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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
81

Freely available prostate specific antigen testing in a population : testing patterns and outcomes on prostate cancer <i>The Saskatchewan Experience</i>

Tonita, Jon Michael 01 April 2009 (has links)
Background: The prostate specific antigen (PSA) test has been available for physicians and free of charge to residents in Saskatchewan since 1990. The PSA test witnessed great growth in use indicative of screening but it was unknown who was being tested, how often, which physicians were ordering PSA tests, or what the variation in utilization was in the population. Whether widespread use of the PSA test resulted in a stage shift among newly diagnosed prostate cancers or changed the clinical management of the disease was also unknown. The purpose of this research was to describe in detail how the PSA test is being used in the Saskatchewan population and investigate the impact of testing on the diagnosis and clinical management of prostate cancer during the PSA era.<p> Methods: Individual records were retrieved from the two labs in Saskatchewan capable of analyzing PSA serum samples. The PSA data represented almost all PSA tests in the population for the five-year period 1997-2001. The PSA data included date of the PSA test, a unique identifier of the men tested, test results including total PSA and the free-PSA amount (for November 1999 to December 2001), and an ID of the physician who ordered the test. This data was linked to the population-based Saskatchewan Cancer Registry to determine who had a previous or subsequent prostate cancer diagnosis and to secure tumour characteristics and clinical management data. This combined data was then linked to Saskatchewan Health data files to obtain information about biopsy procedures and to determine the geographic residence of men at the time of their PSA tests. De-identified data was returned for descriptive analysis.<p> Results: Over 60% of men aged 50 and over had at least one PSA test during 1997 to 2001. Even among men 40-49, 27% had at least one PSA test and there were over 5,300 tests done in men under 40 years of age. Sixteen percent of men 40-49 who had PSA tests had more than one and this percentage increased with age to 59.4% for men in their 70s. Over 80% of all PSA tests were ordered by general practitioners and there were significant geographic variations in testing patterns. Knowledge of the free-PSA-ratio, which began in 1999, reduced biopsy rates 4.7% and increased cancer detection 8.7% for men with total PSA test results in the 4.0-10.0ng/ml range, however these rates were also very age specific. The age-adjusted incidence rate of organ confined disease increased from 38.5 per 100,000 to 108.8 per 100,000 from 1985 to 2001. Almost 80% of prostate cancers were detected by needle biopsy in 2001 compared to only 34% in 1985, while 20% of cases in 2001 were treated with radical surgery compared to only 2% for 1985. Mortality rates have remained stable up to 2001.<p> Conclusion: PSA testing is very common in Saskatchewan consistent with extensive screening activity. Conflicting guidelines and the universal availability of the test has resulted in significant inappropriate testing and considerable variation of use. Most prostate cancers are now found by needle biopsy and are organ confined at the time of diagnosis. No benefit in prostate cancer mortality has yet been realized in Saskatchewan from extensive PSA testing.
82

