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)

To evaluate the applicability of recombinant adenoviral vectors in gene transfer to liver cancers, we infused the recombinant adenoviruses AD5CMV-LacZ and Ad5CMV-p53 through the portal veins into two lines of transgenic mice, one bearing the SV40 T antigen and the other the human hepatitis B viral envelope protein. These transgenic animals develop hepatocellular carcinomas (HCC) with predictable pathological manifestations. The levels of expression of the transgenes were dependent upon the viral doses. In all cases, high levels of expression were detected within 2 or 3 days after infusion, but were drastically reduced 7 days after infusion. Significant toxicities were found in the infused animals: > 80% of them died within 7 days after infusion with 10(10) pfu, and transgenic animals bearing HCC apparently were more sensitive to viral toxicity. Although a lower dose (10(9) pfu/animal) produced less toxicity, the levels of expression were substantially reduced (only about 10% of that in animals infused with 10(10) pfu). When Ad5CMV-p53 was infused into animals with nodular hyperplastic stage, the expression of the reporter gene seemed to distribute preferentially at the peripheries of the tumor nodules, and low levels of transgene expression were seen inside the nodules. In tumors in which necrotic lesions were evident, p53 was also expressed at the perpheries of the lesions. These distribution patterns were seen in both tumor models. There was no apparent suppression of tumor growth in the Ad5CMV-p53-infused animals. Our results suggest that alternative methods for gene therapy for HCC need to be explored.
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PMID:Adenoviral delivery of recombinant DNA into transgenic mice bearing hepatocellular carcinomas. 883 22

The p53 tumor suppressor protein induces cell-cycle arrest or cell death in response to DNA-damaging agents, such as radiation and many of the chemotherapeutics used in cancer therapy. The function of p53 is dependent on its ability to bind DNA in a sequence-specific manner, but in one-half of all human tumors, its sequence-specific DNA binding domain is compromised by single-amino acid substitutions. The nature of these substitutions, which target residues that directly contact DNA or that stabilize the structure of the DNA binding domain, has raised concerns as to whether the function of p53 mutants could ever be rescued. Nevertheless, pharmaceuticals that restore function to p53 mutants could specifically suppress proliferation of cancer cells in patients. To determine whether tumor-derived p53 mutants are irreversibly inactivated, we introduced basic residues in their DNA binding domains, aiming to establish novel contacts between p53 and the DNA phosphate backbone. In three of the seven most common p53 mutants, replacement of Thr284 with Arg significantly enhanced DNA binding affinity, without affecting DNA binding specificity, and rescued their transactivation and tumor suppressor functions. Thus, many tumor-derived p53 mutants retain their sequence-specific DNA binding determinants and can be activated to suppress tumor growth.
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PMID:Structure-based rescue of common tumor-derived p53 mutants. 883 16

This study analyzes the effects of estradiol on p53 and bcl-2 expression, tumor growth and cell kinetic parameters in three human endometrial adenocarcinomas grown in nude mice. The tumors used were estradiol receptor (ER) positive but differed in receptor concentration and hormone sensitivity. All three tumors expressed wild-type p53 protein. Using a tumor with an estradiol independent but responsive (inhibited) growth phenotype, we found that an increase in the circulating estradiol concentration led to increases in p53 expression and a decrease in bcl-2 levels, resulting in increased cell loss (CL) measured as delayed tumor growth. In another tumor which demonstrated estradiol independent and resistant growth, we observed an estradiol dose-related increase in p53 expression but no changes in bcl-2 expression or cell kinetic parameters. The ER mechanism of these cells was at least partly intact, as evidenced by maintained PgR induction. The third tumor showed an estradiol independent and resistant growth phenotype and a non-functional ER mechanism, lacking PgR induction. After estradiol treatment of the tumor-bearing animals no changes were observed in p53 or bcl-2 expression or in cell kinetics. We conclude that estradiol may regulate tumor growth in some ER positive human endometrial adenocarcinomas through regulation of p53 expression, which in turn regulates the bcl-2 protein concentration. Furthermore, this regulation of p53 expression is estradiol dose dependent. These growth regulating functions appear to be strongly influenced by ER mechanisms and do not seem to operate synchronously in tumors with an estradiol resistant growth phenotype.
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PMID:Estradiol regulates tumor growth by influencing p53 and bcl-2 expression in human endometrial adenocarcinomas grown in nude mice. 883 87

