Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The linkage of herpes simplex virus (HSV) and human papillomavirus (HPV) to the development of oral cancer has been studied. In spite of the presence of viral nucleic acids in some human oral cancer specimens, HSV alone is not carcinogenic in animals: repeated viral inoculation to mouse or hamster oral mucosa fails to produce tumours or histopathological evidence of malignancy. However, HSV demonstrates co-carcinogenicity in vivo: viral inoculation significantly enhances the oncogenic capacity of chemical carcinogens in the oral cavity of mice and hamsters. Though the detailed mechanisms of HSV cocarcinogenicity are unknown, HSV promotes the chemical carcinogen-induced activation of certain cellular proto-oncogenes and inactivation of p53 tumour suppressor gene. Human papillomaviruses type 16 (HPV-16) and 18 (HPV-18) demonstrate oncogenicity by transforming normal human oral keratinocytes in vitro. While normal cells exhibit a limited life-span, cells transformed by these viruses show immortality and altered morphology in comparison with their normal counterparts. The HPV-immortalised cells contain multiple copies of intact viral genome integrated into cellular chromosomes. These cells also express several viral-specific mRNAs including viral E6/E7 mRNAs. Notably, these cells contain low levels of p53 protein and overexpressed cellular myc proto-oncogene compared to their normal counterpart; however, the immortilised cell lines are non-tumorigenic in nude mice.
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PMID:In vitro and animal studies of the role of viruses in oral carcinogenesis. 133 29

Malignant cells usually show altered gap junctional intercellular communication and are often associated with aberrant expression or localization of connexins. Transfection of connexin genes into tumorigenic cells restores normal cell growth, suggesting that connexins form a family of tumour suppressor genes. Some studies have also shown that specific connexins may be necessary to control growth of specific cell types. Although we have found that genes encoding connexin32 (Cx32; beta 1), Cx37 (alpha 4) and Cx43 (alpha 1) are rarely mutated in tumours, our recent studies suggest that methylation of the connexin gene promoter may be a mechanism by which connexin gene expression is down-regulated in certain tumors. We have produced various dominant negative mutants of the genes encoding Cx26 (beta 2), Cx32 and Cx43, some of which prevent the growth control exerted by the corresponding wild-type genes. A decade ago, we proposed a method to enhance killing of cancer cells by diffusion of therapeutic agents through gap junctions. Recently, we and others have shown that gap junctional intercellular communication is responsible for the bystander effect seen in herpes simplex virus thymidine kinase/ganciclovir gene therapy. Thus, connexin genes can exert dual effects in tumour control: tumour suppression and a bystander effect for cancer therapy.
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PMID:Connexins in tumour suppression and cancer therapy. 1020 8

Normally, thyroid cancer is a disease with a good prognosis, but about 30% of the tumours dedifferentiate and may finally develop into highly malignant anaplastic thyroid carcinomas with a mean survival time of less than 8 months. Due to the loss of thyroid-specific functions associated with dedifferentiation, these tumours are inaccessible to standard therapeutic procedures such as radioiodide therapy and thyroxine-mediated thyrotrophin suppression. Medullary thyroid carcinomas are also highly aggressive. Here, therapy is limited to surgery, and no alternative is left if patients do not respond to this standard procedure. Obviously, new approaches would be desirable. Several novel approaches are currently being tested for the treatment of thyroid cancer. Many of them utilise methods of gene therapy, but follow different strategies: (1) reintroduction of the tumour suppressor p53 into a background lacking functional p53; (2) suicide gene therapy with ganciclovir and a transduced gene for herpes simplex virus thymidine kinase controlled by the thyroglobulin promoter; (3) strengthening of the antitumour immune response by expression of an adenovirus-delivered interleukin-2 (IL-2) gene; (4) induction of an immune response by DNA vaccination against the tumour marker calcitonin; (5) transduction of the thyroid sodium/iodide transporter gene to make tissues that do not accumulate iodide treatable by radioiodide therapy; (6) blocking of the expression of the oncogene c-myc by antisense oligonucleotides. While these approaches are still tested in vitro or in animal models, first results from pilot studies concerning other novel treatment modalities are available: (7) radioimmunotherapy exploits the carcinoembryonic antigen expressed on medullary thyroid carcinomas to target a radiolabelled antibody to the tumour; and (8) retinoic acid is used for a redifferentiation therapy in the case of thyroid cancer. Hopefully, one or the other of these novel strategies may probably extend after some time the current therapeutic repertoire for thyroid cancers and provide a perspective for otherwise untreatable patients.
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PMID:Innovative strategies for the treatment of thyroid cancer. 1087 26