Nutritional and hormonal biomarkers in prostate cancer epidemiology

Price, Alison Jane January 2012 (has links)
Evidence from international comparisons and migrant studies suggest that environmental factors, such as a Western diet, may be important in prostate cancer development, possibly through effects on hormone and growth factor secretion and metabolism. However, despite considerable research, convincing associations between diet and risk for prostate cancer have not been established. Random and systematic measurement error in dietary assessment using traditional survey methods may contribute to inconsistent findings, particularly as they may not capture adequately specific nutritional constituents of the diet that may be associated with risk, such as fatty acids or vitamins. Validated biomarkers of nutritional factors and hormonal activity, as used in this thesis, provide more precise, objective and integrated measures of exposure, with the capacity to clarify potential mechanisms in the causal pathway of prostate cancer development. Nutritional and hormonal biomarkers investigated for their potential role in the development of prostate cancer include: folate and vitamin B<sub>12</sub>, which are essential for DNA methylation, repair and synthesis; phytanic acid, obtained predominantly from ruminant fat intake and associated with an enzyme (α-Methylacyl-Coenzyme A Racemase (AMACR)) that is consistently over-expressed in prostate cancer tissue; and insulin-like growth factor (IGF-I), a growth factor influenced by diet and involved in the regulation of cell proliferation, differentiation, and apoptosis. All work presented in this thesis is from the European Prospective Investigation into Cancer and Nutrition (EPIC) study of 500,000 European men and women, using prospectively collected diet and lifestyle data and biological samples. The large number of prostate cancer cases diagnosed during long-term follow-up of EPIC participants enabled investigation of heterogeneity in risk for prostate cancer by time from recruitment to diagnosis (of particular importance for a disease with a long pre-clinical phase) and cancer characteristics such as disease grade and stage. Plasma phytanic acid concentration was highly correlated with dietary intake of fat from dairy products (r = 0.46) and beef (r = 0.30); capturing differences between countries in consumption of fat from these foods. Although phytanic acid is a useful biomarker of ruminant fat consumption, there was little evidence to support the hypothesis that the association between dairy products and prostate cancer risk (as suggested by previous work in EPIC and other studies) is mediated by phytanic acid (OR for doubling in concentration 1.05; 95%CI 0.91 – 1.21; P <sub>trend</sub> = 0.53). There was strong evidence for an association between higher circulating IGF-I concentration and risk for prostate cancer (OR for highest versus lowest fourth 1.69; 95% CI: 1.35, 2.13; P <sub>trend</sub> = 0.0002). Furthermore, the positive association observed among men diagnosed with advanced stage disease and among men diagnosed more than seven years after blood collection, supports the hypothesis that high IGF-I concentration is associated with clinically significant prostate cancer many years before diagnosis. There was no evidence of an association between prostate cancer risk and dietary folate or vitamin B<sub>12</sub> intake, or between circulating levels of folate (OR for doubling in concentration 1.05; 95%CI 0.95 – 1.15; <en>P <sub>trend</sub> = 0.33) or vitamin B<sub>12</sub> (1.05; 95%CI 0.92 – 1.21; P <sub>trend</sub> = 0.47) and only limited evidence for an increased risk associated with elevated vitamin B<sub>12</sub> in a meta-analysis of six prospective studies, that included the present study. All of these analyses were based on a blood sample taken at one point in time, with the assumption that this reflects the ‘true’ underlying concentration over the long-term. The poor to modest reliability estimates (intra-class correlation coefficients ranging from 0.18 to 0.48) for circulating concentrations of folate, IGF-I, phytanic acid and vitamin B<sub>12</sub> taken in samples approximately six years apart in a sub-sample of participants from EPIC Oxford, show that estimates of usual concentrations based on a single blood measurement weaken the ability to detect associations with disease risk. Where small effect sizes are anticipated, this may bias associations toward the null. In conclusion, there is convincing evidence that IGF-I is an important and potentially modifiable risk factor for prostate cancer many years before diagnosis. However, there is little evidence for an association between biomarkers of folate, vitamin B<sub>12</sub> and phytanic acid concentrations and risk for prostate cancer. Future studies should, where possible, incorporate multiple blood samples taken several years apart to better characterise long term relationships between biomarkers of nutritional and hormonal exposure and disease risk and pool individual participant data from multiple prospective studies to strengthen the power to detect modest associations.
83

Genes candidatos a marcadores tumorais na progressão do adenocarcinoma de próstata indentificados por análise de HR-CGH e CGH-ARRAY