The lethal phenotypes of advanced prostate cancer are androgen independent (AI) and metastatic to the axial skeleton. Our laboratory has developed an AI mouse model of metastatic human prostate cancer. In this communication, we report the development of tumor suppressor gene therapy in this AI and metastatic (C4-2) cancer model. By using recombinant adenovirus as a delivery vehicle, we introduced a wild-type p53 tumor suppressor gene into prostate cancer cell lines. Despite a silent mutation at codon 152 of the p53 gene, C4-2 cells express functional, but low, levels of p53 protein. However, the other prostatic cell lines, PC-3 and DU145, have a deletion mutation and two point mutations of the p53 gene, respectively. In vitro studies showed that cell growth, as measured by the thymidine incorporation assay, was inhibited in the C4-2, PC-3, and DU145 cells infected with wild-type p53 adenovirus in comparison to control viruses. Recombinant wild-type p53 adenovirus inhibited prostate tumor growth and its production of prostate-specific antigen (PSA) when injected into C4-2 tumors in nude mice. All p53-treated mice were tumor free as long as 12 weeks after cessation of the 8-week treatment regimen. Two of 8 p53-treated mice developed small tumors growing at distant sites after a prolonged period of follow-up observation. Moreover, other AI prostate cancer cells, PC-3 and DU145, treated with Ad5-CMV-p53 failed to develop into tumors in vivo. This gene therapy strategy may be used against AI prostatic cancer regardless of p53 gene mutation status.
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PMID:Molecular therapy with recombinant p53 adenovirus in an androgen-independent, metastatic human prostate cancer model. 888 39

To explore the potential of an adenoviral antisense RNA transcript for gene therapy of cervical cancer, we introduced the antisense RNA transcript of E6 and E7 genes of human papillomavirus (HPV) 16 into cervical cancer cells harboring HPV 16 via a recombinant adenoviral vector, Ad5CMV-HPV 16 AS and analyzed the effects of expression of these genes on cell growth and tumor growth. Ad5CMV-HPV 16 AS contains the cytomegalovirus-promoter, E6 and E7 genes of HPV 16 in antisense orientation, and the SV40 polyadenylation signal in a mini-gene cassette, which is inserted into the E1-deleted region of modified adenovirus 5. The entire E6/E7 region of HPV 16 was amplified by polymerase chain reaction (PCR) before cloning into the mini-gene cassette. By reverse transcriptase-PCR, HPV 16 E6/E7 antisense RNA was detected in SiHa cells infected with Ad5CMV-HPV 16 AS. The growth of the Ad5CMV-HPV 16 AS-infected cells was greatly suppressed, as evidenced by a decrease in cell count. The growth inhibitory effect of Ad5CMV-HPV 16 AS was significantly enhanced by an adenoviral p53 construct, Ad5CMV-p53. In an ex vivo study in nude mice, tumorigenicity was completely inhibited in mice injected with Ad5CMV-HPV 16 AS-infected SiHa cells. These data suggest that transfection of cervical cancer cells with HPV 16 E6/E7 antisense RNA in a form such as Ad5CMV-HPV 16 AS is a potential novel approach to the therapy of HPV 16-positive cervical cancer.
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PMID:Adenovirus-mediated transfer of HPV 16 E6/E7 antisense RNA to human cervical cancer cells. 891 Jun 31

A more effective gene therapy strategy for lung cancer using sequential cisplatin administration and adenovirus-mediated p53 gene transfer was developed on the basis of our previous observation of enhanced expression of a reporter gene in malignant cells exposed to cisplatin before gene transfer. Transfer of the normal (wildtype) p53 gene into cisplatin-treated H1299 cells, in which p53 is homozygously deleted, resulted in up to a 60% further inhibition of cell proliferation in vitro than p53 transfer into untreated H1299 cells. The cisplatin plus p53 gene transfer strategy yielded significantly greater apoptosis and tumor growth suppression in an animal model of subcutaneous H1299 tumor nodules than wildtype p53 gene transfer alone. The timing of cisplatin administration and p53 gene transfer was shown to be critical: cisplatin administration simultaneous with or subsequent to p53 gene transfer was less effective than cisplatin-first sequential treatment. Moreover, the in vivo inhibition of tumor growth was maintained by repeated cycles of treatment. This gene therapy strategy has been incorporated into a phase I clinical trial for the treatment of lung cancer and provides a basis for the development of improved therapeutic protocols.
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PMID:Gene therapy for lung cancer: enhancement of tumor suppression by a combination of sequential systemic cisplatin and adenovirus-mediated p53 gene transfer. 891 37

