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)

Using fluorescence in situ hybridization (FISH) to interphase nuclei, we examined the replication timing of 1 allele relative to its counterpart in PHA-stimulated peripheral blood lymphocytes of normal subjects and patients suffering from a solid tumor (renal cell carcinoma). In the FISH assay, an unreplicated DNA sequence is identified by a single dot-like hybridization signal, whereas a replicated region gives rise to a duplicated, bipartite signal. Accordingly, lymphocytes of normal individuals show 2 patterns of allelic replication: (i) synchronized replication of allelic counterparts, as exemplified by the biallelically expressed loci TP53 and D21S55; and (ii) non-synchronized replication of allelic partners, as exemplified by the early and late replicating alleles of GABRB3, an imprinted locus subjected to monoallelic expression. However, when present in lymphocytes of the cancer patients, all 3 loci change their replication mode: alleles of TP53 and D21S55 become asynchronous, whereas the early replicating allele of GABRB3 delays replication, leading to relaxation in the imprinted mode of replication. Based on the tight relationship between temporal order of allelic replication and allelic mode of expression, the modified order of allelic replication observed in nonmalignant cells of individuals diagnosed with cancer represents a novel genetic alteration associated with malignancy. This alteration detected by simple cytogenetic means, applied to peripheral blood lymphocytes, offers a potential test for cancer identification. Genes Chromosomes Cancer 27:270-277, 2000.
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PMID:Modification in the inherent mode of allelic replication in lymphocytes of patients suffering from renal cell carcinoma: a novel genetic alteration associated with malignancy. 1067 16

Anticancer activity and main mechanisms of action of free doxorubicin (DOX) and HPMA copolymer-bound DOX (P(GFLG)-DOX) were studied in solid tumor mice models of DOX sensitive and resistant human ovarian carcinoma. Free DOX was effective only in sensitive tumors decreasing the tumor size about three times, whereas P(GFLG)-DOX decreased the tumor size 28 and 18 times in the sensitive and resistant tumors. An enhanced accumulation of P(GFLG)-DOX in the tumor was observed, whereas only low concentrations of DOX were detected in other organs following P(GFLG)-DOX administration. This effect was dependent on the high permeability of blood vessels in untreated tumors. After treatment with P(GFLG)-DOX the permeability decreased concomitantly with the downregulation of VEGF gene expression. P(GFLG)-DOX effectively killed both types of tumors inducing apoptosis and necrosis through the activation of p53, Apaf-1, caspase 9, c-fos, or c-jun pathways, and the downregulation of the bcl-2 gene. HPMA copolymer-bound DOX preserved its activity inside cells, inhibited detoxification and defensive mechanisms encoded by GST-pi, BUDP, and HSP-70 genes, and limited DNA repair, replication, and biosynthesis by downregulation of Topo-IIalpha,beta, and TK1 genes. P(GFLG)-DOX also produced tumor tissue hypoxia and significantly activated lipid peroxidation in tumors. No damage to other organs after exposure to P(GFLG)-DOX was detectable. On the other hand, free DOX activated lipid peroxidation and led to tissue hypoxia in many organs. All data relevant to the mechanism of anticancer action of P(GFLG)-DOX indicated a higher antitumor activity and lower systemic toxicity of HPMA copolymer-bound DOX when compared with free DOX.
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PMID:Efficacy of the chemotherapeutic action of HPMA copolymer-bound doxorubicin in a solid tumor model of ovarian carcinoma. 1072 3

