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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is often a considerable lapse of time between the definition of what causes a disease in the laboratory and the development of successful therapy. However, the history of medicine teaches us that the need to understand the scientific basis of disease before the discovery of new treatments is both essential and inevitable. During the middle of the 19th century, the work of the great German pathologist, Rudolf Virchow, defined disease as having an anatomic or histologic basis. In the clinic, this scientific perspective would lead to increasingly effective and, often, increasingly aggressive surgical approaches to disease. Later in the 19th century, Koch's discovery of the tubercle bacillus (a discovery Virchow disbelieved and publication of which he thwarted, since he hypothesized that cancer, not microbes, caused consumption!), would define a microbiological basis for disease. With bacteria defined as a major cause of human suffering, the stage was set for the development of the discovery of effective antibiotics. In the early 20th century, the pioneering work of Banting, Best and others would show that disease can also have an endocrine or metabolic basis. This new body of scientific knowledge would lead not only to the specific discovery of insulin as an effective treatment for diabetes but also to a more general understanding of the role of hormones, vitamins and co-factors in human health and disease. Basic medical research and its successful translation into effective treatments has fundamentally altered the cause of human death. In the developed world, where access to the benefit of this work is available, infectious disease is not the problem it was in the days of Pasteur, Metchnikoff and Ehrlich. As we approach the millennium, science is now teaching us that diseases, particularly cancer, can have a molecular or genetic basis. Can successful application of this new knowledge be far behind? We are already seeing the application of this new knowledge in cancer drug screening and cancer drug development. At the NCI, for example, the old in vivo mouse screen using mouse lymphomas has been shelved; it discovered compounds with some activity in lymphomas, but not the common solid tumors of adulthood. It has been replaced with an initial in vitro screen of some sixty cell lines, representing the common solid tumors-ovary, G.I., lung, breast, CNS, melanoma and others. The idea was to not only discover new drugs with specific anti-tumor activity but also to use the small volumes required for in vitro screening as a medium to screen for new natural product compounds, one of the richest sources of effective chemotherapy. The cell line project had an unexpected dividend. The pattern of sensitivity in the panel predicted the mechanism of action of unknown compounds. An antifolate suppressed cell growth of the different lines like other antifolates, anti-tubulin compounds suppressed like other anti-tubulins, and so on. It now became possible, at a very early stage of cancer drug screening, to select for drugs with unknown-and potentially novel-mechanisms of action. The idea was taken to the next logical step, and that was to characterize the entire panel for important molecular properties of human malignancy: mutations in the tumor suppressor gene p53, expression of important oncogenes like ras or myc, the gp170 gene which confers multiple drug resistance, protein-specific kinases, and others. It now became possible to use the cell line panel as a tool to detect new drugs which targeted a specific genetic property of the tumor cell. Researchers can now ask whether a given drug is likely to inhibit multiple drug resistance or kill cells which over-express specific oncogenes at the earliest phase of drug discovery. In this issue of The Oncologist, Tom Connors celebrates the fiftieth anniversary of cancer chemotherapy. His focus is on the importance of international collaboration in clinical trials and the negative impact of unnecessary bureaucracy and regulation. As a student of Tom's in the 1970s in London, working on hepatoma-specific alkylating agents at Charing Cross Hospital in collaboration with his lab on the other side of town, I can attest to the fact that the regulatory hurdles to cancer drug development just twenty years later have added immeasurably to the effort and cost of cancer drug development. However, I look with optimism to the future of cancer diagnosis, prevention and treatment. It is a future where what we are learning now about the molecular and genetic basis of cancer will find their clinical outlet just as surely as the anatomic, microbial, metabolic and endocrine basis for disease has in the past. This new knowledge will provide new techniques in molecular diagnosis, which will allow us to predict which in situ cancers are destined for malignant behavior, and which can be safely watched without the need for intervention. Individual patient risk for particular cancers will be accurately predictable, so that patients can alter lifestyle habits or begin other prevention strategies. Oncogenes and growth suppressor genes give us new targets to inhibit or replace. Tumor-specific kinases will meet their inhibitors. The oncologist will play a leading role in understanding, applying and interpreting this new information in the clinic-an exciting and challenging future!
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PMID:Cancer Drug Development: New Targets for Cancer Treatment. 1038 87

