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)

The recent finding that the 1p36.3 locus gene encodes an array of different p73 isoforms with apparently distinct and sometimes opposing cellular functions, might explain the difficulty in establishing the protein's role as tumor suppressor. Therefore we need to investigate the roles of each of these splicing variants in cellular functions when expressed alone or in combination with other family members, as well as the genetic background on which the proteins are expressed. We investigated, in two p53 null cell lines, the human SCLC line H1299 and a subline derived from the human colon carcinoma cell line HCT116 (HCT116/379.2), the effects of DeltaNp73alpha overexpression on cell growth and the response to anticancer treatment. We generated three different clones overexpressing DeltaNp73alpha under a tetracycline inducible promoter. Immunofluorescent staining and luciferase reporter assays confirmed that clones HCT116/DeltaNA and H1299/DeltaN7 and H1299/DeltaN11 did express a functional, nuclear localized DeltaNp73alpha protein. The stable overexpression of DeltaNp73alpha protein did not confer any cell growth advantage. Doubling time of clones overexpressing DeltaNp73alpha were comparable to counterparts not expressing it. Clonogenic assays showed that the cytotoxic activity of different DNA damaging agents, such as cDDP, UV light and doxorubicin, were comparable in clones expressing DeltaNp73 or not. The overall data argue against an oncogenic role for this isoform. These findings are independent of the p53 status since they overlap with those previously obtained by our group in HCT116 cell lines, wild type for p53.
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PMID:Questioning the oncogenic role of DeltaNp73alpha in different cell lines expressing p53 or not. 1692 Dec 61

BBR 3464 is a novel triplatinum compound that has exhibited anti-tumor activity in both cisplatin-sensitive and cisplatin-resistant, as well as in p53 mutant tumor models. In phase I testing, the dose-limiting toxicities have included myelosuppression and diarrhea. Both an intermittent (day 1 every 21-28 days) and a continuous (dailyx5 days) schedule have been studied, and the intermittent schedule has been chosen for further development. The primary objective of this study was to assess the efficacy of BBR 3464 administered at a dose of 0.9 mg/m i.v. over 1 h every 21 days in patients with small cell lung cancer who have progressed after first-line therapy. Pharmacokinetic analysis was also performed and will be reported. Patients were stratified based on prior response into resistant and sensitive (response duration 3 months or longer) subgroups. Thirty-seven patients were enrolled onto this multicenter study. The median number of cycles delivered was 2 in the resistant subgroup (range 1-12) and 3 in the sensitive subgroup (range 1-8). Most common grade 3/4 hematological toxicities included neutropenia (62%), febrile neutropenia (16%), anemia (10%), fatigue (5%) and hypokalemia (5%). Although no objective responses were seen in 34 evaluable patients, 11 patients (32%) had disease stabilization (four resistant/seven sensitive) with 23 patients (68%) experiencing continued disease progression (12 resistant/11 sensitive). Median time to progression was 53 days in the resistant subgroup [95% confidence interval (CI) 37-63] and 66 days in the sensitive subgroup (95% CI 51-136). The median and 1-year survival rate based on subgroup was 78 (resistant) (95% CI 56-165) versus 209 days (sensitive) (95% CI 83-296) and 6 (resistant) (95% CI 0-17) versus 20% (95% CI 2-38%), respectively. We conclude that the toxicity profile of BBR 3464 in this phase II trial is consistent with the phase I experience. The lack of activity in either patient subgroup, however, does not support further evaluation of this drug as a single agent in this disease.
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PMID:Phase II study of BBR 3464 as treatment in patients with sensitive or refractory small cell lung cancer. 1691 15

