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1.
Cell Prolif ; 53(10): e12900, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32914514

RESUMO

Colorectal cancer (CRC) has become a concern because of its high recurrence rate and metastasis rate, low early diagnosis rate and poor therapeutic effect. At present, various studies have shown that autophagy is closely connected with the occurrence and progression of CRC. Autophagy is a highly cytosolic catabolic process involved in lysosomes in biological evolution. Cells degrade proteins and damaged organelles by autophagy to achieve material circulation and maintain cell homeostasis. Moreover, microRNAs are key regulators of autophagy, and their mediated regulation of transcriptional and post-transcriptional levels plays an important role in autophagy in CRC cells. This review focuses on the recent research advances of how autophagy and related microRNAs are involved in affecting occurrence and progression of CRC and provides a new perspective for the study of CRC treatment strategies.


Assuntos
Autofagia , Neoplasias Colorretais/patologia , MicroRNAs/metabolismo , Antineoplásicos/uso terapêutico , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Pontos de Checagem do Ciclo Celular/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/radioterapia , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
2.
J Cancer Res Clin Oncol ; 146(10): 2509-2517, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32620986

RESUMO

BACKGROUND: Colorectal cancer (CRC) is now a major human cancer, and B-cell translocation gene 3 (BTG3) has been reported as a tumor-suppressor in CRC, but its upstream regulator has not been identified. METHODS: Endogenous expression levels of BTG3 were compared between normal colorectal cell line CCD-18Co and two CRC cell lines SW480 and HT29, as well as between CRC patient tumor and adjacent normal tissues. Analysis of BTG3 genomic region was performed which identified a putative hypoxia response element (HRE). Effects of hypoxia condition, BTG3 overexpression, and their combination on the radiation sensitivity of CRC cell lines were assessed. RESULTS: BTG3 was downregulated in CRC cell lines and patient tumor samples, via the HRE in its promoter region. Hypoxia and BTG3 overexpression could both induce radiation resistance in CRC cells. Combining hypoxia with BTG3 overexpression effectively rendered the resistance of CRC cells to radiation to a level lower than hypoxia alone and higher than normoxia alone, indicating the essential role of BTG3 in hypoxia-induced radiation resistance of CRC cells. CONCLUSION: We therefore propose a novel signaling cascade involving hypoxia/BTG3 to be a potential risk factor for CRC patients undergoing radiation therapy, which could possibly serve as therapeutic targets among CRC patients with acquired radiotherapy resistance.


Assuntos
Proteínas de Ciclo Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/radioterapia , Idoso , Apoptose/efeitos da radiação , Proteínas de Ciclo Celular/biossíntese , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HT29 , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Tolerância a Radiação , Elementos de Resposta
3.
J Cancer Res Clin Oncol ; 146(10): 2575-2587, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32715436

RESUMO

BACKGROUND: Limited treatment options are available in chemotherapy-refractory metastatic colorectal cancer (mCRC). The objective was to conduct a systematic literature review (SLR) and exploratory network meta-analysis (NMA) to compare the tolerability and effectiveness of SIRT with Y-90 resin microspheres, regorafenib, TAS-102 (trifluridine/tipiracil), and best supportive care (BSC) as third-line treatment in patients with mCRC. METHODS: An SLR was conducted to identify studies comparing two or more of the treatments and reporting overall survival (OS), progression-free survival, tumor response, or adverse event (AE) incidence. An exploratory NMA was conducted to compare hazard ratios (HRs) for OS using Markov chain Monte Carlo (MCMC) techniques. RESULTS: Seven studies were identified in the SLR: two double-blind randomized-controlled trials (RCT) for each drug, one open-label RCT, and two non-randomized comparative studies for SIRT. Patient selection criteria differed between studies, with SIRT studies including patients with liver-dominant colorectal metastases. Nausea and vomiting were more frequent with TAS-102 than regorafenib or SIRT; diarrhea was more common with TAS-102 and regorafenib than SIRT. The exploratory NMA suggested that all active treatments improved OS, with HRs of 0.48 (95% CrI 0.30-0.78) for SIRT with Y-90 resin microspheres, 0.63 (0.38-1.03) for TAS-102, and 0.67 (0.40-1.08) for regorafenib each compared to BSC. CONCLUSIONS: Regorafenib, TAS-102 and SIRT using Y-90 resin microspheres are more effective than BSC in third-line treatment of mCRC; however, study heterogeneity made comparisons between active treatments challenging. SIRT is a viable treatment for third-line mCRC and its favorable AE profile should be considered in the therapeutic decision-making process.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Braquiterapia/métodos , Neoplasias Colorretais/dietoterapia , Neoplasias Colorretais/radioterapia , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Pirrolidinas/uso terapêutico , Trifluridina/uso terapêutico , Uracila/análogos & derivados , Radioisótopos de Ítrio/administração & dosagem , Método Duplo-Cego , Combinação de Medicamentos , Humanos , Microesferas , Metástase Neoplásica , Metanálise em Rede , Cuidados Paliativos/métodos , Compostos de Fenilureia/administração & dosagem , Intervalo Livre de Progressão , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Trifluridina/administração & dosagem , Uracila/administração & dosagem , Uracila/uso terapêutico
4.
Int J Nanomedicine ; 15: 3843-3850, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32581534

