65 tumors (57%) within the region of p53 analyzed. Interestingly, none of the tumors from females contained more than one mutation, whereas four of the tumors from males contained more than one mutation. The most common mutation in this population was an adenosine-to-guanine transition (27%), followed by guanine-to-thymidine transversion (17%) and guanine-to-adenosine transition (12%). The gender difference in p53 mutational rate identified in this study suggests that a higher proportion of female tumors may develop through pathways not involving p53 mutations.
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PMID:Gender differences in p53 mutational status in small cell lung cancer. 1058 80

Many studies have revealed the frequency of p53 abnormalities in lung cancer. However, clinico-pathological studies of p53 abnormalities have yielded conflicting results. We examined the p53 immunoreactivity and studied the correlations of p53 status and clinicopathological parameters in 76 primary lung cancers. By using DO-7 antibody, different degrees of p53 immunoreactivity was detected in 8 of 30 small cell lung cancer (SCLC, 26.6%) and 22 of 46 non-small cell lung cancer (NSCLC, 47.8%), 6 of 19 adenocarcinoma, 16 of 27 epidermoid carcinoma cases. In the whole group, no correlation was detected between the p53 status and the histological types of tumor, local tumor invasion, nodal status, and distant metastasis and patient characteristics, such as age, gender or smoking habit. P53 status was also found to have no effect on survival. However, in the NSCLC group, there was a significantly higher p53 immunoreactivity in well- and moderately-differentiated tumors (p<0.05). Patients with p53 immunoreactivity had a poor therapeutic response in the whole group. We concluded that, although p53 immunreactivity may be found in NSCLC, this does not correlate with clinicopathological parameters except therapeutic response. In SCLC p53 immunreactivity can be negligible.
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PMID:Clinical importance of correlations between p53 immunoreactivity and clinicopathological parameters in lung carcinoma. 1060 23

p53 tumour suppressor gene alterations are one of the most frequent genetic events in lung cancer. A subset of patients with p53 mutation and cancer exhibited circulating serum anti-p53 self-antibodies (p53-Ab). The prevalence of these antibodies in lung cancer is currently being analysed in a multicentric study. In a group of homogeneous SCLC patients, p53-Ab were detected in 20/97 (20.6%) individuals. In this group of patients, Cox's multivariate analysis identified disease extent (p = 0.022), WHO initial performance status greater than 0 (p = 0.005), and the absence of a complete response after 6 months of treatment (p < 0.0001) as independent prognostic variables, with p53-Ab being of borderline significance (p = 0.051). In the subset of limited-stage SCLC patients, Cox's multivariate analysis found p53-Ab (p = 0.033), WHO initial performance status greater than 0 (p = 0.028), and absence of a complete response (p < 0.001) to be independent prognostic variables. Thus, actuarial analysis showed that patients with limited-stage SCLC and p53-Ab had a median survival time of 10 months, whereas limited-stage SCLC patients without p53-Ab had a 17-month median survival time (p = 0.014).Therefore, serum assay of p53-Ab could help to identify a population of SCLC patients with an especially poor prognosis. This population could represent patients with tumours harboring aggressive p53 mutations.
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PMID:Prognostic significance of serum p53 antibodies in patients with limited-stage small cell lung cancer. 1071 35

It has been suggested that mutations in the menin gene play a role in the development of multiple endocrine neoplasia type 1 (MEN1)-associated and of sporadic forms of low- and intermediate-grade neuroendocrine tumors of the lung. In the present study, eight tumor specimens of large cell neuroendocrine carcinoma (LCNEC) and 13 of small cell lung cancer (SCLC), which represent a high-grade category of neuroendocrine tumors, were examined for the potential involvement of menin alterations as well as for the expression of various neuroendocrine markers and p53 and Rb abnormalities. All specimens expressed multiple neuroendocrine markers as expected and almost invariably carried p53 and Rb alterations. Unexpectedly, however, mutations in the menin gene were not detected in any of the high-grade neuroendocrine tumors examined. We thus conclude that menin mutations do not play a crucial role in the pathogenesis of high-grade subsets, in contrast to their suggested significant role in the development of low- and intermediate-grade subsets. Interestingly, loss of heterozygosity (LOH) in the menin gene appeared to be more prevalent in LCNEC (50%) than in SCLC (22%), suggesting a possible distinction between SCLC and LCNEC.
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PMID:Characterization of high-grade neuroendocrine tumors of the lung in relation to menin mutations. 1076 Jun 91

The transcription factor achaete-scute homologue-1 (ASH1) is essential for neural differentiation during fetal development and is a cardinal feature of neuroendocrine (NE) tumors such as small cell lung cancer. To explore the potential of ASH1 to promote NE differentiation and tumorigenesis in the lung, we constitutively expressed the factor in nonendocrine airway epithelial cells using transgenic mice. Progressive airway hyperplasia and metaplasia developed beginning at 3 weeks of life. ASH1 potently enhanced the tumorigenic effect of SV40 large T antigen in airway epithelium. These doubly transgenic animals developed massive NE lung tumors, implying that ASH1 may cooperate with defects in p53, pRb, or related pathways in promoting NE lung carcinogenesis.
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PMID:Constitutive achaete-scute homologue-1 promotes airway dysplasia and lung neuroendocrine tumors in transgenic mice. 1094 98

