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)

Cancers develop and progress via activation of oncogenes and loss of tumor suppressor genes, a progression that can be recapitulated through cross breeding mouse strains harboring genetic mutations. To define the role of RET/PTC3, p53 and Fhit in thyroid carcinogenesis, we intercrossed RET/PTC3 transgenics with p53-/- mice. This new strain, RET/PTC3p53-/-, succumb to rapidly growing and strikingly large multilobed thyroid tumors containing mixtures of both well and poorly differentiated, highly proliferative follicular epithelial cells. Interestingly, transplanted tumors from RET/PTC3p53-/- mice grew in SCID but not syngeneic immunocompetent mice indicating that these advanced tumors were immunogenic. RET/PTC3 protein expression was reduced to undetectable levels in tumors of older mice suggesting that the continued elevated expression of RET/PTC3 may not be necessary for tumor progression. Similarly, expression of Fhit protein was reduced in early tumors and undetected in older tumors irrespective of tumor histopathology. In contrast to RET/PTC3p53-/- mice, RET/PTC3Fhit-/- mice did not develop advanced thyroid carcinomas. These studies support a model of human thyroid cancer whereby thyroid epithelium expresses RET/PTC3 protein at early stages of tumor development, followed by the reduction of RET/PTC3 and loss of p53 function with progressive reduction of Fhit protein expression coincident with malignant progression.
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PMID:Altered gene expression in immunogenic poorly differentiated thyroid carcinomas from RET/PTC3p53-/- mice. 1142 73

Caspase-8 is a member of the cysteine protease family that modulates apoptosis induced by a variety of cell death signals and has recently been found to be activated during the process of anoikis, which is a form of apoptosis caused by loss of anchorage in epithelial cells. We previously demonstrated that the inhibition of anoikis promotes peritoneal dissemination of human gastric carcinoma MKN45 cells, which are anchorage dependent. This suggests that augmentation of anoikis may suppress dissemination of carcinoma cells. To determine whether extrinsic overexpression of caspase-8 can augment anoikis in MKN45 cells, we transfected them with the caspase-8 gene using an adenoviral (Adv) vector (Adv-caspase-8). Here we demonstrate that Adv-caspase-8 infection, at 15 multiplicity of infection (MOI), can augment anoikis in MKN45 cells and suppresses MKN45 peritoneal dissemination in SCID mice. The inhibitory effect on peritoneal dissemination resulted in a prolonged survival compared with that in control mice. In contrast, the Adv-caspase-8 (15 MOI) had no distinct effect on cell viability or growth either of attached MKN45 cells or of s.c. tumor growth in SCID mice. Thus, Adv-mediated overexpression of caspase-8 suppressed peritoneal dissemination mainly through augmentation of anoikis. In addition, Adv-caspase-8-mediated augmentation of anoikis was similarly observed in another gastric carcinoma MKN74 cell line. In contrast, Adv-p53 could not augment anoikis in MKN45 cells. These results imply that Adv-mediated gene transfer of caspase-8 can selectively induce apoptosis in detached carcinoma cells and, thus, shows potential as a novel cancer therapy against dissemination of gastric and probably other carcinoma cells originating from epithelial tissues.
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PMID:Adenovirus-mediated transfection of caspase-8 augments anoikis and inhibits peritoneal dissemination of human gastric carcinoma cells. 1158 25

