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1 RNA HELICASES and CANCER Mohamed Abdelhaleem Division Of Abstracts of the 7th International Conference of Anticancer Research, 25-30 October 2004, Corfu, Greece 1 The hepatitis C virus (HCV) is a major cause of chronic RNA HELICASES AND CANCER liver disease worldwide, with approximately 170-200 million people infected. The HCV viruses are transmitted by blood Mohamed Abdelhaleem and blood products and such transmission now occurs, Division of Haematopathology, Department of Paediatric primarily, through injection drug use, sex with an infected Laboratory Medicine, Hospital for Sick Children, 555 partner or multiple partners and occupational exposure. University Avenue, Toronto, Ontario, M5G 1X8, Canada The severity of the disease varies widely from mild chronic hepatitis to cirrhosis and hepatocellular carcinoma (HCC). RNA helicases are conserved enzymes that utilize the energy Nowadays, the reference treatment is combination therapy derived from NTP hydrolysis to unwind double stranded RNA with pegylated interferon and ribavirin, which is an IMP molecules. The amino acid sequence of an RNA helicase is dehydrogenase inhibitor and immunomodulator. The characterized by the presence of a centrally located "helicase efficacy of treatment in our clinical trials was 87% in domain", consisting of eight motifs. Based on variations of the patients infected by HCV genotype 2 or 3, whereas in sequence of the motifs of the helicase domain, RNA helicases patients infected by HCV genotype 1 response to treatment are further classified into families. We have recently identified was 66%. The current combination treatment has significant the two largest human RNA helicase gene families. DDX and side-effects and is sometimes poorly-tolerated. HCV DHX gene families are named after the DEAD-box and genotypes 2 or 3 can be treated with a lower dose of DEAH box (where DEAD and DEAH represent the one- ribavirin and a shorter course of therapy, 24 weeks vs 48 letter-code of the amino acids constituting motif II, the weeks per patients with genotype 1. There is a growing signature motif, of the helicase domain). consensus that acute control of HCV infection is associated RNA helicases play an essential role in various aspects of with a vigorous intrahepatic antiviral CD4+ and CD8+ T RNA metabolism including transcription, splicing, translation cell response, enhanced T(H)1 and natural killer activity. and degradation. Dysregulation of any of these critical steps Pretreatment genotype and response to therapy measured can potentially affect the final expression of cellular proteins at weeks 12 and 24 of treatment have been identified as key and consequently determine cell fate. There are several determinants in decision making about continuing examples of dysregulation of RNA helicases in cancer. The treatment. Elevated serum ferritin levels and hepatic iron majority of cases involve up-regulation. Thus, DDX1, DDX2, deposition, as well as hepatic steatosis and high ALT levels DDX5, DDX6, DHX9, DDX43, DDX48, and DDX53 have with chronic hepatitis C, are risk factors for HCC been shown to be up-regulated in various types of cancer. development. Heterozygosity for the C282Y mutation in DDX6 and DDX10 are involved in lymphoma/leukemia- HFE contributes to iron accumulation and fibrosis associated chromosomal translocations. DHX32 is a novel progression in chronic hepatitis C. Ribavirin could cause helicase with unique structure, expression pattern and sub- dose-dependent reversible haemolytic anaemia, it could be cellular localization, which was originally identified as a gene managed with RBV dose reductions or with administration down-regulated in acute lymphoblastic leukemia. In addition of epoetin alpha at 40,000 IU once weekly, without to dysregulation of expression in cancer, RNA helicases have sacrificing optimal dosing of RBV. Among patients who been shown to be involved in the regulation and molecular received ribavirin alone, serum ALT levels and interaction with molecules implicated in cancer. For example, necroinflammatory features of liver histology were DDX5 and DDX17 regulate the alternative splicing of the improved, whereas symptoms, HCV RNA levels and hepatic proto-oncogene c-H-ras and CD44 (adhesion molecule fibrosis scores were not changed significantly from baseline. implicated in metastasis), respectively. DHX9 affects the For HCV-HIV-coinfected patients, treatment is given when transcription of tumor suppressor gene p16 and p- blood CD4 counts are above 350/ml and before glycoprotein and functionally interacts with the breast and antiretroviral (ART) treatment is needed. ovarian cancer tumor suppressor gene BRCA1. Further characterization of the role of RNA helicases in cancer is 3 required. Studies suggest that helicases could be potential