One of the earliest descriptions of non-neuronal ACh synthesis was by Morris who reported that ACh was synthesized in the placenta [1]; furthermore, Falugi et al. showed the presence of AChE in human fibrosarcoma cells [2]. Afterward, the expression of ACh, AChE, and cholinergic receptors in non-neuronal cells was reported in several studies [3-16]. Indeed, recent data reported that SCLC expresses a cholinergic autocrine loop that can regulate cell growth. Such work demonstrates that SCLC cells have a cholinergic phenotype and that ACh exerts as an autocrine growth factor in human lung tumours [16]. Moreover, it has been recently reported that nicotine in lung adenocarcinoma A549 cells, potently induces Bad phosphorylation at serine (S)112, S136 and S155 in a mechanism involving activation of MAPKs, ERK1/2, PI3K/AKT and PKA through the linking to alpha7-receptors [9]. Bad phosphorylation results in sequestering Bad from mitochondria and subsequently interacting with 14-3-3 in the cytosol [9]. We have recently reported that human malignant pleural mesothelioma expresses a cholinergic system, involved in cell growth regulation. Hence, mesothelioma cells growth is modulated by the cholinergic system in which agonists (i.e. nicotine) have a proliferative effect and antagonists (i.e. curare or alpha-cobratoxin) have an inhibitory effect. Furthermore apoptosis mechanisms are under the control of the cholinergic system (nicotine antiapoptotic via induction of NF-kappaB complexes and phosphorylation of Bad at S112, curare proapoptotic via G0-G1 arrest p21waf-1-dependent, but p53-independent) [16]. The involvement of the non-neuronal cholinergic system in lung cancer and mesothelioma appears reasonable and opens up new translational research strategies.
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PMID:Development of novel therapeutic strategies for lung cancer: targeting the cholinergic system. 1716 19

We analysed the biologic properties of a small cell lung carcinoma cell line (designated KK0206) established from a patient with SCLC who had cancer-associated retinopathy (CAR). Morphological and immunohistochemical studies showed that KK0206 cells have features of the classic type of SCLC. KK0206 cells grew in suspension, forming relatively small clumps of cells with a doubling time of 72 h. On light microscopy, the cells were relatively small with little cytoplasm. On immunohistochemistry using anti-bovine recoverin rabbit antibody, the cells were intensely positive for recoverin. In addition, they were positive for NSE, Ki-67, and TP53. They also expressed human recoverin, a photoreceptor protein, whose presence was confirmed by RT-PCR analysis with cDNA sequencing and Western blot analysis. The point mutation of their TP53 gene (exon 156) was detected as well. The present study demonstrates that human recoverin is expressed in SCLC cells cultured from an anti-recoverin antibody-negative patient with CAR. KK0206 might be important for further research on SCLC related retinopathy.
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PMID:Establishment of a novel small cell lung carcinoma cell line with specific recoverin expression from a patient with cancer-associated retinopathy. 1737 19

The prognosis of lung cancer remains poor, and biological heterogeneity is largely responsible, especially in adenocarcinoma. We previously found that only one third of non-small cell lung cancer (NSCLC) but most small cell lung cancer (SCLC) tissues have strong telomerase activity, representing the difference in the history of multiple clonal selections. To reveal the genes differentially involved in telomerase activation mechanisms, we analyzed the relationship between common genetic aberrations and telomerase activity in 83 lung cancer tissues. We found that half (7 of 14) of lung adenocarcinomas with high telomerase activity showed neither TP53 nor RB1 deletion, while all squamous cell carcinomas and SCLCs with high telomerase activity showed loss of heterozygosity of at least one, if not both, of these suppressor oncogenes, indicating that these genetic aberrations are not required in activation of telomerase in a unique subset of adenocarcinoma. Furthermore, whereas the aberrations in TP53, RB1 and 1p34-pter were mutually related in 42 adenocarcinoma tissues, EGFR aberrations showed no relationship to either of them. These findings indicate that EGFR activating aberrations occur independently of other common genetic aberrations or telomerase activation mechanisms in lung adenocarcinoma, and that the distinct subset of lung adenocarcinoma with high telomerase activity without any common genetic aberrations may possibly have arisen from a telomerase-positive or telomerase-competent normal cell.
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PMID:EGFR activating aberration occurs independently of other genetic aberrations or telomerase activation in adenocarcinoma of the lung. 1748 98