Human T-cell lymphotropic virus type-1 (HTLV-1) is aetiologically associated with adult T-cell leukaemia/lymphoma (ATL). HTLV-1 infection can also lead to various non-malignant diseases, for example, HTLV-1 associated myelopathy/tropical spastic paraparesis and HTLV-1 uveitis. HTLV-1 is endemic in southern Japan and the Caribbean. HTLV-1 infection is mainly transmitted by either breast-feeding, sexual intercourse or blood transfusions. Primary prevention of HTLV-1 in endemic areas by screening of blood and by refraining from breast-feeding have been successful. The incidence of ATL is rather low among HTLV-1 carriers (<5%). The precise mechanism of development of ATL remains unknown. It is a multiple-step process which does not require viral expression in the later stages of leukaemogenesis. Many samples have mutations of the tumour suppressor genes, p53 and/or p16(INK4A). Four subtypes of ATL have been identified, each having distinctive clinical features. Monoclonal integration of HTLV-1 proviral DNA into tumour cells is found in each of the subtypes. At present, no effective therapy for ATL exists.
Baillieres Best Pract Res Clin Haematol 2000 Jun
PMID:Human T-lymphotropic virus type 1 infection. 1094 23

Tumours derived from the thyroid follicular epithelium represent an informative model for understanding the molecular pathogenesis of multistage tumourigenesis, which is the prevailing theory on cancer development and progression nowadays. The early stages of thyroid tumour development appear to be the consequence of the activation or 'de novo' expression of several proto-oncogenes or growth factor receptors, such as ras, ret, NTRK, met, gsp and the thyrotropin (TSH) receptor. Alterations in the expression pattern of these genes are associated with the development of differentiated neoplasms, ranging from benign toxic adenomas (gsp and TSH receptor), to follicular (ras) and papillary (ret/PTC, NTRK, met) carcinomas. They may all be considered to be early events of thyroid cell transformation and, for some, experimental evidence derived from gene transfer studies supports this hypothesis. Alterations in tumour suppressor genes (p53, Rb) are associated instead with the most aggressive and poorly differentiated forms of thyroid cancer, indicating that, in the thyroid tumourigenic process, they represent late genetic events. Specific environmental factors (iodine deficiency, ionizing radiations) have been shown to play a crucial role in promoting the development of thyroid cancer, influencing both its genotypic and phenotypic features. Interestingly, a high percentage of genetic lesions causing thyroid cancer originate from gene rearrangements and chromosomal translocations (ret/PTC, NTRK, Pax-8/PPARgamma) a finding which, being a rare event in most epithelial tumours, makes the molecular pathogenesis of thyroid cancer unique. The uninterrupted flow of information on the molecular genetics of thyroid nodules and cancer will broaden the correlation between genotype and phenotype and will also provide important information for the development of more accurate preoperative diagnostic tools and more efficient treatment choices for the different forms of thyroid cancer.
Baillieres Best Pract Res Clin Endocrinol Metab 2000 Dec
PMID:Molecular pathogenesis of thyroid nodules and cancer. 1128 33

The association between human papillomavirus vulval skin infection and vulval intra-epithelial neoplasia is strong. Vulval skin carcinogenesis is, however, multifactorial. Both human papillomavirus oncogenic subtype infection and p53 mutations are likely to contribute to the risk of malignant transformation of normal epithelium. The long-term cumulative risk of developing vulval squamous carcinoma following the diagnosis of high-grade vulval intra-epithelial neoplasia is thought to be approximately 6% per decade, but observational data supporting this are mostly non-population based and retrospective. Surgical treatment may reduce this risk, but the rates of recurrence and treatment-related morbidity are high. Surveillance should therefore be discussed as an alternative. New treatments being researched include photodynamic therapy, human papillomavirus vaccines, immunotherapy, immune modulators and gene therapy. The advantages of these new modalities over surgery is the potential to preserve body image and sexual functioning while targeting more generalized epithelial molecular dysfunction.
Best Pract Res Clin Obstet Gynaecol 2001 Oct
PMID:Human papillomavirus and vulval intra-epithelial neoplasia. 1156 72