Paiva, Greicy Helen Gambarini [UNESP] 01 February 2009 (has links) (PDF)
Made available in DSpace on 2014-06-11T19:32:14Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-02-01Bitstream added on 2014-06-13T19:02:40Z : No. of bitstreams: 1 paiva_ghrg_dr_botib.pdf: 1701322 bytes, checksum: d1fa5b5c562a2a6ce8ad0d14ab948d4a (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O câncer de próstata (CaP) é a neoplasia mais comumente diagnosticada entre homens no ocidente. Embora tratamentos efetivos para a doença localizada estejam disponíveis atualmente, não há terapia curativa para tumores metastáticos. Além disso, os marcadores diagnósticos utilizados na clínica não conseguem discriminar totalmente a evolução diferencial da doença. Desta forma, o conhecimento das diferenças biológicas entre tumores primários confinados ao órgão e metástases é essencial para o desenvolvimento de novos marcadores e identificação de alvos terapêuticos. Neste estudo a análise baseada na metodologia de HR-CGH cromossômico foi realizada para identificar alterações de ganhos e perdas genômicas em três grupos de amostras: o grupo I, que compreende amostras pareadas de tumor primário e respectivas metástases (11 casos); o grupo II, constituído de pacientes que apresentaram seguimento clínico favorável por mais de 10 anos (5 casos); e o grupo III, constituído por diferentes biópsias do mesmo paciente (5 pacientes com 2 biópsias cada). As amostras foram microdissecadas (amostras a fresco: a partir de lâminas de referência; em blocos de parafina: a laser) e após a obtenção de DNA foram amplificadas (amostras de arquivo: PCR-SCOMP) ou marcadas por nick-translation para a realização de HR-CGH. Os resultados de HR-CGH foram comparados com os dados obtidos da análise de CGH-array num subgrupo de amostras e revelaram concordâncias significativas. Os resultados obtidos na presente investigação revelaram perdas dos cromossomos 1p, 2, 3q, 4p, 5q, 7, 8, 9q, 10q, 11q, 12q, 14q, 15q, 16q, 17q, 18q, 19, 20q e 22q em 80% dos casos avaliados. Além disso, perdas em 17q11.2-25, por exemplo, foram detectadas exclusivamente nos tumores do grupo I e nas suas metástases, e não nos tumores do grupo II, sugerindo que esta alteração deve ser importante... / Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer mortality in men from Occident. Although effective treatments for the localized disease are available, there is no efficient therapy for metastatic tumors. Additionally, clinical diagnostic markers are not able to completely discriminate the differential evolution of the disease. The knowledge of biological differences between localized primary tumors and metastasis can establish new molecular markers and therapeutic targets. In this study, an analysis based on HR-CGH methodology was performed to identify imbalances genomic in three groups of samples: group I, paired samples of primary tumors and its metastasis (11 cases); group II, patients that exhibited favorable follow-up over 10 years (5 cases); and group III, different biopsies from the same patient (5 patients with 2 biopsies each). The tumor samples were submitted to microdissection procedures (fresh samples: from reference slides; paraffin embedded samples: laser), DNA extracted and amplified (archive sample: PCR-SCOMP) or labeled by nick-translation to HR-CGH. The HRCGH results were compared with data obtained from CGH-array analysis of a subgroup of samples and revealed significant concordances. In the present investigation, there were observed losses on chromosomes 1p, 2, 3q, 4p, 5q, 7, 8, 9q, 10q, 11q, 12q, 14q, 15q, 16q, 17q, 18q, 19, 20q and 22q in 80% of the cases. Losses in 17q11.2-25, for instance, were detected exclusively in tumor from group I and its metastasis, but were not found in tumors from group II, suggesting that this alteration must be important in the progression of the disease. Five genes were selected after the comparison between the HR-CGH and CGH-array data. The tumor suppressor genes ARID1A, MTSS1, NME1 and S100A4 and TOP2A (oncogenes) were evaluated by quantitative real time... (Complete abstract click electronic access below)
84

Metastatic characteristics of tumor progression in Prostate Cancer

Donald, Carlton Dewitt 01 March 1995 (has links)
Tumor biologist have long appreciated that both cell to cell and cell to extracellular matrix (ECM) interactions are involved in the invasive and metastatic events that are characteristic of malignancy. Cancer cell attachment to and invasion of an ECM has been associated with metastatic potential of cell lines of the Dunning rat prostate model. It was postulated that differences observed in the metastatic potential of four Dunning cell lines may correlate with cell-matrix interactions. Four cell lines, highly metastatic ML, MLL, AT-3 and non-metastatic AT-1 were studied. The adhesive, invasive and chemoinvasive capability of each cell line was compared. Cell adhesion was examined by plating the cells on plastic dishes coated with various components of the ECM (fibronectin, laminin and collagen) as well as EHS Natrix (a natural ECM) . Invasion was determined by examining cells ability to traverse a matrigel barrier. Correlations were found between the cells' adhesive and invasive abilities in response to the ECM. These observations suggest that ECM components are highly involved in prostate cancer cell activities and loss may contribute to tumor progression and metastasis.
85