Cancers of the lung and pleura remain a major cause of cancer deaths, both in men and women, with strong causal relationships between cigarette smoking and asbestos fibres, and deaths from lung cancer and mesothelioma, respectively. The poor survival rates for small cell lung cancer and mesotheliomas argue powerfully for greater understanding of mechanisms of carcinogenesis, genetic abnormalities and the role of tumour suppressor genes and proteins in carcinomas of the lung and pleura. Despite progress in the development of newer cytotoxic drugs, lung cancer remains a lethal disease. Chemotherapy and radiotherapy produce only a modest improvement in survival of patients with advanced disease. Increased knowledge of molecular mechanisms of lung cancer and apoptosis are providing opportunities for treating lung cancer with new classes of molecularly targeted drugs. These novel therapies should target the abnormalities in lung cancer by maximizing the effects of anti-tumour molecules, with minimal side effects on normal tissues. Of the several molecular targets, those receiving attention are p53 gene replacement, Bcl-2 downregulation, apoptosis by induced by TNF, the FAS/CD95 receptor system and TRAIL, and inhibition of NF-kappaB. Although several studies have shown benefits, there is a need for well planned clinical trials of drugs that target the apoptotic cascade. Stem cell therapy and gene replacement offer the prospect of novel approaches that are likely in the near future to play a definitive role in the treatment of advanced lung cancer. Furthermore, with their apparent minimal toxicity to normal tissues, the newer molecular targets represent attractive investigational directions for innovative cancer therapies.
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PMID:Molecular genetics and mechanisms of apoptosis in carcinomas of the lung and pleura: therapeutic targets. 1803 30

Determining an effective predictor of clinical drug resistance in small cell lung cancer (SCLC) is considered to be important. In this study, the relationship between the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and MRP2, which are the members of ATP-binding cassette superfamily transporter, and of the p53 tumor suppressor gene and the response to chemotherapy were analysed. The expression of P-gp, MRP1, MRP2, and p53 was determined by an immunohistochemical analysis of transbronchial biopsy (TBB) specimens from 61 SCLC patients. The relationship of such expression was also investigated regarding chemotherapy and clinicopathological factors. The response rate in the MRP2-negative group was significantly higher than that in the MRP2-positive group (88% versus 50%). The P-gp-negative group responded significantly better to chemotherapy than the P-gp-positive group, with a response rate of 81% versus 39%. No relationship could be found between the response to chemotherapy and immunostaining for MRP1 or p53. In 37 patients treated with platinum-based chemotherapy, the response rate of patients in the MRP2-negative group was significantly higher than that in the positive group (92% versus 50%). In a multiple logistic regression analysis, MRP2 as well as P-gp were shown to be statistically significant predictors of chemotherapy resistance. These results suggest that immunostaining of MRP2 for TBB specimens may help to predict clinical resistance to platinum agents. This is the first report which indicates that the immunohistochemical expression of MRP2 is positively related to a clinical resistance to platinum.
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PMID:Immunohistochemical expression of MRP2 and clinical resistance to platinum-based chemotherapy in small cell lung cancer. 1821 43