Functional studies using freshly isolated tumor-infiltrating B lymphocytes(TIB) are difficult to perform and interpret. Here we document a novel function of TIB using fresh human lung cancer tissues engrafted in SCID mice; they are at activated state and produce tumor-specific antibodies in tumor microenvironment: (a) TIB engrafted in SCID mice produced human IgG; (b) IgG derived from TIB highly bound intracellular and membrane-bound antigens of autologous cancer cells; and (c) less recognition of autoantigens expressed on normal lymphocytes by IgG derived from TIB compared with IgG from the serum of the patient. On the basis of the novel findings presented in this study, we modified the original serological analysis of antigens by recombinant cDNA expression cloning design in a patient with lung cancer who expressed unusually favorable clinical evolution and analyzed humoral immunity against identified mutated p53 antigen. This study provides the first demonstration that antibodies derived from TIB recognize tumor antigens by serological analysis of antigens by recombinant cDNA expression cloning methodology and circulating anti-p53 antibodies in sera derived from TIB in tumor microenvironment. Our approach using TIB may allow the identification of key antigens in the humoral cancer-related immune system.
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PMID:Tumor-infiltrating B lymphocytes as a potential source of identifying tumor antigen in human lung cancer. 1191 50

Acute lymphoblastic leukemia cells from 19 children, including 7 who remain in first complete remission (CR1), were engrafted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. High-level infiltration of bone marrow, spleen, and liver was observed, with variable infiltration of other organs. The immunophenotypes of xenografts were essentially unaltered compared with the original patient sample. In addition, sequencing of the entire p53 coding region revealed no mutations in 14 of 14 xenografts (10 from patients at diagnosis and 4 at relapse). Cells harvested from the spleens of engrafted mice readily transferred the leukemia to secondary and tertiary recipients. To correlate biologic characteristics of xenografts with clinical and prognostic features of the patients, the rates at which individual leukemia samples engrafted in NOD/SCID mice were analyzed. Differences in biologic correlates were encountered depending on stage of disease: a direct correlation was observed between the rate of engraftment and length of CR1 for samples harvested at relapse (r = 0.96; P =.002), but not diagnosis (r = 0.38; P =.40). In contrast, the in vivo responses of 6 xenografts to vincristine showed a direct correlation (r = 0.96; P =.002) between the length of CR1 and the rate at which the leukemia cell population recovered following vincristine treatment, regardless of whether the xenografts were derived from patients at diagnosis or relapse. This study supports previous findings that the NOD/SCID model of childhood ALL provides an accurate representation of the human disease and indicates that it may be of value to predict relapse and design alternative treatment strategies in a patient-specific manner.
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PMID:The nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model of childhood acute lymphoblastic leukemia reveals intrinsic differences in biologic characteristics at diagnosis and relapse. 1201 Aug 13

In order to develop an effective therapeutic intervention for patients with pancreatic cancer, we analyzed the association of loss of heterozygosity (LOH) with the clinicopathological features of the disease. Based on these results, we are developing a new gene therapy that targets the genetic character of pancreatic cancer, using mutant adenoviruses that are selectively replication-competent in tumor cells. LOH of 30% or more was observed on chromosome arms 17p (47%), 9p (45%), 18q (43%), 12q (34%), and 6q (30%). LOH of 12q, 17p, and 18q showed significant association with poor prognosis. These data strongly suggest that mutations of the putative tumor suppressor genes, TP53 and SMAD4, play significant roles in the disease progression. Based on this rationale, we are developing a new gene therapy that targets tumors without normal TP53 function. The E1B-55kDa-deleted adenovirus can selectively replicate in TP53-deficient human tumor cells, but not in cells with functional TP53. We evaluated the therapeutic effect of this E1B-55kDa-deleted mutant adenovirus on pancreatic cancer without normal TP53 function. The growth of a human pancreatic tumor in a severe combined immunodeficiency (SCID) mouse model was markedly inhibited by consecutive injections of the E1B-55kDa-deleted adenovirus. Furthermore, the replication-competent adenovirus is not only a strong weapon itself but it is also a useful carrier of genes that possess antitumor activities, as a virus vector specific to tumors without normal TP53 function.
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PMID:Gene therapy for pancreatic cancer based on genetic characterization of the disease. 1202 95