An evaluation of novel antineoplastic agent on prostate cancer

Parker- Johnson, Kitani A. 01 July 2003 (has links)
This study examines the effects of novel antineoplastic agents(isochalcones) on human metastatic prostate cancer cell lines by screening cells for their relative antiproliferative effects, measuring the protein expression levels of specific oncogenes by Western blotting, and evaluating an array of genes ( 5184) to determine possible mechanisms of action of these novel isochalcones. The array data were supported by real-time polymerase chain reaction (PCR) techniques. The antineoplastic agents were screened in human metastatic prostate cancer cell lines (LNCaP, DU145, PC-3, and MDA-PCa-2b) and non-cancerous prostate epithelial cell line PZ-HPV-7 in concentrations ranging from nanomolar to millimolar. The alamar blue exclusion dye assay, a redox indicator, was used to evaluate cell proliferation when compared to the untreated control. DJ52 demonstrated a growth inhibitory effect on LNCaP, PC-3, and DU145 cell lines at the micromolar concentration (p<0.05). Based on these data, 1 x 106 cells were treated, protein isolated, and expression levels of epidermal growth factor (EGF) and omithine decarboxylase (ODC) were measured and compared to theuntreated controls. These data indicated a dose-dependent decrease of expression of EGF and ODC, therefore, suggesting that other key oncogenes may also have a decrease in expression when treated with these novel antineoplastic agents. Therefore, gene arrays were used to identify possible families of genes and/or specific pathways that may be responsible for the antiproliferative effects noted. It was determined that the key families of genes significantly induced by these agents (Pathways 4®) were proapoptotic and cell cycle regulators. ABI 7700 Prism was used to perform quantitative RT-PCR via the AB Sequence Detector® software.
86

Genetic epidemiology of prostate cancer statistical analyses of genome-wide association studies of prostate cancer

Amin Al Olama, Seyed Ali January 2013 (has links)
No description available.
87

Roles of Nanog, a transcription factor for self-renewal of embryonic stem cells, in prostate tumor initiation and chemoresistance

Wang, Man-Tzu 01 December 2010 (has links)
Prostate cancer is one of the most common cancers affecting one of every six men in United States. It is increasingly appreciated that tumor or cancer stem cells are the cells responsible for initiating tumor formation and therefore should be targeted for eradication in cancer treatment. But the mechanism involved in the acquisition of unlimited self-renewal and tumor initiation by cancer stem cells is unknown. Nanog, along with Oct3/4 and Sox-2, constitute the core transcriptional circuitry for the maintenance of stemness in embryonic stem cells. Herein we report that Nanog expression was detected at mRNA and protein levels in prostate cancer cells. The Nanog-expressing LNCaP-T and DU145 cells were enriched by infection with lentiviruses expressing GFP under the control of Nanog promoter. The Nanog-enriched prostate cancer cells had stronger expressions of stem and progenitor cell surface markers, including CD44 and CD133, when compared with those in the control group. Colony formation assay found that the Nanog-enriched LNCaP-T and DU145 cells formed more holoclones and prosta-spheres, which contained more self-renewing cells, than the control cells did. On the other hand, knockdown of Nanog in DU145 or LNCaP-T cells, via shRNAs, reduced their ability to form holoclones. Instead, most clones derived were meroclone and paraclones as result of increased differentiation and senescence due to knockdown of Nanog. When injected into mice, Nanog-enriched DU145 cells were found to possess increased tumorigenic potentials when compared to the vector controls. On the other hand, LNCaP-T cells with Nanog knocked down did not form tumors, while the vector controls readily formed tumors. Taken together, our data suggest an essential role for Nanog in the self-renewal and tumor initiation of prostate cancer cells. Chemotherapy is the major salvage therapeutic modality available for the patients with advanced cancers. However, drug resistance by some prostate cancer cells is a major barrier to efficacious chemotherapy. It has been increasingly appreciated that cancer stem cells are responsible for resistance to chemo- or radio-therapy, in addition to tumor initiation. However, the mechanisms involved remain unknown. In this study, we examined whether Nanog plays an essential role of Nanog in resistance to chemotherapy. In the surviving fractions of prostate cancer cells, we found increased levels of Nanog protein when compared to the cells treated with solvent control. To determine the role of Nanog in resistance of prostate cancer cells, we marked and enriched Nanog-expressing prostate cancer DU145 and LNCaP-T cells using a reporter gene under control of 2.5 kb hNanog1 promoter. When compared to the control, the prospectively enriched Nanog-expressing cells presented increased resistance to Taxol, vinblastine, and doxorubicin. Profiling of genes in drug resistance and metabolism revealed a marked increase in the mRNA level of ATP-binding cassette (ABC) efflux transporters B1 and G2 in tumor cells enriched with endogenous Nanog expression. The increased expression of ABCB1 and ABCG2 at protein levels in Nanog expressing cells was confirmed by Western blot and immunocytochemistry. Inhibition of ABCB1 activities sensitized Nanog expressing cells toward Taxol and vinblastine, and to less extent, doxorubicin. Blocking of ABCG2 activity sensitized Nanog expressing cells toward doxorubicin, but not Taxol and vinblastine. In addition, the tumor cells enriched with Nanog expression showed reduced apoptosis in response to Taxol treatment. Interestingly, Nanog-enriched prostate carcinoma cells displayed aberrantly activated â-catenin signaling, which is potentially associated with their increased chemo-resistant ability as well as the increased acquisition of epithelial to mesenchymal transition. In summary, Nanog is expressed in prostate cancer cells, especially in those positive for stem/progenitor markers. Enrichment of Nanog expressing cells led to enrichment of tumor cells with increased tumor initiating ability and increased resistance toward chemotherapy. Knockdown of Nanog reduces tumor initiating ability of prostate cancer cells and further sensitizes them toward chemotherapy. The gain-of-function and loss-of-function studies suggest an essential role of Nanog for prostate cancer cells to initiate tumor formation and resist chemotherapy.
88

