RESUMO
PURPOSE: Hypoxic tumors are associated with therapy resistance and poor cancer prognosis, but methods to detect and counter tumor hypoxia remain insufficient. Our purpose was to investigate 64Cu(II)-elesclomol ([64Cu][Cu(ES)]) as a novel theranostic agent for hypoxic tumors, by implementing an improved production method and assessing its therapeutic and diagnostic potential compared to the established Cu-64 radiopharmaceuticals [64Cu]CuCl2 and [diacetyl-bis(N4-methylthiosemicarbazone) [64Cu][Cu(ATSM)]. METHODS: Cu-64 was produced using a biomedical cyclotron at 12 MeV with the reaction 64Ni(p,n)64Cu, followed by synthesis of [64Cu]CuCl2, [64Cu][Cu(ATSM)], and [64Cu][Cu(ES)]. In vitro therapeutic effects were assessed in both normoxic and hypoxic cells (22Rv1 and PC3 prostate cancer cells, and U-87MG glioblastoma cells) using the clonogenic assay and analyzing cellular uptake and internalization. In vivo therapeutic effects were assessed in 22Rv1 xenografts in BALB/cAnN-Foxn1nu/nu/Rj mice receiving a single or multiple doses of radiopharmaceutical, before their feasibility to detect tumor hypoxia was assessed by positron emission tomography (PET) in 22Rv1 and U-87MG xenografts. RESULTS: In vitro and in vivo studies demonstrated that [64Cu][Cu(ES)] reduced cell survival and inhibited tumor growth more effectively than [64Cu][Cu(ATSM)] and [64Cu]CuCl2. Hypoxia increased the cellular uptake and internalization of [64Cu][Cu(ES)] and [64Cu][Cu(ATSM)]. [64Cu][Cu(ES)]-PET tumor hypoxia detection was feasible and also revealed an unexpected finding of uptake in the brain. CONCLUSION: To the best of our knowledge, this is the first time that ES is radiolabeled with [64Cu]CuCl2 to [64Cu][Cu(ES)]. We demonstrated superior therapeutic effects of [64Cu][Cu(ES)] compared to [64Cu][Cu(ATSM)] and [64Cu]CuCl2 and that [64Cu][Cu(ES)]-PET is feasible. [64Cu][Cu(ES)] is a promising theranostic agent for hypoxic solid tumors.
RESUMO
AIM: This study aimed to evaluate the dosimetric impact of uncorrected yaw rotational error on both target coverage and OAR dose metrics in this patient population. BACKGROUND: Rotational set up errors can be difficult to correct in lung VMAT SABR treatments, and may lead to a change in planned dose distributions. MATERIALS AND METHODS: We retrospectively applied systematic yaw rotational errors in 1° degree increments up to -5° and +5° degrees in 16 VMAT SABR plans. The impact on PTV and OARs (oesophagus, spinal canal, heart, airway, chest wall, brachial plexus, lung) was evaluated using a variety of dose metrics. Changes were assessed in relation to percentage deviation from approved planned dose at 0 degrees. RESULTS: Target coverage was largely unaffected with the largest mean and maximum percentage difference being 1.4% and 6% respectively to PTV D98% at +5 degrees yaw.Impact on OARs was varied. Minimal impact was observed in oesophagus, spinal canal, chest wall or lung dose metrics. Larger variations were observed in the heart, airway and brachial plexus. The largest mean and maximum percentage differences being 20.77% and 311% respectively at -5 degrees yaw to airway D0.1cc, however, the clinical impact was negligible as these variations were observed in metrics with minimal initial doses. CONCLUSIONS: No clinically unacceptable changes to dose metrics were observed in this patient cohort but large percentage deviations from approved dose metrics in OARs were noted. OARs with associated PRV structures appear more robust to uncorrected rotational error.