The resistance of cancers to conventional therapies has inspired the search for novel strategies. One such approach, namely gene therapy, is based upon the introduction of genes such as those encoding suicide proteins, tumour suppressor proteins or cytokines into tumour cells by means of a genetic vector. The efficiency with which viruses transfer their genes from one host cell to another has led to the widespread use of viruses as genetic vectors. For safety reasons, such virus vectors are generally replication-defective but, unfortunately, this has limited the efficacy of treatment by restricting the number of cells to which the therapeutic gene is delivered. For this reason, the use of replication-competent viruses has been proposed, since virus replication would be expected to lead to amplification and spread of the therapeutic genes in vivo. The replication of many viruses results in lysis of the host cells. This inherent cytotoxicity, together with the efficiency with which viruses can spread from one cell to another, has inspired the notion that replication-competent viruses could be exploited for cancer treatment. Some viruses have been shown to replicate more efficiently in transformed cells but it is unlikely that such examples will exhibit a high enough degree of tumour selectivity, and hence safety, for the treatment of patients. Our increasing knowledge of the pathogenesis of virus disease and the ability to manipulate specific regions of viral genomes have allowed the construction of viruses that are attenuated in normal cells but retain their ability to lyse tumour cells. Such manipulations have included modifying the ability of viruses to bind to, or replicate in, particular cell types, while others have involved the construction of replication-competent viruses encoding suicide proteins or cytokines. Naturally occurring or genetically engineered oncolytic viruses based upon adenovirus, herpes simplex virus, Newcastle disease virus, poliovirus, vesicular stomatitis virus, weasles virus and reovirus have been described. The results of animal studies are encouraging and a number of viruses are now being evaluated in clinical trials.
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PMID:Cytolytic viruses as potential anti-cancer agents. 1184 43

VP22, a structural protein from herpes simplex virus type I, exhibits the unique property of intercellular trafficking. This protein is exported from primary expressing cells and subsequently imported into neighbouring cells. This property is conserved when VP22 is genetically fused to a protein, making it a promising tool to enhance the delivery of a gene product. We chose to study the intercellular transport and biological effect of a fusion protein between the putative tumour suppressor gene p27(Kip1) and VP22. We show that in vitro, P27VP22 is able to spread as efficiently as VP22. Functionality of the P27VP22 protein was demonstrated by its ability to inhibit cyclin/CDK2 complexes activity. In proliferation and clonogenicity assays, transfection with the P27VP22 plasmid resulted in a stronger cell growth inhibition when compared to transfection with the p27(Kip1) vector. In vivo, sub cutaneous tumours established in nude mice were injected with naked DNA encoding P27 or P27VP22. Our results show that P27VP22 can spread in vivo and that injections of the P27VP22 plasmid resulted in a significantly greater antitumour activity than injections of the P27 plasmid. This study confirms the usefulness of VP22-mediated delivery and suggests that P27VP22 may have applications in cancer gene therapy.
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PMID:Intercellular trafficking and enhanced in vivo antitumour activity of a non-virally delivered P27-VP22 fusion protein. 1259 90

Infection by high-risk HPV (human papillomavirus) is supposed to be the primary cause of cervical cancer. The HPV E2 protein (E2) is a DNA-binding protein that regulates viral gene expression and is required for efficient viral replication. Overexpression of the E2 protein in cervical cancer cells can induce growth arrest and/or apoptotic cell death, suggesting that E2 might be useful in the treatment of this disease. In the present study, we show that VP22 (herpes simplex virus VP22 protein) can be used to deliver E2 to target cells. VP22-E2 fusion proteins induce apoptosis in transiently transfected HPV-transformed cervical carcinoma cell lines. However, VP22-E2 fusion proteins do not kill COS-7 cells, probably because these cells constitutively express the simian-virus-40 T antigen and this protein sequesters the tumour suppressor protein p53. When COS-7 cells producing VP22-E2 are seeded into cultures of HPV-transformed cells, VP22-E2 enters the non-producing cells and induces apoptosis. VP22-E2 proteins produced in bacterial cells can also enter cervical cancer cells and induce apoptosis in a dose-dependent manner. Our results suggest that local delivery of VP22-E2 fusion proteins could be used to treat cervical cancer and other HPV-associated diseases.
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PMID:Herpes simplex virus VP22-human papillomavirus E2 fusion proteins produced in mammalian or bacterial cells enter mammalian cells and induce apoptotic cell death. 1470 62

Novel treatment strategies such as gene therapy are warranted in view of the failure of current treatment approaches to cure a high percentage of patients with advanced bladder cancers. The emergence of cancer gene therapy potentially offers a number of exciting treatments. The majority of approaches involve strategies to suppress the function of activated oncogenes to restore the expression of functional tumour suppressor genes or to initiate tumour self-destruction. One gene therapy approach against tumours that holds great promise is suicide gene therapy. Herpes simplex virus thymidine kinase (HSV-TK) phosphorylates ganciclovir (GCV), which in turn interacts with cellular DNA polymerase and interferes with DNA synthesis to cause death of rapidly dividing cells. The development of an effective delivery system is absolutely critical to the usefulness and safety of gene therapy. At present, the adeno-associated virus (AAV) vector has the most promising potential in view of its non-pathogenicity, wide tropisms and long-term transgene expression in vivo. Gene therapy studies using different serotypes of recombinant AAV (rAAV) as delivery vehicles have proved rAAVs to be an effective modality of cancer gene therapy. In the present study, we investigated the suppression effect of AAV-mediated HSV-TK/GCV system on the bladder cancer cells and in mice xenograft models of bladder cancer. Our data demonstrate that rAAV-HSV-TK system controlled tumour cell growth and achieves strong antitumour efficacy in vivo. These findings provide a foundation for the development of potential targeted clinical therapies for bladder cancer in humans.
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PMID:The adeno-associated virus-mediated HSV-TK/GCV suicide system: a potential strategy for the treatment of bladder carcinoma. 2201 35