Because in the normal state, cells of the pancreas show a very low rate of proliferation, entering the cell cycle is assumed to be the initial event during tumorigenesis. So-called checkpoints monitor cell cycle progression and guarantee the proper duplication of the entire genome. Loss of one or more checkpoints causes subsequent accumulation of genetic alterations which finally results in cancer. Cancer cells are characterized by unrestricted growth, invasion of adjacent tissue and metastasis. All of these features can be explained in terms of genetic changes and the functional consequence of these changes. Activation of the proto-oncogene K-Ras and inactivation of the tumour suppressor gene loci INK4a, p53 and SMAD4 are characteristic for pancreatic cancer. The progression model of pancreatic cancer proposes that pancreatic intraepithelia neoplasia is the pre-cancerous lesion. A preferred genetic pathway has started to evolve. Germ-line mutations in specific genes are responsible for cases in which there is a familial predisposition to pancreatic cancer.
Best Pract Res Clin Gastroenterol 2002 Jun
PMID:Genetic basis of pancreatic cancer. 1207 67

Ovarian cancer is caused by genetic alterations that disrupt proliferation, apoptosis, senescence and DNA repair. Approximately 10% of ovarian cancers arise in women who have inherited mutations in cancer susceptibility genes (BRCA1 or BRCA2). The ability to perform genetic testing allows identification of women at increased risk who can be offered prophylactic oophorectomy or other interventions aimed at preventing ovarian cancer. The vast majority of ovarian cancers are sporadic, resulting from the accumulation of genetic damage over a lifetime. Several specific genes involved in ovarian carcinogenesis have been identified, including the p53 tumour suppressor gene and HER2/ neu andPIC3KA oncogenes. The recent availability of expression microarrays has facilitated the simultaneous examination of thousands of genes, and this promises to extend further our understanding of the molecular events involved in the development of ovarian cancers. Hopefully, this knowledge can be translated into effective screening, treatment, surveillance, and prevention strategies in the future.
Best Pract Res Clin Obstet Gynaecol 2002 Aug
PMID:Molecular aspects of ovarian cancer. 1241 30

Pivotal genetic information has been derived for a host of rare genetic disorders, but progress has been much slower in relation to the common causes of female infertility. In this chapter, we shall illustrate the approaches being applied in elucidating conditions causing infertility that are inherited in a polygenic/multifactorial fashion. The task is to determine the number of genes responsible and their chromosomal location(s). The first approach is to use genome-wide quantitative linkage analysis, searching throughout the genome with no prior expectation that a given gene or chromosomal region is casually involved. A second approach is to search across the genome for altered gene expression, for example comparing endometriosis and normal (non-endometriosis)cells. The third approach is less indiscriminate and more focused, depending upon identifying specific candidate genes. Aromatase, calhedrin, oestrogen receptor, galactose-1-phosphate uridyl transferase (GALT) and tumour suppressor genes such as p53 are attractive candidate genes for endometriosis. Endometriosis, which has long been suspected to possess a familial tendency, has been subjected to genome-wide linkage analysis in Oxford, UK, where sib-pair analysis uses polymorphic DNA markers and fluorescence-based automated analysis. Several regions of exclusion have been found, but no linkages have so far been reported. A candidate gene approach focuses on the presence of chromosomal aberrations, the assumption being that endometriosis parallels neoplasia. At Baylor College of Medicine, we thus began by showing chromosome alterations involving trisomy 11, monosomy 16 and monosomy 17 in late-stage endometriosis. A loss of only the p53 tumour suppressor gene, rather than a loss (monosomy) of chromosome 17 per se, however, seems to be the pivotal event. A second representative polygenic/multifactorial disorder causing female infertility is polycystic ovarian syndrome. Both quantitative linkage analysis and candidate gene approaches are being pursued. In the far more commonly observed 'idiopathic' variety (non-adrenal polycystic ovarian syndrome and hirsutism), consensus has long existed that one or more dominant genes causes the condition. Although the mode of inheritance in 'essential' polycystic ovarian syndrome remains uncertain, dominant tendencies are clearly more pertinent than recessive ones. Genes for adrenal biosynthetic enzymes, insulin receptors, leptin and leptin receptors, follistatin, activin and inhibins are attractive candidates for polycystic ovarian disease. A linkage to 37 candidate genes was sought using affected sib-pair analysis and transmission/disequilibrium methods.
Best Pract Res Clin Obstet Gynaecol 2002 Oct
PMID:Molecular approach to common causes of female infertility. 1247 48