RESUMO
Esophageal adenocarcinoma (EAC) has a poor prognosis and is increasing in incidence in many western populations. Neoadjuvant chemoradiation therapy (CRT) followed by surgery is increasingly the standard of care for locally advanced EAC; however, resistance to treatment is a significant clinical problem. The identification of both novel biomarkers predicting response to treatment and novel therapeutic targets to enhance the efficacy of CRT are key to improving survival rates in EAC. In this study we performed global microRNA (miRNA) profiling of pre-treatment EAC biopsies and identified 67 miRNA significantly altered in patients who are resistant to CRT. One of these miRNA, miR-187, was significantly decreased in pre-treatment EAC tumors from patients having a poor response to neoadjuvant CRT, highlighting downregulation of miR-187 as a potential mechanism of treatment resistance in EAC. In vitro, miR-187 was demonstrated to play a functional role in modulating sensitivity to X-ray radiation and cisplatin in EAC and its dysregulation was demonstrated to be due to chromosomal alterations. In vitro, miR-187 altered expression of a diverse array of pathways, including the immune regulator complement component 3 (C3), serum levels of which we have previously demonstrated to predict patient response to CRT. In vivo, expression of C3 was significantly increased in tumors from patients having a poor response to CRT. This study highlights for the first time a role for miR-187 as a novel biomarker of response to CRT and a potential therapeutic target for enhancing the efficacy of CRT in EAC.
Assuntos
Adenocarcinoma/genética , Cisplatino/farmacologia , Complemento C3/genética , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas/genética , Perfilação da Expressão Gênica/métodos , MicroRNAs/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Adulto , Idoso , Linhagem Celular Tumoral , Quimiorradioterapia , Regulação para Baixo , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Erythropoietin-stimulating agents (ESAs) are used in breast cancer patients with chemotherapy-induced anemia to alleviate anemia and in turn, reduce fatigue. These drugs may also decrease overall survival and increase the incidence of serious adverse effects such as thrombovascular events (TVEs). This review evaluates the evidence to date on administering ESAs to breast cancer patients with chemotherapy-induced anemia. Our findings suggest a clear need for well-designed clinical trials that follow current Food and Drug Administration (FDA) ESA label changes to guide clinical practice in an effort to reduce harm to these patients.
Assuntos
Anemia/tratamento farmacológico , Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Hematínicos/uso terapêutico , Anemia/induzido quimicamente , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Ensaios Clínicos como Assunto , Feminino , Humanos , Metástase NeoplásicaRESUMO
The Y-box binding protein-1 (YBX1) gene codes for a multifunctional oncoprotein that is increasingly being linked to the regulations of many aspects of cancer cell biology. Disparities in treatment outcomes between male and female cancer patients are increasingly reported. This study aimed to examine the relationship between YBX1 expression and overall survival in male and female patients with solid tumours. Overall survival and YBX1 expression data for cohorts of male and female cancer patients obtained from freely available databases were analysed with a cox proportional hazard model with covariates of biological sex and YBX1 expression. Kaplan-Meier curves and Violin plots were constructed for segregated male and female cohorts. High YBX1 expression was significantly associated with poor survival in 2 female-only and 4 mixed-sex cancer sites. In female lung cancer patients, better survival and lower YBX1 expression were identified. The clinical importance of YBX1 expression in cancer ought to be evaluated in a sex-specific manner, especially in lung cancer.
Assuntos
Neoplasias Pulmonares , Humanos , Masculino , Feminino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteína 1 de Ligação a Y-Box/genética , Proteína 1 de Ligação a Y-Box/metabolismo , Regulação Neoplásica da Expressão Gênica , Proliferação de CélulasRESUMO
Over half of patients with cancer receive radiation therapy during the course of their disease. Decades of radiobiological research have identified 6 parameters affecting the biological response to radiation referred to as the 6 "Rs": Repair, Radiosensitivity, Repopulation, Redistribution, Reoxygenation, and Reactivation of the anti-tumour immune response. Extracellular Vesicles (EVs) are small membrane-bound particles whose multiple biological functions are increasingly documented. Here we discuss the evidence for a role of EVs in the orchestration of the response of cancer cells to radiotherapy. We highlight that EVs are involved in DNA repair mechanisms, modulation of cellular sensitivity to radiation, and facilitation of tumour repopulation. Moreover, EVs influence tumour reoxygenation dynamics, and play a pivotal role in fostering radioresistance. Last, we examine how EV-related strategies could be translated into novel strategies aimed at enhancing the efficacy of radiation therapy against cancer.