We have studied the effect of a newly identified tumor suppressor tissue inhibitor of metalloproteinases- 3 (TIMP-3) on the growth of human melanoma and squamous-cell carcinoma (SCC). Adenoviral delivery of the TIMP-3 gene to human melanoma (A2058) and SCC (UT-SCC-7) cells ex vivo inhibited tumorigenesis after subcutaneous (s.c.) injection of the infected cells into SCID/SCID mice. Three daily consecutive intratumoral injections of 1.4x10(9) plaque-forming units (pfu) of TIMP-3 adenovirus (RAdTIMP-3) inhibited the growth of preestablished melanoma and SCC xenografts in SCID/SCID mice, whereas growth of control virus-injected tumors was not affected. The antitumor effect of RAdTIMP-3 was obtained with in vivo adenoviral transduction efficiency of 8-10%, and it was more potent than that of adenovirally delivered p53. Adenovirusmediated expression of TIMP-3 potently reduced gelatinolytic activity, increased the number of apoptotic cells, and inhibited vascularization of melanomas. Escalation of the adenoviral dose to three rounds of three daily consecutive injections with 1.4x10(9) pfu of RAdTIMP-3 every 6 days entirely inhibited growth of injected melanomas for 32 days. Mixing RAdTIMP-3-infected A2058 cells with uninfected cells in 1:1 ratio in culture resulted in death of all cells in 96 hours. Adenovirally delivered TIMP-3 was also expressed by A2058 cells in soluble form into the culture medium, where it exerted a cytotoxic effect on uninfected A2058 cell cultures after relocating to the cell layer. These results identify TIMP-3 as a novel type of secreted tumor suppressor, which has antiinvasive, antiangiogenic, and proapoptotic effects in vivo, and which displays a potent bystander effect validating further exploration of its applicability in human cancer gene therapy.
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PMID:Antitumor activity and bystander effect of adenovirally delivered tissue inhibitor of metalloproteinases-3. 1202 54

Potent and safe vaccinia virus vectors inducing cell-mediated immunity are needed for clinical use. Replicating vaccinia viruses generally induce strong cell-mediated immunity; however, they may have severe adverse effects. As a vector for clinical use, we assessed the defective vaccinia virus system, in which deletion of an essential gene blocks viral replication, resulting in an infectious virus that does not multiply in the host. The vaccinia virus Lister/Elstree strain, used during worldwide smallpox eradication, was chosen as the parental virus. The immunogenicity and safety of the defective vaccinia virus Lister were evaluated without and with the inserted human p53 gene as a model and compared to parallel constructs based on modified vaccinia virus Ankara (MVA), the present "gold standard" of recombinant vaccinia viruses in clinical development. The defective viruses induced an efficient Th1-type immune response. Antibody and cytotoxic-T-cell responses were comparable to those induced by MVA. Safety of the defective Lister constructs could be demonstrated in vitro in cell culture as well as in vivo in immunodeficient SCID mice. Similar to MVA, the defective viruses were tolerated at doses four orders of magnitude higher than those of the wild-type Lister strain. While current nonreplicating vectors are produced mainly in primary chicken cells, defective vaccinia virus is produced in a permanent safety-tested cell line. Vaccines based on this system have the additional advantage of enhanced product safety. Therefore, a vector system was made which promises to be a valuable tool not only for immunotherapy for diseases such as cancer, human immunodeficiency virus infection, or malaria but also as a basis for a safer smallpox vaccine.
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PMID:Immunogenicity and safety of defective vaccinia virus lister: comparison with modified vaccinia virus Ankara. 1209 85