Determining Biological Effectors of alpha6 Integrin Cleavage

Kacsinta, Apollo Daniel January 2010 (has links)
Cancer metastasis is a multi–step process that initiates with a tumor cell obtaining the ability to migrate. A multitude of changes occur in such a cell including changes to cell adhesion molecules such as integrins. In cancer cells, integrins are known to be involved in migration, invasion and metastasis. Investigation by our group of the α6 integrin led to the discovery of a cleaved form of the integrin lacking the ligand binding domain, called α6p. While it is known that the integrin is cleaved by urokinase plasminogen activator (uPA) little is known about how this process is regulated. There is a need to better understand the players involved in regulation of α6 cleavage as inhibiting this event from occurring may contribute to prolonged or increased patient survival or ultimately a cure.The existence of the integrin–actin complex has been known for many years. In this study actin was identified as a potential regulator of α6 cleavage. Using a diverse set of tumor cell lines (DU145, PC3 and MDA–MB–231) and a number of actin modifing compounds (latrunculin A, jasplakinolide and siRNA) it is reported here that disassembling actin filaments leads to an increase in α6p production. Although the increase in cleavage product did not always correlate with an increase in uPA receptor, an increase in uPAR was observed when actin was complexed by small molecule inhibitors. Taken together the results demonstrate a potential role for actin filaments to protect α6 integrin from uPA–uPAR induced cleavage via a multi–protein complex.
89

A study of the role of spermidine/spermine N¹-acetyltransferase (SSAT) in polyamine homeostasis in human prostate cancer cells