NEUROENDOCRINE DIFFERENTIATION IN targets of novel therapeutic agents. PROSTATIC CARCINOMA Per-Anders Abrahamsson 2 RIBAVIRIN IN TREATMENT OF HEPATITIS C Department of Urology, Malmö University Hospital, Lund University, S-205 02 Malmö, Sweden Margit E. Abonyi and Peter L. Lakatos First Department of Medicine, Semmelweis University, The statistics for prostate cancer make alarming reading and Koranyi Sandor str. 2/a, 1083 Budapest, Hungary set undoubted challenges for oncological research. In the 3415 ANTICANCER RESEARCH 24: 3393-3698 (2004) Western world, where the incidence is highest, a man has a are differentiated cancer cells, a subset of androgen- 10-11% chance of developing clinically apparent prostate independent cancer cells, that regulate the proliferation of cancer, and a 3-4% chance of dying from the disease. In many neighbouring non-NE phenotype cancer cells in a paracrine countries prostate cancer is now the second leading cause of fashion by secretion of NE products. NE differentiation in cancer-related death and in Northern Europe it has already PC, including its identification, quantitation and evaluation taken number one position as the leading cause of cancer- in the presence of prostate cancer, has been recognised as related death in males. In view of its profound impact on the one of the future directions for basic research in PC. healthcare sector, our current knowledge of the factor(s) In PC, NE differentiation occurs in from 60% to almost responsible for the development of benign or malignant 100% of tumours, depending on how tissues are fixed and neoplastic changes in the prostate is surprisingly rudimentary. what immunohistochemical techniques are used. In some The widely accepted concept of the human prostate as an cases, the NE differentiation may even be the predominant organ dependent on androgens for its normal development phenotype. The most common pattern of NE differentiation and function has been corroborated over the years by in PC is a prostatic adenocarcinoma with scattered NE cells. numerous studies. Thus, the elucidation of androgens and The frequent occurrence of NE differentiation in PC most androgen receptors, and their effects on prostate physiology probably reflects the differentiation potentials of prostatic and biochemistry, has been the central theme in prostate stem cells. NE cells in individual malignant acini often research for more than fifty years, and different surgical and retained certain morphological characteristics found in the drug-related androgen ablation treatments have been benign counterpart, i.e. dendritic processes extending laterally developed. However, it has also become apparent that, as an around adjacent non-NE phenotype cancer cells, yet clear accessory male sex-organ, the prostate is not exclusively cytological features of malignancy are consistently present. dependent on androgens, but also on additional factors of Both in normal prostate and in PC, NE phenotype cells paramount importance in maintaining normal prostate consistently lack the proliferation marker Ki67, as function and in the development of various pathological documented by immunohistochemistry, while malignant cells conditions. Currently, there is increased awareness of the vital in the vicinity of NE cells have a higher Ki67-index than but complex regulatory function of cell-to-cell communication distant cells. This indicates that NE cells are probably at the local prostatic level. The importance of peptide terminally-differentiated, although one can not exclude the hormones, growth factors, autocrine-paracrine regulatory possibility that these cells might dedifferentiate and lose their loops and stromal-epithelial interactions is now widely NE features when dividing. The identification of NE cells in recognised. In this context, a type of cell, commonly referred regional lymph node deposits and osseous metastases implies to as neuroendocrine cells, has attracted attention owing to that they are unlikely to be "innocent" (i.e. unrelated to the intriguing link between neuroendocrine cell differentiation prostatic carcinogenesis) cells trapped in PC. and tumour progression in prostate cancer. The scientific There are some indications that NE differentiation in PC understanding of the normal prostatic neuroendocrine cell may portend a poor prognosis and resistance to hormonal and neuroendocrine differention in prostatic carcinoma (PC) therapy. It was concluded, in several studies, that the – with clinical implications in terms of prognosis and therapy detection of NE cells is a significant predictor of poor – originate, to a large extent, from our laboratories. survival. It has also been shown that serum levels of neuron The mainstay for PC control is radical surgery or specific enolase and CgA correlate with
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