Melanoma incidence is growing at a faster rate than any other human malignancy. Wild-type (wt) p53 is important in both G(1) and G(2) cell cycle arrest, and cyclin D1 (CD1) is necessary for G(1)-->S progression in melanoma cells. We reported that an adenoviral vector containing wt p53 significantly reduced [(3)H]thymidine uptake in melanoma cells containing mutant but not wt p53. Subsequently we showed that CD1 decreased melanoma proliferation and increased apoptosis. We now extend these findings by evaluating the effect on preformed melanomas of (1) intratumoral therapy with wt p53 alone, (2) wt p53 in combination with antisense (AS) CD1, both short (< or =14 days) and longer term, and (3) doubling the dose or repeat doses of wt p53 or AS CD1. Two melanoma cells lines that metastasize in SCID mice (451 and 1205) were used, one containing a p53 mutation (451) and the other a normal p53 gene sequence (1205). Compared to injection with a control adenoviral vector containing beta-galactosidase (LacZ), intratumoral injection of wt p53 slowed the growth of tumors formed from 451 cells. Using 5 x 10(8) plaque forming units as our standard intratumoral dose, neither doubling the dose of LacZ, p53 or AS CD1, nor repeat doses of the vectors, was as effective as combined therapy with wt p53+AS CD1, which resulted in the shrinkage of all tumors treated and 4/7 (57%) tumors vanished. No tumors treated with wt p53 or AS CD1 alone vanished. Wt p53+AS CD1 treatment resulted in significantly more cells undergoing apoptosis compared to either therapy alone. In summary, combining the separately effective treatment vectors p53 and AS CD1 led to an enhanced growth-suppressive and apoptotic effect, supporting a role for combination gene therapy to treat human malignant melanoma.
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PMID:p53 alone or in combination with antisense cyclin D1 induces apoptosis and reduces tumor size in human melanoma. 1222 20

We have recently shown that proteasome inhibitor PS-341 induces apoptosis in drug-resistant multiple myeloma (MM) cells, inhibits binding of MM cells in the bone marrow microenvironment, and inhibits cytokines mediating MM cell growth, survival, drug resistance, and migration in vitro. PS-341 also inhibits human MM cell growth and prolongs survival in a SCID mouse model. Importantly, PS-341 has achieved remarkable clinical responses in patients with refractory relapsed MM. We here demonstrate molecular mechanisms whereby PS-341 mediates anti-MM activity by inducing p53 and MDM2 protein expression; inducing the phosphorylation (Ser15) of p53 protein; activating c-Jun NH(2)-terminal kinase (JNK), caspase-8, and caspase-3; and cleaving the DNA protein kinase catalytic subunit, ATM, and MDM2. Inhibition of JNK activity abrogates PS-341-induced MM cell death. These studies identify molecular targets of PS-341 and provide the rationale for the development of second-generation, more targeted therapies.
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PMID:Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. 1239

A number of human cell lines derived from well-differentiated, myxoid/round cell, or pleomorphic liposarcoma have been described. To our knowledge, however, no human cell line established from dedifferentiated liposarcoma has been reported. In this study, we established a new human cell line, FU-DDLS-1, which originated from a dedifferentiated liposarcoma arising in the retroperitoneum of a 61-year-old man. This cell line was characterized by immunocytochemistry, conventional banding analysis, fluorescence in situ hybridization with chromosome painting probe, and comparative genomic hybridization (CGH). FU-DDLS-1 cells were spindle or polygonal shaped and possessed oval nuclei and slender cytoplasmic processes. The cultured cells were successfully maintained in vitro for over 90 passages over more than 30 months. The histologic features of heterotransplanted tumors in severe combined immunodeficiency mice were essentially the same as those of the original nonlipogenic sarcoma resembling a malignant fibrous histiocytoma. Both in vitro and in vivo, the cells exhibited immunopositive reaction for mdm2 and p53 proteins. Cytogenetically, FU-DDLS-1 displayed a hypertetraploid karyotype with giant marker chromosomes composed partly of chromosome 12 material. In addition, CGH analysis demonstrated that DNA sequence copy number changes including a gain of 12q12-q21 detected in FU-DDLS-1 were essentially the same as those in the original sarcoma. The FU-DDLS-1 cell line, which exhibits the unique conventional and molecular cytogenetic characteristics of dedifferentiated liposarcoma, should be a particularly useful model for studying the molecular pathogenesis of human dedifferentiated liposarcoma.
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PMID:Establishment of a novel human dedifferentiated liposarcoma cell line, FU-DDLS-1: conventional and molecular cytogenetic characterization. 1257 6


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