Li, Jun January 2014 (has links)
Prostate cancer is the second leading cancer in men. A large amount of polyamines are synthesised in the human prostate and are involved in prostate cell growth and its physiological functions. The content of intracellular polyamines is closely related to cell growth. An increase in cell growth is accompanied by a rise of intracellular polyamine content, and a depletion of intracellular polyamine pools can cause growth arrest or cell death. Therefore, maintaining polyamine concentrations is critical to the cell. Spermidine/spermine N1-acetyltransferase (SSAT) is the first and rate-limiting enzyme in the polyamine catabolic pathway. SSAT gene is highly inducible, with many stimuli including polyamine analogues and some anticancer drugs producing dramatic increases in activity. Many studies have focussed on polyamine analogues as inducers of SSAT activity as increases in SSAT are associated with a growth inhibition in many tumour cells. However, the mechanisms of this inhibition are not fully understood with respect to polyamine content. Additionally, in vivo results in SSAT transgenic mice studies are contradictory. For example, prostate carcinogenesis is reduced in TRAMP mice but Apcmin/+ mice show a promoted intestinal tumorigenesis. It is thus necessary to characterise the regulation of polyamine content and metabolism by SSAT in prostate cancer cells. The aim of the present study was to characterise the role of SSAT in both the growth of LNCaP prostate carcinoma cells and the response of these cells to anticancer drugs. Our hypothesis is that increased SSAT activity will inhibit cell growth and that this is associated with a decrease of intracellular polyamine pools. Furthermore, if SSAT induction is an essential part of the response of cancer cells to anticancer drugs, then altered SSAT activity should affect sensitivity of the cells to the drugs. The present study used a cell culture model of human prostate cancer: LNCaP wild type (WT) and SSAT cDNA transfected prostate carcinoma cell lines. The expression of SSAT in the transfected cell line (SSAT- & SSAT+) was controlled through the “Tet-off” system. This model system provided a background for comparison of effects under basal (WT), low (SSAT-), and high (SSAT+) SSAT activity. Due to our interest in acetylpolyamine derivatives and their low concentrations in cells, a new method for quantifying polyamine concentrations was developed using liquid chromatography-mass spectrometry (LC-MS). This method was highly sensitive and can detect polyamines about 250 fold lower than HPLC, as well as N-acetylpolyamines and N1,N12-diacetylspermine. In addition, a variety of methods were utilised to measure cell growth, enzyme activity, protein expression, polyamine efflux and apoptosis, which includes enzyme assays, western blot, radiochemical labelled assays, flow cytometry, spectrophotometry and fluorescent microscopy. A stable increase in SSAT activity was inhibitory to the cell growth. This inhibition was associated with significant changes in the activity of the polyamine pathway. The alterations included an increase in ODC, APAO, and SMO activity; an accumulation of intracellular N1-acetylspermidine and putrescine; a decrease in intracellular spermidine and spermine; an increased polyamine flux and efflux; and an increase in apoptosis. Combination treatment to the cells with DFMO and MDL72527 partially restored the growth of SSAT+ cells. The original contribution of this study to the field is that the cells with a higher SSAT activity are less sensitive to aspirin and 5-FU, and the sensitivity increased while the overexpressed SSAT activity decreased. The growth inhibition was associated with a depletion of total intracellular polyamine pools by the drug treatments. Moreover, to our knowledge, it is first time that the extracellular polyamine concentrations were quantified by LC-MS in human tumour cells. Overall, an increase in SSAT activity led to an inhibition of prostate cancer cell growth, and vice versa. Thereby, this study suggests that SSAT is a potential target for novel drug discovery for cancer chemotherapy or chemoprevention. For example, a combination treatment could be designed that acts as an inducer of SSAT activity in tumour cells, leading to an inhibition of the cell growth in the first place and increased sensitivity to cytotoxic agents. This would then be followed by an agent to decrease SSAT activity when the sensitivity of cancer cells to the cytotoxic treatment was optimal.
90

Ethonafide-Induced Cytotoxicity is Mediated by Topoisomerase II Inhibition in Human Prostate Cancer Cells

Pourpak, Alan January 2006 (has links)
Ethonafide is an anthracene-containing derivative of amonafide that belongs to the azonafide series of anticancer agents. The lack of cross-resistance in MDR-expressing cancer cell lines and the absence of a quinone and hydroquinone moiety make ethonafide a possible less-cardiotoxic replacement for existing anthracene-containing anticancer agents, such as mitoxantrone and doxorubicin. For this study, we investigated the anticancer activity and mechanism of action of ethonafide in human prostate cancer cell lines. Ethonafide was cytotoxic against three human prostate cancer cell lines at nanomolar concentrations. Ethonafide was also found to be better tolerated and more effective at inhibiting tumor growth compared to mitoxantrone in DU 145 prostate cancer-bearing mice. Mechanistically, we found that ethonafide inhibits topoisomerase II activity in human prostate cancer cell lines and equally inhibits purified topoisomerase IIα and recombinant topoisomerase IIβ. The inhibition of topoisomerase II activity was due to stabilization of the cleavable complex, involving both topoisomerase IIα and β. By creating stable DU 145 cell lines with decreased expression of either topoisomerase IIα or β, we found that topoisomerase IIα is necessary for ethonafide-induced cytotoxicity. The decrease in sensitivity to ethonafide was due to a decrease in DNA damage and an increase in DNA repair as measured by the neutral comet assay. Additionally, ethonafide induces potent G₂ cell cycle arrest in the DU 145 human prostate cancer cell line. Ethonafide also induces apoptosis as measured by procaspase and PARP cleavage. In conclusion, we have identified ethonafide as a topoisomerase II poison and determined that it is topoisomerase IIα-specific in the DU 145 human prostate cancer cell line. Due to ethonafide’s activity in vitro and in vivo, decreased toxicity in mice compared to mitoxantrone, and its activity in multi-drug resistant cancer cell lines, ethonafide may be a suitable replacement to mitoxantrone for the treatment of hormone-refractory prostate cancer.

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