Calpain is a calcium-dependent cysteine protease that is implicated in calcium-dependent cell death, and calpain inhibitors are generally considered as inhibitors of apoptosis. To the contrary, in the present study, we found that calpain inhibitor II (CPI-2) triggers rapid apoptosis in acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) cells. All target cell lines were killed by CPI-2, including: ALL-1, a multidrug-resistant BCR-ABL fusion transcript-positive t(9;22) pro-B ALL cell line; RS4;11, a highly radiation-resistant MLL-AF4 fusion transcript-positive t(4;11) pre-pre B ALL cell line; RAMOS, a highly radiation-resistant and p53-deficient Burkitt's lymphoma cell line; DAUDI, a Burkitt's leukemia/lymphoma cell line; NALM-6, a pre-B ALL cell line; and JURKAT and MOLT-3, two T-lineage ALL/NHL cell lines. CPI-2-induced apoptosis in LYN-deficient and BTK-deficient subclones of the DT-40 lymphoma B cell line as effectively as it did in wild-type DT-40 cells. Thus, CPI-2-induced apoptosis is not dependent on the protein tyrosine kinases LYN or BTK. Notably, caspase inhibitor I effectively inhibited CPI-2-induced apoptosis, suggesting that the inhibition of a CPI-2-susceptible protease results in caspase activation, leading to apoptosis in ALL/NHL cells. Unlike the high calpain-expressing ALL/NHL cell lines, myeloid leukemia cell lines HL-60/AML, K562/CML, and U937/AMML, or solid tumor cell lines BT-20/breast cancer, PC-3/prostate cancer, U373/glioblastoma, and HeLa/epitheloid cancer, were not susceptible to the cytotoxicity of CPI-2. Taken together, our results identify calpain as a new molecular target for the treatment of ALL and NHL. CPI-2 and its analogues represent a promising new class of antileukemia/lymphoma agents that deserves further development.
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PMID:Calpain inhibitor II induces caspase-dependent apoptosis in human acute lymphoblastic leukemia and non-Hodgkin's lymphoma cells as well as some solid tumor cells. 1087 99

Specific immunotherapy of cancer utilizes tumor-directed cytotoxic T lymphocytes (CTL) that lyse tumor cells presenting MHC class I-associated peptides derived from tumor-associated proteins. Many tumor-associated gene products are known, but corresponding T cell epitopes are only known for relatively few of these. The most commonly used approaches to identify such antigens require pre-existing CTL lines or clones. By using a CTL-independent high performance liquid chromatography mass spectrometry (HPLC MS)-based approach we identified HLA-A2-presented peptides from carcinoembryonic antigen and wild-type p53 with a copy number as low as eight molecules per cell. Potential epitopes were predicted from the sequences of known tumor antigens and the corresponding synthetic peptides were analyzed by nanocapillary HPLC MS. In parallel, peptides were extracted from fresh, solid tumor tissue or tumor cell lines and analyzed in the same way. Upon co-elution of a natural peptide with a predicted peptide of the same mass, the peptide sequence was confirmed by on-line tandem MS. This approach allows rapid screening of large numbers of tumor-associated gene products for naturally processed peptides presented by different MHC class I molecules as a prerequisite for efficient epitope identification and rapid transfer to therapeutic vaccine trials.
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PMID:Identification of tumor-associated MHC class I ligands by a novel T cell-independent approach. 1094 Sep 13

Circulating tumor cells could provide a relatively noninvasive and repeatable source of information about tumor cell genotype that might influence treatment and estimation of prognosis. We developed a technique for identifying p53 mutations in tumor cells isolated from the peripheral venous blood of colorectal cancer patients and compared the prevalence and position of these mutations with multiple solid tumor samples from the same patient. We used immunomagnetic beads to isolate tumor cells, reverse transcriptase-nested polymerase chain amplification of the coding region between exons 4 and 9 within the p53 gene, and automated gene sequencing. Nineteen p53 mutations were detected in solid tumor samples from 19 of 41 colorectal carcinoma patients. An identical p53 mutation was invariably present in all samples from primary and metastatic colorectal tumor biopsies within the same patient. p53 mutations were detected in peripheral blood from 8 of these 19 patients with p53-mutated solid tumors. Where identified, the pattern of mutation in peripheral blood samples was invariably the same as in matching solid tumor samples. A single colorectal carcinoma biopsy provided reliable p53 gene mutational information in colorectal carcinoma. Detection of this p53 mutation in tumor cells from peripheral blood was achieved with an approach based on cell selection for epithelial characteristics, reverse transcription-PCR, and gene sequencing.
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PMID:P53 mutations in primary and metastatic tumors and circulating tumor cells from colorectal carcinoma patients. 1099 35