Hairy-cell leukaemia-variant (HCL-variant) is a rare B-cell disorder which accounts for 10% of HCL cases. It affects elderly or middle-aged males. The main features are splenomegaly, lymphocytosis and cytopenias without monocytopenia. The circulating cells have a morphology intermediate between prolymphocytes and hairy cells. The immunophenotype shows a mature B-cell phenotype with expression of the B-cell antigens CD11c and CD103-but unlike typical HCL the cells are CD25- and HC2-negative. The histology of bone marrow and spleen shows a pattern of infiltration similar to that in HCL. There is no recurrent chromosomal abnormality but complex karyotypes and monoallelic p53 deletion by fluorescence in situ hybridization are common. Patients are resistant to alkylating agents and interferon-alpha (IFN-alpha) and only half achieve partial responses to pentostatin and/or cladribine. Splenectomy results in long-lasting partial responses in over two-thirds of the patients and is a good palliative treatment. Despite the lack of response to most therapies, the clinical course of HCL-variant is chronic. The median survival is 9 years and 42% of patients die of unrelated causes. Transformation to large cell is seen in 6% of patients. The inferior survival in HCL-variant compared with typical HCL cases may reflect the chemotherapy resistance.
Best Pract Res Clin Haematol 2003 Mar
PMID:The variant form of hairy-cell leukaemia. 1267 Apr 64

Human papillomavirus (HPV) infection is the most common sexually transmitted disease, with more than 80% of the population infected at some time in their life. In rare cases, this infection may lead to cervical cancer. Virtually all squamous cell carcinomas and the overwhelming majority of adenocarcinomas of the cervix are HPV positive. HPV integration in the genome will lead to inactivation of the p53 pathway and the Rb pathway. Integration is essential for the onset of cervical carcinogenesis, but is probably not sufficient for progression to invasive cervical cancers. It is likely that several cofactors, such as environmental, viral and host-related factors, are necessary for the development of cervical cancer. There are several similarities and differences between the two major histological types. This article will address the role of HPV in cervical carcinogenesis as well as the molecular biology involved in the process.
Best Pract Res Clin Obstet Gynaecol 2005 Aug
PMID:Role of human papillomavirus in the carcinogenesis of squamous cell carcinoma and adenocarcinoma of the cervix. 1615 Mar 88

Endocrine tumours of the gut and pancreas originate from cells of the diffuse endocrine system and are characterised by the production of a wide variety of bioactive substances including growth factors. Two major tumour categories are distinguished-well-differentiated and poorly differentiated neoplasms-with distinct phenotypes and significantly diverse clinical behaviour. Here, genetic background data are summarised on an anatomical basis for tumours of foregut, midgut and hindgut derivatives. For well-differentiated tumours, independent techniques identified the abnormality of multiple chromosomal sites and genes, pointing to a complex genetic background. Differences in foregut tumours compared with midgut and hindgut tumours are, however, outlined. The multiple endocrine neoplasia syndrome type 1 (MEN1) gene is reported to be involved in about one-third of sporadic foregut endocrine tumours and exceptionally in midgut and hindgut tumours. Similarly, X chromosome markers are associated with malignant behaviour in foregut tumours only. For poorly differentiated carcinomas, a high degree of chromosomal instability is the common genetic trait independent of tumour site and frequently involving the p53 gene.
Best Pract Res Clin Gastroenterol 2005 Aug
PMID:Endocrine tumours of the gastrointestinal tract: aetiology, molecular pathogenesis and genetics. 1618 25


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