Inactivation of p53, which represents the most prevalent genetic alteration in lung cancer, has been shown to play a crucial role in the acquisition of genomic instability. We examined 44 lung cancer specimens to search for mutations in the CHK1 and CHK2 genes, which have been suggested to play roles in regulating p53 after DNA damage. We found that the CHK2 gene was somatically mutated in lung cancer in vivo, although at a low frequency, and that a previously undescribed shorter isoform of CHK1 was expressed preferentially in small cell lung cancer in a tumor-predominant manner. Additional studies are warranted to investigate the functional significance of these changes as well as the potential involvement of other components in this important pathway to maintain genomic stability.
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PMID:Histological type-selective, tumor-predominant expression of a novel CHK1 isoform and infrequent in vivo somatic CHK2 mutation in small cell lung cancer. 1098 68

To identify the major tumor suppressor gene (TSG) loci involved in the pathogenesis of lung cancer, we have conducted a high-resolution (10 cM), genome-wide search of loss of heterozygosity (LOH). Thirty-six lung cancer cell lines [14 small cell lung cancers (SCLCs) and 22 non-SCLCs (NSCLCs)] and their matched control DNAs were analyzed using 399 fluorescent microsatellite markers from the ABI Prism linkage mapping set v.2 on an ABI 377 sequencer/genotyper. Overall, 22 different regions with more than 60% LOH were identified: (a) 13 regions with a preference for SCLC; (b) 7 regions with a preference for NSCLC; and (c) 2 regions affecting both SCLC and NSCLC. The chromosomal arms with the most frequent LOH were 1p, 3p, 4p, 4q, 5q, 8p, 9p (p16), 9q, 10p, 10q, 13q (Rb), 15q, 17p (p53), 18q, 19p, Xp, Xq. In addition, new homozygous deletions were found at 2p23, 8q24, 18q11, and Xq22. On average, 34% (SCLC) to 36% (NSCLC) of markers showed allele loss in individual tumors, with an average size of subchromosomal region of loss of five to six markers (50-60 cM). Whereas SCLC and NSCLC had different regions of frequent LOH (hot spots), and NSCLC had more of these regions (n = 22) than SCLC (n = 17), in all other parameters (fractional allelic loss, number of breakpoints, and number of microsatellite alterations), SCLC and NSCLC were not significantly different. Clustering analysis revealed correlations between LOH on different chromosomes that suggest previously unknown genetic interactions for lung cancer development. We conclude that (a) in lung cancer cell lines, at least 17-22 chromosomal regions with frequent allele loss are involved, suggesting that the same number of putative TSGs are inactivated; (b) SCLC and NSCLC frequently undergo different specific genetic alterations; and (c) clusters of TSGs are likely to be inactivated together. Overall, these data provide global estimates of the extent of genetic changes leading to lung cancer and will be useful for the positional cloning of new TSGs and for the identification of multiple new biomarkers for translational research.
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PMID:Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering. 1098 4

Allyl sulfur compounds play a major role in the chemoprevention against carcinogenesis. The present study compared the antiproliferative effects of diallyl sulfide (DAS), diallyl disulfide (DADS) and garlic extract on p53-wild type H460 and p53-null type H1299 non small cell lung cancer cells (NSCLC). The DAS and DADS treatment of both H460 and H1299 cells resulted in the highest numbers of cells in apoptotic state as measured by acridine orange staining, however, garlic extract treatment did not induce any significant apoptotic cells by MTT assay. DADS was found to be more effective in inducing apoptosis on NSCLC. The level of p53 protein in H460 cell was increased following DADS treatment. DAS and garlic extract treatment of H460 cells induced a rise in the level of Bax and a fall of Bcl-2 level. These results demonstrate that DAS, DADS and garlic extract are effective in reduction of anti-proliferative gene in NSCLC and suggest that modulation of apoptosis-associated cellular proteins by DAS, DADS and garlic extract may be the mechanism for apoptosis which merit further investigation as potential chemoprevention agents.
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PMID:Effects of allyl sulfur compounds and garlic extract on the expression of Bcl-2, Bax, and p53 in non small cell lung cancer cell lines. 1104 43

Prognostic relevance of serum p53 antibodies was assessed in 96 patients with microscopically proven small cell lung cancer (SCLC). The study group included 67 males and 29 females; mean age 58 years; range 35--86 years; 60 with limited disease (LD), and 36 with extensive disease (ED). The control group consisted of 41 patients with non-malignant diseases. The presence of p53 antibodies was assayed by the immunoenzymatic method (P53 ELISA kit, PharmaCell, France). Antibodies were present in 26 SCLC cases (27%); 15 (25%) in LD and 11 (31%) in ED. Antibodies were also found in one out of 41 control subjects (2%). There was no correlation between the level of antibodies and clinical characteristics of SCLC patients including age, gender and extent of disease. The median follow-up for the entire group was 30 months (range: 11--39 months). By the time of analysis, 78 patients (82%) had deceased. Median survival in SCLC patients with and without antibodies was 42 and 39 weeks, respectively (log rank, P=0.81). These results indicate the lack of clinical relevance of serum p53 antibodies in SCLC.
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PMID:Serum p53 antibodies in small cell lung cancer: the lack of prognostic relevance. 1116 62


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