Genomic changes are a hallmark of the neoplastic process. These range from alterations at specific loci and defined karyotypic changes which influence tumor behavior to generalized alterations exemplified by microsatellite instability. Generalized genomic changes within a tumor would be evidence in favor of the mutator hypothesis which postulates a role for such extensive changes during tumorigenesis. In this report, we have used the DNA fingerprinting technique of randomly amplified polymorphic DNA (RAPD) analysis to study genomic alterations within primary human astrocytic tumors (gliomas) in a locus non-specific manner. The RAPD fingerprinting profile of consecutive segments of tumors 2 mm across was studied; 17 astrocytic (high- and low-grade) tumors were sectioned end to end. Tissue from 50 consecutive sections, 40 microm thick (total 2 mm across), was pooled and taken to be a tumor compartment. DNA was subjected to RAPD amplification by 15 random 10-mer primers. A tumor segment was taken to have a DNA fingerprinting pattern different from others in the same specimen when its RAPD profile differed from others by at least one band of one RAPD reaction. All but one of the tumors showed compartments with a unique genetic profile, indicating genomic instability leading to widespread intra-tumor genetic heterogeneity. Eight tumors were also studied for loss of heterozygosity (LOH) of the p53 and D17S379 loci in the different segments as examples of alteration of specific tumor influencing loci. Three showed LOH of p53, which was limited to only one compartment of each tumor. The extensive intra-tumor genetic instability detected in this study is suggestive of the overall high rate of change in the genomes of tumors including those of a lower grade. It is hypothesized that some of these altered clones, which manifest as zones of heterogeneity in a solid tumor, may accumulate changes at loci known to influence tumor behavior, and thus clinical outcome.
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PMID:Extensive intra-tumor heterogeneity in primary human glial tumors as a result of locus non-specific genomic alterations. 1102 91

New drug development requires simple in vitro models that resemble the in vivo situation more in order to select active drugs against solid tumours and to decrease the use of experimental animals. In this paper, we review the characteristics and scope of a relatively simple cell-culture system with a three-dimensional organisation pattern - the multilayered postconfluent cell culture model. Solid tumour cell lines from diverse origins when grown in V-bottomed microtiter plates reach confluence in 3-5 days and then start to form multilayers. The initial exponential growth of the culture is followed by a plateau phase when cells reach confluence. This produces changes in the morphology of the cells. For some cell lines, it is possible to observe cell differentiation. A substantial advantage of the system is the use of the sulforodamine B (SRB) assay to determine relative cell growth or viability, which allows semiautomation of the experiments. Several experiments were performed to assess the differences and similarities between cells cultured as monolayers and multilayers, and eventually, compared with the results for solid tumours and some other models such as spheroids. Cell-cycle analysis for multilayers showed a lower S-phase arrest, which is accompanied by a decrease in the expression of cell-cycle-related proteins and a decrease in cellular nucleotide pools. Gene and protein expression of topoisomerase I, topoisomerase II and thymidylate synthase expression were lower for multilayers, but no substantial changes were observed for the expression of DT-diaphorase. P53 expression increased. Multilayer cultures present distinctive properties for drug transport across the membrane, drug accumulation and retention. In fact, the transport of antifolates across the membrane, accumulation of topotecan and gemcitabine-triphosphate are reduced in multilayers when compared with monolayers, which may be related to a decrease in drug penetration to the inner regions of the multilayers. Alteration of these pharmacodynamic parameters is directly related to a decrease in drug activity. The most powerful application of multilayers is in the assessment of cytotoxicity. Solid tumour cell lines from different origins have been treated with several conventional and investigational anticancer drugs. The data show that multilayers are more resistant to the drugs than the corresponding monolayers, but there are substantial differences between the drugs depending on culture conditions, e.g. the difference was rather small for a drug such as cisplatin, miltefosine and EO9, a drug, which is activated under hypoxic conditions. Gemcitabine was active against ovarian cancer but not against colon cancer, resembling the in vivo situation. This observation was not evident with monolayer experiments. Another interesting application is the possibility to perform drug combination studies. The combination of gemcitabine and cisplatin proved to produce selective cell kill in H322 cells (non-small cell lung cancer cell line). Neither of the drugs was independently able to produce similar effects. In summary, multilayer cultures are relatively simple three-dimensional systems to study the effect of microenvironmental conditions on anticancer drug activity. The model might serve as a base for a more rigorous secondary in vitro screening.
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PMID:The multilayered postconfluent cell culture as a model for drug screening. 1103 3