Assuntos
Vesículas Extracelulares , Neoplasias , Tolerância a Radiação , Humanos , Vesículas Extracelulares/efeitos da radiação , Vesículas Extracelulares/metabolismo , Neoplasias/radioterapia , Reparo do DNA , AnimaisRESUMO
Aberrant activation of Wnts is common in human cancers, including prostate. Hypermethylation associated transcriptional silencing of Wnt antagonist genes SFRPs (Secreted Frizzled-Related Proteins) is a frequent oncogenic event. The significance of this is not known in prostate cancer. The objectives of our study were to (i) profile Wnt signaling related gene expression and (ii) investigate methylation of Wnt antagonist genes in prostate cancer. Using TaqMan Low Density Arrays, we identified 15 Wnt signaling related genes with significantly altered expression in prostate cancer; the majority of which were upregulated in tumors. Notably, histologically benign tissue from men with prostate cancer appeared more similar to tumor (r = 0.76) than to benign prostatic hyperplasia (BPH; r = 0.57, p < 0.001). Overall, the expression profile was highly similar between tumors of high (≥ 7) and low (≤ 6) Gleason scores. Pharmacological demethylation of PC-3 cells with 5-Aza-CdR reactivated 39 genes (≥ 2-fold); 40% of which inhibit Wnt signaling. Methylation frequencies in prostate cancer were 10% (2/20) (SFRP1), 64.86% (48/74) (SFRP2), 0% (0/20) (SFRP4) and 60% (12/20) (SFRP5). SFRP2 methylation was detected at significantly lower frequencies in high-grade prostatic intraepithelial neoplasia (HGPIN; 30%, (6/20), p = 0.0096), tumor adjacent benign areas (8.82%, (7/69), p < 0.0001) and BPH (11.43% (4/35), p < 0.0001). The quantitative level of SFRP2 methylation (normalized index of methylation) was also significantly higher in tumors (116) than in the other samples (HGPIN = 7.45, HB = 0.47, and BPH = 0.12). We show that SFRP2 hypermethylation is a common event in prostate cancer. SFRP2 methylation in combination with other epigenetic markers may be a useful biomarker of prostate cancer.
Assuntos
Metilação de DNA , Epigênese Genética , Perfilação da Expressão Gênica , Proteínas de Membrana/genética , Neoplasias da Próstata/genética , Adulto , Idoso , Linhagem Celular Tumoral , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Neoplasias da Próstata/patologia , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Aberrant gene expression is a hallmark of cancer. Quantitative reverse-transcription PCR (qRT-PCR) is the gold-standard for quantifying gene expression, and commonly employs a house-keeping gene (HKG) as an endogenous control to normalize results; the choice of which is critical for accurate data interpretation. Many factors, including sample type, pathological state, and oxygen levels influence gene expression including putative HKGs. The aim of this study was to determine the suitability of commonly used HKGs for qRT-PCR in prostate cancer. METHODS: Prostate cancer (LNCaP, 22Rv1, PC3, and DU145) and normal (PWR1E and RWPE1) cell lines were cultured in air and hypoxia. The performance of 16 HKGs was assessed using Normfinder and coefficient of variation. In silico promoter analysis was performed to identify putative hypoxia response elements (HREs). The impact of the endogenous control on expression levels of HIF1A and GSTP1 was investigated by qRT-PCR in cell lines and tissue specimens respectively. RESULTS: Hypoxia altered expression of several HKGs: IPO8, B2M, and PGK1. The most stably expressed HKGs were ACTB, PPIA, and UBC. Both UBC and ACTB showed constitutive expression of HIF1A in air and hypoxia, while PGK1 falsely implied a sixfold hypoxia-induced down-regulation. In prostate tumors, UBC and PGK1 both revealed down-regulation of GSTP1 relative to matched benign, whereas ACTB showed variability. CONCLUSIONS: This study demonstrates that no universal endogenous control exists for gene expression studies, even within one disease type. It highlights the importance of validating expression of intended HKGs between different sample types and environmental exposures.
Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Hipóxia Celular/fisiologia , Glutationa S-Transferase pi/biossíntese , Glutationa S-Transferase pi/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Neoplasias da Próstata/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/normas , Células Tumorais CultivadasRESUMO
The development of in vitro isogenic models of radioresistance through exposure to fractionated radiation is an increasingly used approach to investigate the mechanisms of radioresistance in cancer cells. Owing to the complex nature of the biological effect of ionizing radiation, the generation and validation of these models requires the careful consideration of radiation exposure protocols and cellular endpoints. This chapter presents a protocol we used to derive and characterize an isogenic model of radioresistant prostate cancer cells. This protocol may be applicable to other cancer cell lines.
Assuntos
Neoplasias da Próstata , Tolerância a Radiação , Masculino , Humanos , Linhagem Celular Tumoral , Neoplasias da Próstata/radioterapia , Radiação IonizanteRESUMO
BACKGROUND/AIM: Radiomics involves high throughput extraction of mineable precise quantitative imaging features that serve as non-invasive prognostic or predictive biomarkers. High levels of hypoxia are associated with a poorer prognosis in prostate cancer and limit radiation therapy efficacy. Most patients with prostate cancer undergo magnetic resonance imaging (MRI) as a part of their diagnostics, and T2 imaging is the most utilised imaging method. The aim of this study was to determine whether hypoxia in prostate tumors could be identified using a radiomics model extracted from T2-weighted MR images. MATERIALS AND METHODS: Eighty eight intermediate or high-risk prostate cancer patients were evaluated. Prior to radical prostatectomy, all patients received pimonidazole (PIMO). PIMO hypoxic scores were assigned in whole-mount sections from prostatectomy specimens by an experienced pathologist who was blinded to MRI. The region of interest used for radiomics analysis included the prostatic index tumor. Radiomics extraction yielded 165 features using a special evaluation version of RadiomiX [RadiomiX Research Toolbox version 20180831 (OncoRadiomics SA, Liège, Belgium)] for non-clinical use. Multivariable logistic regression with Elastic Net regularization was utilised using 10 times repeated 10-fold cross-validation to select the best model hyperparameters, optimizing for area under the receiver operating characteristic curve (AUC). RESULTS: The average (out of sample) performance based on the repeated cross validation using the ONESE model yielded an AUC of 0.60±0.2. Shape-based features were the most prominent in the model. CONCLUSION: The development of a radiomics hypoxia model using T2 weighted MR images, standard in the staging of prostate cancer, is possible.
Assuntos
Nitroimidazóis , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/patologia , Imageamento por Ressonância Magnética/métodos , Próstata/patologia , Estudos RetrospectivosRESUMO
UNLABELLED: What's known on the subject? and What does the study add? Today, numerous assays for PSA detection are available from various manufacturers. However, these various assays do not detect PSA equally and several studies have demonstrated variability between them. In order to harmonise PSA results and reduce the discrepancies, reference materials are available for assay calibration. We have demonstrated significantly variability between 6 different assay methods currently in use in 9 hospitals despite assay calibration. Variability in PSA values was reduced with the standardisation of the assay method in 4 hospitals. Our results highlight the dilemma of PSA assay variability and stress the need for nationwide standardisation of PSA testing. OBJECTIVE: To determine whether standardization of total prostate-specific antigen (tPSA) assay methods reduces variability in tPSA measurements. PATIENTS AND METHODS: Blood samples from 84 patients attending a single urology department were distributed across nine hospitals selected throughout Ireland for the independent determination of tPSA under the same conditions. The selected hospitals collectively used six different assay methods for tPSA detection: Beckman Hybritech WHO Calibrated (used as reference method), Tosoh AIA 1800, Roche E170 (used in three hospitals), Abbott AxSYM, Immulite 2500 2nd Generation (used