Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A malignant course of juvenile laryngeal papillomatosis has rarely been reported. In the present case the patient had had laryngeal papillomas since the age of three years. The papillomas gradually spread to the entire respiratory system, and during 30 years the patient was operated on more than 80 times. At present an invasive tumour spreading from the tongue into the parapharyngeal space, extending to the cranial base, has been demonstrated by magnetic resonance imaging (MRI). Intralesional therapy with Cidofovir, a promising antiviral drug against human papillomavirus (HPV) infection, was started with some clinical effect, although only on the superficial tumour growth. Histology of removed tumour tissue has demonstrated a mixture of exophytic and inverted growth pattern, and has mainly been interpreted as benign, in spite of a focally high mitotic index and an intermittent lack of maturation in the epithelium. In the most recent biopsies a verrucous carcinoma has been diagnosed. Expression of p53 was noted to increase in papillomas with time. All samples have been shown to harbour HPV 11, but no other HPV types.
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PMID:An aggressive and invasive growth of juvenile papillomas involving the total respiratory tract. 1019 57

High-risk human papillomaviruses (HPVs) have been associated to the development of cervical and some other human cancers. Most of them express E6 and E7 oncoproteins, able to bind to p53 and retinoblastoma (pRb) tumor suppressor proteins respectively and neutralize their function. Restoration of these pathways by blocking E6 and E7 expression would provide a selective therapeutic effect. Here, we show that a clinically approved antiviral agent Cidofovir reduced E6 and E7 expression in cervical carcinoma Me180 and head and neck squamous cell carcinoma HEP2 cells at the transcriptional level. Cidofovir induced the accumulation of active p53 and pRb associated to induction of cyclin dependent kinase inhibitor p21(WAF1/CIP1) in Me180 and HEP2 cells. p53 induction was also shown in Hela HPV-positive cervical carcinoma cell line. In addition, S phase cell cycle accumulation with concomitant decrease of cyclin A expression were associated to the antiproliferative activity of Cidofovir in HPV-treated cells. Combining Cidofovir to irradiation both in vivo and in nude mice xenografts resulted in a marked radiosensitization in HPV-positive cells, which was not observed in virus negative cells. This study provides the basis for a new anticancer strategy to enhance the antitumor effect of ionizing radiation in HPV-related cancers, without increase deleterious effects.
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PMID:Antiviral agent Cidofovir restores p53 function and enhances the radiosensitivity in HPV-associated cancers. 1194 17

High risk HPV types 16 and 18 are associated with cervical cancer and squamous cell carcinoma of the head and neck (SCCHN). Cidofovir is an antiviral drug used to treat HPV-induced laryngeal papillomatosis and other viral infections, with initial reports suggesting activity in cervical carcinoma cells. We investigated the effects of Cidofovir on a naturally HPV-16-transformed SCCHN cell line (UPCI:SCC090), in comparison with a cervical carcinoma cell line (CasKi) of similar viral characteristics, to evaluate its therapeutic potential. HPV-16 gene transcription was only marginally reduced, and the antiviral and p53 restorative effects were modest in SCC90 cells. However, combination with irradiation enhanced the effects of Cidofovir treatment on these cells. Several days of treatment were required for this effect, which may limit its clinical applicability. Future therapies for HPV-associated tumors may include intralesional antiviral therapy in combination with radiation therapy, but optimization for clinical utility is needed.
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PMID:Antiviral activity of Cidofovir on a naturally human papillomavirus-16 infected squamous cell carcinoma of the head and neck (SCCHN) cell line improves radiation sensitivity. 1579 15

Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine; (S)-HPMPC] is an antiviral drug that has been approved for the treatment of cytomegalovirus retinitis in patients with AIDS. Cidofovir also possesses potent activity against human papillomavirus-induced tumors in animal models and patients. We have recently shown that cidofovir inhibits the development of vascular tumors induced by basic fibroblast growth factor (FGF2)-overexpressing endothelial cells (FGF2-T-MAE) in mice. Here, we demonstrate that the inhibitory activity of cidofovir in FGF2-T-MAE cells may result from the specific induction of apoptosis. Cell cycle analysis revealed that cidofovir induces accumulation of cells in the S phase and, upon prolonged treatment, a significant increase in sub-G1 cells, exhibiting a subdiploid DNA content. Moreover, annexin V binding, an early event in apoptosis induction, was increased in cidofovir-treated FGF2-T-MAE cells. Cidofovir also caused nuclear fragmentation and the activation of caspase-3-like proteases, as evidenced by the cleavage of poly(ADP-ribose)polymerase. In addition, cidofovir treatment of FGF2-T-MAE cells resulted in a pronounced up-regulation of the tumor suppressor protein p53. However, the expression of Bax and Bcl-2 remained unchanged, and cidofovir did not induce the release of cytochrome c from the mitochondria. In addition, cidofovir did not suppress the phosphorylation of protein kinase B/Akt, a transmitter of antiapoptotic survival signals, or its downstream regulator Bad, indicating that the Akt pathway is not affected by cidofovir in FGF2-T-MAE cells. However, the compound inhibited the expression of FGF2 and FGF2 signaling through Erk42/44, as shown by Western blot analysis. Our results indicate that cidofovir inhibits the growth of FGF2-T-MAE cells via inhibition of FGF2 expression and signaling and via the induction of apoptosis. These findings suggest that the clinical use of cidofovir might be expanded to tumors that are not induced by oncogenic viruses.
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PMID:The nucleotide analog cidofovir suppresses basic fibroblast growth factor (FGF2) expression and signaling and induces apoptosis in FGF2-overexpressing endothelial cells. 1715