In solid tumors hypoxia and reoxygenation may be important factors in secondary expansion after anti-cancer therapy. Our study examined the effect of hypoxia and reoxygenation on the apoptotic potential of cancer cells. Four experimental groups were studied using a human colorectal cancer cell line (HCT116) that is apoptosis-competent in conventional culture: (1) sham, cells grown under conventional conditions; (2) hypoxic, cells cultured in 95% N2 and 5% CO2 for 24 hr; (3) continued hypoxic, cells cultured for 48 hr; and (4) reoxygenation, cells grown in hypoxic conditions for 24 hr followed by another 24 hr under conventional conditions. Protein expression of p53, bcl-2 and PCNA were determined by immunohistochemistry and immunoblotting (p53), and viable cell growth rate was determined. Hypoxia for 24 hr induced significant up-regulation of p53 and bcl-2 expression, accompanied by significant decreases of cell growth rate and PCNA expression. Up-regulation of p53 and bcl-2 expression persisted with both continued hypoxia and reoxygenation, despite increased cell growth rate and PCNA expression. Cells escaping hypoxia acquired sustained resistance to apoptosis and proliferate despite an elevated p53 level, suggesting that p53 transfer to hypoxic solid tumor should be reevaluated as a cancer gene therapy approach.
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PMID:Cancer cells surviving hypoxia obtain hypoxia resistance and maintain anti-apoptotic potential under reoxygenation. 1116 54

Resistance to chemotherapy commonly compromises the treatment of many advanced cancers. Evidence suggests a correlation between chemoresistance and more aggressive tumor growth, possibly through accumulation of additional genetic defects in drug-treated or resistant cells. To study this process in a human ovarian cancer model, we examined OVCAR-3 cells for acute sensitivity to cisplatin (cDDP) and subsequent emergence of drug-resistant clones following chronic cDDP exposure. Clonal cells (OVCAR-3/C-1) that displayed 20-fold reduced sensitivity to cisplatin but retained equivalent sensitivity to paclitaxel, as compared with the parental population, were isolated. The cDDP-resistant clone had growth kinetics similar to those of parental population, but when transplanted into the peritoneal cavity of nude mice, they acquired the ability to grow with the development of both ascites and solid tumor masses; such growth was not detectable after transplantation of the drug-sensitive parental cell line. C-1 cells had a p53 gene mutation (codon 266) that was not detected in the parental OVCAR-3 cell line, and infection of C-1 cells with p53-adenovirus (rAd-p53) caused greater apoptosis and gene transduction than that observed in the similarly infected parental population. rAd-p53 induced high levels of p21WAF1, p27Kip1, activated caspase 3 and apoptosis in C-1 cells, without causing major changes in bax or bcl-XL levels. Together, the results suggest that alterations in tumor growth and gene mutations characterize cDDP-resistance in OVCAR-3 cells, and viral replacement of one of these defective genes (p53) may provide an effective treatment for elimination of drug-resistant cells.
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PMID:Emergence of cisplatin-resistant cells from the OVCAR-3 ovarian carcinoma cell line with p53 mutations, altered tumorigenicity, and increased apoptotic sensitivity to p53 gene replacement. 1124 Jun 61

Delivery of electric pulses to an established solid tumor augments the permeability of cell membrane and increases the susceptibility of tumors to an anti-cancer agent that is administered in the vicinity of tumors. Forced expression of the wild-type p53 gene in tumor cells that have non-functional p53 gene(s) can also enhance their sensitivity to a DNA-damaging agent. To investigate the feasibility of electroporation-mediated therapy for cancer, electric pulses were delivered to human esophageal tumors developed in nude mice after they received an anti-cancer agent and/or plasmid DNA containing the wild-type p53 gene. The growth of esophageal tumors was suppressed with electroporation-mediated chemotherapy compared with the treatment with an anti-cancer agent or electroporation alone. Intratumoral injection of the wild-type p53 gene into p53-mutated esophageal tumors followed by electroporation also inhibited tumor growth. When mice were administered with the wild-type p53 gene and an anti-cancer agent, subsequent electroporation produced a synergistic therapeutic effect. Combinatory transfer of plasmid DNA and a pharmacological agent by electroporation is thereby a possible therapeutic strategy for the treatment of solid tumors.
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PMID:Combinatory anti-tumor effects of electroporation-mediated chemotherapy and wild-type p53 gene transfer to human esophageal cancer cells. 1125 Nov 80


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