in two hospitals) and Siemens ADVIA Centaur. The method of tPSA detection was next standardized in a subset of four hospitals using the same assay method and the measurements were repeated. The difference in mean tPSA in the cohort across the hospitals tested was determined and the Bland-Altman test was used to assess the agreement between each test. Analysis was performed over both the full (0.5-30 µg/L, N = 84) and a narrow (3-7 µg/L, n = 25) tPSA range. RESULTS: The range and the mean tPSA of the full cohort were inflated across the eight test hospitals, when compared with the reference hospital. The poorest agreement between assay methods was associated with a bias of 2.2 ± 2.4 µg/L. The variability in tPSA measurements between assay methods was inconsistent across the range of tPSA values tested and increased with increasing mean tPSA. Agreement in reported tPSA was excellent after standardization of tPSA assay methods (bias <0.2 µg/L). Over the narrow 3-7 µg/L PSA range, 12/25 (48%) patients had a tPSA range of values across all hospitals in excess of 2 µg/L. Following standardization of the tPSA assay method, patient tPSA ranges were <0.5 µg/L for 13/25 (52%) patients. CONCLUSIONS: We have shown that the lack of standardization of tPSA assay methods across a panel of Irish hospitals leads to significant variability in the measured tPSA values for the same patient samples. Variability in tPSA values was reduced with the standardization of the assay method in four hospitals. Standardization of PSA testing on a nationwide scale is warranted.
Assuntos
Detecção Precoce de Câncer/normas , Imunoensaio/normas , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Institutos de Câncer , Estudos de Coortes , Detecção Precoce de Câncer/métodos , Humanos , Masculino , Padrões de Referência , Sensibilidade e EspecificidadeRESUMO
Androgen deprivation therapy is initially successful in treating advanced prostate cancer. However, after a period of time tumors inevitably recur. Improved understanding of the various biochemical causes of resistance to hormonal therapy is of crucial importance for developing more effective therapeutic strategies in this cohort of patients. This review discusses the preclinical evidence for androgen hypersensitivity (AH), as a mechanism by which tumors become hormone-refractory (HR). We propose that the growth of some such tumors may be not only stimulated by, but also dependent on low hormone levels, and furthermore, that normal hormone concentrations can have an inhibitory effect on growth. The incidence and importance of AH merits further investigation both in preclinical studies and during clinical trials of intermittent androgen withdrawal or testosterone replacement. We suggest that a subset of HR prostate cancer patients who have androgen-hypersensitive tumors could be particularly amenable to these treatments. Finally, potential approaches for developing biomarkers to identify such patients are explored.
Assuntos
Antagonistas de Androgênios/farmacologia , Androgênios/farmacologia , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Antagonistas de Androgênios/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Humanos , Hipersensibilidade Tardia/induzido quimicamente , Masculino , CamundongosRESUMO
Decisions on how to treat prostate cancer with radiation therapy are guideline-based but as such guidelines have been developed for populations of patients, this invariably leads to overly aggressive treatment in some patients and insufficient treatment in others. Heterogeneity within prostate tumors and in metastatic sites, even within the same patient, is believed to be a major cause of treatment failure. Radiomics biomarkers, more commonly referred to as radiomics 'features", provide readily available, cost-effective, non-invasive tools for screening, detecting tumors and serial monitoring of patients, including assessments of response to therapy and identification of therapeutic complications. Radiomics offers the potential to analyse whole tumors in 3D, as well as sub-regions or 'habitats' within tumors. Combining quantitative information from imaging with pathology, demographic details and other biomarkers will pave the way for personalised treatment selection and monitoring in prostate cancer. The aim of this review is to consider if MRI-based radiomics can bridge the gap between population-based management and personalised management of prostate cancer.