The immunohistochemical expression of proliferating cell nuclear antigen (PCNA) and p53 was investigated in 9 cases of epithelial dysplasia and 38 cases of squamous cell carcinoma of the oral cavity. The intensity of immunoreactivity for each marker was assessed using a semiquantitative grading system, and was correlated with tumor differentiation, nuclear atypia and the patterns of invasive margins in the underlying connective tissue. PCNA expression, in dysplastic epithelium, was observed in the suprabasal and lower spinous layers; and the labeling grade and intensity of staining increased along with the degree of cellular atypia. In 2 cases of dysplasia, weak positive immunoreactivity for p53 could be seen in a few isolated cells of the basal layer. In squamous cell carcinoma, PCNA expression was correlated with the degree of tumor differentiation and nuclear atypia in well and moderately differentiated carcinoma, but not with the invasive pattern of tumor growth. Immunoreactivity for p53 was positive in 30 cases and showed a distribution pattern very similar to PCNA but with fewer positive cells. Three distinct categories of expression for PCNA and p53 were observed, among them a combination of intense reactivity for both markers was indicative of poor differentiation, higher nuclear atypia and more invasive growth of tumor cells.
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PMID:Proliferating cell nuclear antigen (PCNA) and p53 in epithelial dysplasia and squamous cell carcinoma of oral mucosa--a marker for poor tumor differentiation, increasing nuclear atypia and invasiveness? 892 Jul 67

Progression through the cell cycle is regulated by cyclins and cyclin-dependent kinases (Cdks). The cyclin kinase inhibitor p21 (also known as WAF1, CIP1, SDI1, and MDA-6) can induce G1 arrest and block entry into S phase by inactivating Cdks or by inhibiting activity of proliferating cell nuclear antigen (PCNA). In normal cells, p21 exists in quaternary complexes with cyclin, Cdk, and PCNA. Transcription of the p21 gene is activated by p53-dependent and -independent mechanisms. Mice deficient in p21 exhibit no apparent phenotype, although p21 function has been demonstrated to be necessary for p53-mediated G1 arrest following irradiation of p21-deficient mouse embryonic fibroblasts. Thus, the function of p21 under normal circumstances appears to be redundant. p21 is expressed in terminally differentiating cells of a variety of tissues in a p53-independent manner. Overexpression of p21 results in G1 arrest and has been shown to suppress effectively tumor growth in vitro and in vivo. We review the recent literature describing the functional characterization of p21. This protein plays a key role in regulating the cell cycle and may have potential gene therapy applications.
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PMID:p21--negative regulator of the cell cycle. 893 60

The analyzed material included 41 sections originating from patients with squamous cell carcinoma at the III stage of clinical advancement. Size of tumor growth fractions and expression of p53 were evaluated using immunohistochemical methods. In most of cases, the Ki 67 index for uterine cervix carcinoma at the III stage of clinical advancement ranged between 5 and 30%. The p53 protein could seldom be detected, indicating infrequent p53 mutations in uterine cervix carcinoma. In cases exhibiting nuclear accumulation of p53 the proliferative index was high and ranged between 50% and 80%.
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PMID:Studies on tumor proliferation using monoclonal antibody, Ki 67 and expression of p53 in cancer of the uterine cervix. 893 35

Mutations of the p53 tumor suppressor gene are the most frequently observed genetic lesion in human cancer. Previously, we found that multiple intravenous injections of a liposome:p53 complex inhibited the growth of a malignant human breast cancer cell line that was implanted into nude mice. In the present study, we evaluated the toxicity of the liposome:p53 complex and the mechanism of this in vivo treatment in reducing tumor growth. Intravenously delivered liposome:p53 complex at dosages sufficient to inhibit human breast cancer in nude mice showed no evidence of toxicity. Clinical chemistries, complete blood counts, and histopathologic examination of various organs from the p53-treated groups did not demonstrate any difference from the control groups. To elucidate the mechanism by which the liposome:p53 complex inhibits cancer, the transfection efficiency of a liposome:chloramphenicol acetyltransferase (CAT) complex into the tumor was determined. Interestingly, less than 5% of the tumor was transfected with a liposome:CAT complex. A mechanism that could account for p53 reduction of tumor size and a low transfection efficiency is inhibition of angiogenesis. After one treatment, we found that the liposome:p53 complex reduced the number of blood vessels in the p53-treated group by approximately 60% compared to the control group (p < 0.001). The close correlation between the antitumor effect of p53 and the reduction of blood vessel density in the tumor suggests that p53 effects are mediated, at least in part, by an antiangiogenesis mechanism.
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PMID:Parenteral gene therapy with p53 inhibits human breast tumors in vivo through a bystander mechanism without evidence of toxicity. 901 21


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