Potent thymidine phosphorylase (TP) inhibitors with anti-angiogenic activity are required to improve the prognosis of patients with TP-positive tumors. We have designed and developed novel structural and functional classes of TP inhibitors that also inhibit TP-induced angiogenesis, i.e. (i) the first purine analogue inhibitor of TP (7DX), (ii) the first multifunctional TP inhibitor (TP65), and (iii) the purine riboside analogue KIN59, which inhibits TP without interacting with the substrate-binding sites. The latter finding indicates that a, yet unidentified, allosteric site in TP contributes to its biological activities. In order to identify the amino acid residues in TP that interact with KIN59, we performed co-crystallograpy of the KIN59-TP complex. Our preliminary data suggest the existence of a putative KIN59 binding site. Identification of the allosteric site(s) in TP is important to gain more insight into the different biological activities of TP and may aid in the design of novel TP inhibitors. The nucleotide analogue cidofovir, which is being used clinically for the treatment of cytomegalovirus-induced retinitis in AIDS patients, emerged as a promising antitumor agent. So far, cidofovir has only been evaluated clinically for the treatment of HPV-associated tumors. Our results demonstrate the potent activity of cidofovir against tumors that are not associated with a virus. Cidofovir inhibits the growth of strongly vascularized tumors via inhibition of the growth factor FGF2, and by increasing the expression of the tumor suppressor p53, leading to apoptosis. These exciting results open new perspectives for the use of cidofovir as an anti-tumor agent in the therapy of tumors that are not associated with an oncogenic virus.
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PMID:Regulation of cancer progression by inhibition of angiogenesis and induction of apoptosis. 1866 59

Cidofovir (CDV) is an acyclic nucleoside phosphonate analog that shows broad spectrum anti-DNA virus activity. In this study, we have investigated the influence of cidofovir on the tumor xenografts derived from HeLa and SiHa cells on nude mice. The HeLa/SiHa xenografts in nude mice were established by inoculating cells subcutaneously. Administration of cidofovir by intratumoral injection led to significant tumor reduction. Enhanced protein levels of p53 and p-pRb within the tumor samples were observed. Immunohistology analysis of the tumor sections indicated decreased PCNA index and increased apoptosis index. Our study gives more evidence and explanation on in vivo inhibition effect of cidofovir on HPV genome-positive cervical carcinoma cell line xenografts.
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PMID:Effects of cidofovir on human papillomavirus-positive cervical cancer cells xenografts in nude mice. 2093 27

Besides its well-recognized antiviral activity, Cidofovir (CDV) has been shown to exert anticancer properties both within in vitro and in vivo models. The aim of this study was to evaluate the effects of CDV on still unexplored cultured cancer cells from human mesothelioma as well as breast, colon, liver, lung, prostate, and thyroid carcinomas. Overall, a dose- and time-dependent inhibition of cell viability was observed after CDV exposure. To clarify the mechanisms underlying CDV action, apoptotic cell death was investigated in two infected cell lines [Ist-Mes1 and Ist-Mes2 mesothelioma cells (SV40+)] and in two uninfected cell lines (NCI-H2425 mesothelioma cells and FTC-133 thyroid cancer cells), which resulted the most sensitive to CDV treatment. Reduced expression of procaspase-3 and increased expression of PARP p85 fragment were observed in both infected and uninfected mesothelioma cells, indicating apoptosis induction by CDV in a virus-independent manner. Similarly, the increase of the pro-apoptotic proteins p53, cytochrome c and caspase-3, the decrease of the survival protein Bcl-x, and the increment of Bax/Bcl-2 ratio revealed the occurrence of apoptosis in CDV-treated FTC-133. The presence of nuclear DNA fragmentation confirmed apoptotic cell death by CDV. Overall, our findings warrant further investigations to explore the therapeutic potential of CDV for human mesothelioma and follicular thyroid carcinoma.
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PMID:Reduced cell viability and apoptosis induction in human thyroid carcinoma and mesothelioma cells exposed to cidofovir. 2822 40