Assuntos
Imageamento por Ressonância Magnética/métodos , Medicina de Precisão/métodos , Neoplasias da Próstata/radioterapia , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Próstata/efeitos da radiaçãoRESUMO
Background: The sex-neutral language used in preclinical and clinical research intends to be inclusive of both the female and the male population, but the practice of data pooling prevents the detection of the impact of sex on cancer biology and response to medications and treatment. This study aimed to examine the consideration of sex as biological variable in the evaluation of radiation therapy in preclinical and clinical studies.Methods: Preclinical and clinical studies published over a 12-month period were reviewed for the reporting of cells, animal or patient sex and the inclusion of sex as a biological variable in both study design and data analysis.Results: A total of 321 articles met the inclusion criteria: 41 (13%) preclinical and 280 (87%) clinical studies. Two articles reported separate outcome data for males and females. Where the sex of participants was stated (230/280 (82%), 81% reported a larger number of male participants, compared to females. Less than half (45%) of studies used sex as a variable in data analysis. Sex disparity was not dependent on study location but may be more prominent in certain cancer sites. In preclinical studies, sex was at best stated in those reporting on animals (48% of studies).Conclusion: Referring to a radiotherapy cancer patient, the literature is female inclusive, but a gap does exist when it comes to consideration of sex in data analysis. The pooled analysis of female and male data could introduce statistical biases and prevent the identification of key sex-specific biological subtilities that do affect radiation responses.
Assuntos
Neoplasias/radioterapia , Animais , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Distribuição por SexoRESUMO
The use of passively scattered proton therapy (PSPT) or intensity modulated proton therapy (IMPT) opens the potential for dose escalation or critical structure sparing in thoracic malignancies. While the latter offers greater dose conformality, dose distributions are subjected to greater uncertainties, especially due to interplay effects. Exploration in this area is warranted to determine if there is any dosimetric advantages in using IMPT for thoracic malignancies. This review aims to both compare organs-at-risk sparing and plan robustness between PSPT and IMPT and examine the mitigation strategies for the reduction of interplay effects currently available. Early evidence suggests that IMPT is dosimetrically superior to PSPT in thoracic malignancies. Randomised control trials are required before any clinical benefit of IMPT can be confirmed.
RESUMO
Y-box-binding protein 1 (YB-1) is a DNA/RNA binding protein increasingly implicated in the regulation of cancer cell biology. Normally located in the cytoplasm, nuclear localisation in prostate cancer is associated with more aggressive, potentially treatment-resistant disease. This is attributed to the ability of YB-1 to act as a transcription factor for various target genes associated with androgen receptor signalling, survival, DNA repair, proliferation, invasion, differentiation, angiogenesis and hypoxia. This review aims to examine the clinical potential of YB-1 in the detection and therapeutic management of prostate cancer.
Assuntos
Biomarcadores Tumorais , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Proteína 1 de Ligação a Y-Box , Humanos , Masculino , Medicina de Precisão , Neoplasias de Próstata Resistentes à Castração/genéticaRESUMO
BACKGROUND: We proposed to exploit hypoxia-inducible factor (HIF)-1alpha overexpression in prostate tumours and use this transcriptional machinery to control the expression of the suicide gene cytosine deaminase (CD) through binding of HIF-1alpha to arrangements of hypoxia response elements. CD is a prodrug activation enzyme, which converts inactive 5-fluorocytosine to active 5-fluorouracil (5-FU), allowing selective killing of vector containing cells. METHODS: We developed a pair of vectors, containing either five or eight copies of the hypoxia response element (HRE) isolated from the vascular endothelial growth factor (pH5VCD) or glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (pH8GCD) gene, respectively. The kinetics of the hypoxic induction of the vectors and sensitization effects were evaluated in 22Rv1 and DU145 cells in vitro. RESULTS: The CD protein as selectively detected in lysates of transiently transfected 22Rv1 and DU145 cells following hypoxic exposure. This is the first evidence of GAPDH HREs being used to control a suicide gene therapy strategy. Detectable CD levels were sustained upon reoxygenation and prolonged hypoxic exposures. Hypoxia-induced chemoresistance to 5-FU was overcome in both cell lines treated with this suicide gene therapy approach. Hypoxic transfectants were sensitized to prodrug concentrations that were ten-fold lower than those that are clinically relevant. Moreover, the surviving fraction of reoxygenated transfectants could be further reduced with the concomitant delivery of clinically relevant single radiation doses. CONCLUSIONS: This strategy thus has the potential to sensitize the hypoxic compartment of prostate tumours and improve the outcome of current therapies.