Histopathologic and clinical findings suggest that small cell lung cancer is derived from a multipotent proximal airway epithelial cell. In order to investigate the histogenetic origin of small cell lung cancer, we compared stem cell marker expression in human fetal lung tissue, human adult bronchial tissue, and a cohort of 64 small cell lung cancers. Supporting derivation of a multipotent precursor cell, 87.5% (56/64) of small cell lung cancers showed a dot-like expression of podocalyxin-like protein 1 (PODXL-1), a marker of embryonic and hematopoetic stem cells. Of small cell lung cancers, 98.4% (63/64) ubiquitously expressed Bmi-1, a key player in self-renewal of stem cells. Oct4 and AP2gamma were not expressed. Although podocalyxin-like protein 1 did not correlate with p53 or Wilms tumor suppressor 1, known regulators of podocalyxin-like protein 1, we could demonstrate demethylated CpG islands in the podocalyxin-like protein 1 promoter in small cell lung cancer, indicating epigenetic regulation. During fetal lung development and within adult bronchial mucosa, Bmi-1 was expressed ubiquitously. In contrast, podocalyxin-like protein 1 was detected in few stromal cells during the pseudoglandular phase (n = 7) and, importantly, in clustered epithelial cells within proximal bronchi and the trachea during the canalicular phase (n = 10). Interestingly, podocalyxin-like protein 1 was not expressed in normal or metaplastic adult bronchial epithelium (n = 36) but was expressed in sparse epithelial cells in half of the cases of normal tumor adjacent bronchial mucosa (20/40). Taken together, we show that small cell lung cancers and clustered epithelial cells in developing proximal bronchi share the expression of stem cell markers, suggesting a possible histogenetic link.
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PMID:Stem cell marker expression in small cell lung carcinoma and developing lung tissue. 1865 41

Small cell lung cancer (SCLC) exhibits highly aggressive behavior and has a poor prognosis. While numerous investigations have been carried out, the exact mechanism of its carcinogenesis and aggressiveness is still unclear. SCLC is categorized as a neuroendocrine neoplasia and has a genetic profile characterized by universal alterations of the RB and TP53 genes. Epidemiological studies indicate the majority of SCLCs to be caused by smoking and the TP53 mutational pattern to be consistent with that evoked by smoke carcinogens; however, there is no direct evidence that such carcinogens induce alterations to RB in SCLC. While the importance of these alterations in the carcinogenesis of SCLC is strongly suggested, the exact molecular mechanism has been only little elucidated. SCLC cells almost always express mammalian achaete-scute homolog-1 (MASH1) and thyroid transcription factor-1 (TTF-1). MASH1 plays a critical role in neuroendocrine differentiation. TTF-1 is a characteristic marker of distal airway cells and pulmonary adenocarcinomas, but is also expressed in extrapulmonary neuroendocrine cancers. Thus, TTF-1 may well play a significant role in the development of neuroendocrine cancers. Recent studies indicate that the airway stem cell is committed to the neuroendocrine lineage through MASH1 and Notch signaling and that only RB-deleted neuroendocrine cells selectively proliferate in response to E2F3, eventually undergoing transformation to neuroendocrine cancer cells, probably in concert with TP53 gene aberrations. Thus, alterations of both the RB and TP53 genes are central to the carcinogenesis of SCLC, while many other factors including MASH1 and TTF-1 contribute to the development and biological behavior of SCLC.
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PMID:Small cell lung cancer: significance of RB alterations and TTF-1 expression in its carcinogenesis, phenotype, and biology. 1939 Sep 95

Small cell lung cancer constitutes 15-20% cases of lung cancers, currently the leading cause of death from malignant diseases. It also causes the demise of >90% of affected individuals in 5 years. We have established a new SCLC cell line STP54 derived from fine needle aspirate of metastatic supraclavicular lymph node of 54 -year-old women for model experiments. The primary tumor was diagnosed by histopathological examination as combined type of small cell lung cancer with a non-small cell component. We cultured the cancer cells in the RPMI 1640 medium. In the long-term culture only the small cell component survived. The cell line was established after 30 passages and then characterized by performing cell morphology, cell growth analysis, tumorigenicity in vitro and flow cytometry analysis of selected markers (like NCAM, cytokeratines, HLA-ABC, Fas, Bcl-2, p53, CXCR4, CD210). The cells were growing in floating aggregates and show features suggesting its invasiveness. We suggest that this new cell line may serve as a valuable tool for further studies on lung tumor biology, molecular pathogenesis and metastatic mechanism.
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PMID:Characterization of a new small cell lung cancer (SCLC) cell line STP54 derived from a metastatic bioptate of a combined type of SCLC with Non-SCLC component. 1941 48


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