Assuntos
Citosina Desaminase/genética , Citosina Desaminase/uso terapêutico , Flucitosina/uso terapêutico , Neoplasias da Próstata/terapia , Tolerância a Radiação/genética , Elementos de Resposta/genética , Hipóxia Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Citosina Desaminase/metabolismo , Flucitosina/metabolismo , Flucitosina/farmacologia , Terapia Genética/métodos , Vetores Genéticos/genética , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , TransfecçãoRESUMO
Low-dose hyper-radiosensitivity (HRS) is the phenomenon whereby cells exposed to radiation doses of less than approximately 0.5 Gy exhibit increased cell killing relative to that predicted from back-extrapolating high-dose survival data using a linear-quadratic model. While the exact mechanism remains to be elucidated, the involvement of several molecular repair pathways has been documented. These processes in turn are also associated with the response of cells to O6-methylguanine (O6MeG) lesions. We propose a model in which the level of low-dose cell killing is determined by the efficiency of both pre-replicative repair by the DNA repair enzyme O6-methylguanine methyltransferase (MGMT) and post-replicative repair by the DNA mismatch repair (MMR) system. We therefore hypothesized that the response of cells to low doses of radiation is dependent on the expression status of MGMT and MMR proteins. MMR (MSH2, MSH6, MLH1, PMS1, PMS2) and MGMT protein expression signatures were determined in a panel of normal (PWR1E, RWPE1) and malignant (22RV1, DU145, PC3) prostate cell lines and correlated with clonogenic survival and cell cycle analysis. PC3 and RWPE1 cells (HRS positive) were associated with MGMT and MMR proficiency, whereas HRS negative cell lines lacked expression of at least one (MGMT or MMR) protein. MGMT inactivation had no significant effect on cell survival. These results indicate a possible role for MMR-dependent processing of damage produced by low doses of radiation.
Assuntos
Reparo de Erro de Pareamento de DNA , Guanina/análogos & derivados , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Doses de Radiação , Tolerância a Radiação , Divisão Celular/efeitos dos fármacos , Divisão Celular/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Reparo de Erro de Pareamento de DNA/efeitos da radiação , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Ativação Enzimática/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Fase G2/efeitos da radiação , Guanina/metabolismo , Guanina/farmacologia , Humanos , Fenótipo , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/efeitos da radiação , TemozolomidaRESUMO
Aspirin has cyclooxygenase-2 (COX2)-mediated anti-inflammatory and anti-coagulant properties that may confer a positive effect in preventing and limiting the progression of prostate cancer. Prostate cancer has been shown to have poor treatment outcomes due to therapeutic resistance; therefore, COX2 inhibition caused by aspirin could represent an opportunity to augment current therapies. This is particularly of interest to patients undergoing radiation therapy (RT) where inflammation is a common side-effect. This review discusses the evidence for the potential role of aspirin in the management of patients with prostate cancer undergoing RT.
Assuntos
Aspirina/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Anti-Inflamatórios não Esteroides/administração & dosagem , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Humanos , Masculino , Neoplasias da Próstata/enzimologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Melatonin is an endogenous hormone primarily known for its action on the circadian rhythms. But pre-clinical studies are reporting both its radioprotective and radiosensitizing properties, possibly mediated through an interaction between melatonin and the regulation of estrogens. Melatonin pre-treatment prior to ionizing radiation was associated with a decrease in cell proliferation and an increase in p53 mRNA expression, leading to an increase in the radiosensitivity of breast cancer cells. At the same time, a decrease in radiation-induced side effects was described in breast cancer patients and in rodent models. This review examines the potential for melatonin to improve the therapeutic outcomes of breast radiation therapy, specifically estrogen receptor positive patients. Evidence suggests that melatonin may offer a novel, non-toxic and cheap adjuvant therapy to improve the existing treatment modalities. But further research is required in the clinical setting before a clear understanding of its therapeutic benefits is determined.