RESUMO

Purpose: Despite tremendous results achieved by immune checkpoint inhibitors, most patients are not responders, mainly because of the lack of a pre-existing anti-tumor immune response. Thus, solutions to efficiently prime this immune response are currently under intensive investigations. Radiotherapy elicits cancer cell death, generating an antitumor-specific T cell response, turning tumors in personalized in situ vaccines, with potentially systemic effects (abscopal effect). Nonetheless, clinical evidence of sustained anti-tumor immunity as abscopal effect are rare. Methods: Hafnium oxide nanoparticles (NBTXR3) have been designed to increase energy dose deposit within cancer cells. We examined the effect of radiotherapy-activated NBTXR3 on anti-tumor immune response activation and abscopal effect production using a mouse colorectal cancer model. Results: We demonstrate that radiotherapy-activated NBTXR3 kill more cancer cells than radiotherapy alone, significantly increase immune cell infiltrates both in treated and in untreated distant tumors, generating an abscopal effect dependent on CD8+ lymphocyte T cells. Conclusion: These data show that radiotherapy-activated NBTXR3 could increase local and distant tumor control through immune system priming. Our results may have important implications for immunotherapeutic agent combination with radiotherapy.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/radioterapia , Háfnio/farmacologia , Óxidos/farmacologia , Animais , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacocinética , Disponibilidade Biológica , Linfócitos T CD8-Positivos/imunologia , Neoplasias Colorretais/imunologia , Feminino , Háfnio/química , Háfnio/farmacocinética , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/química , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/radioterapia , Óxidos/química , Óxidos/farmacocinética
5.
J Food Sci ; 85(6): 1924-1931, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32418198

RESUMO

Radioresistance is an important factor affecting the radiotherapy effect of colorectal cancer (CRC). Allicin is a versatile sulfur-containing organic compound extracted from garlic (Allium sativum L.), which has many pharmacological effects. However, the effect of allicin on the sensitivity of CRC radiotherapy has not been confirmed. The present study is to observe the radiosensitivity effects of allicin and to explore its mechanism in CRC radiotherapy. The proliferation inhibition effects of allicin combined with X-ray radiotherapy in HCT116 cells were measured by growth curve of cell and colony formation assays. The cell apoptosis was detected by Hoechst 33258 nucleus staining assay. The migration ability of cells was detected by Transwell chamber migration assay. The animal model of CRC was established in BALB/c mice via transplantation of CT26 cell, and the radiosensitization effect of allicin on CRC was detected in vivo. The mRNA expressions of NF-κB, IKKß, and IκBα were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). The protein expressions of NF-κB, p-NF-κB, IKKß, p-IKKß, IκBα, and p-IκBα were detected by western blotting. Our results showed that allicin improves the sensitivity of X-ray radiotherapy in CRC, and its mechanism may be associated with inhibition of NF-κB signaling pathway. These findings suggest that allicin may be used as a potential sensitizer for tumor radiotherapy in the clinic.


Assuntos
Neoplasias Colorretais/radioterapia , NF-kappa B/metabolismo , Ácidos Sulfínicos/administração & dosagem , Animais , Apoptose/efeitos da radiação , Proliferação de Células/efeitos da radiação , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/genética , Tolerância a Radiação , Transdução de Sinais/efeitos da radiação
6.
Am J Clin Oncol ; 43(5): 311-318, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32235162

RESUMO

OBJECTIVES: Although current guidelines continue to recommend trimodality therapy for stage II to III rectal cancers, a lower incidence of local recurrence has been observed in patients with upper rectal tumors, including those in the rectosigmoid. In practice, patients with upper rectal tumors may not be receiving all 3 modalities of therapy. Patterns of care for patients with rectosigmoid cancers have not previously been described. METHODS: The National Cancer Database (NCDB) was used to identify patients diagnosed with stage II to III rectosigmoid cancer who underwent definitive surgery between 2004 and 2015. Multivariable logistic regression defined adjusted odds ratio and associated 95% confidence intervals of receipt of any pelvic radiotherapy and preoperative and postoperative pelvic radiotherapy. Multivariable logistic regression also assessed odds of treatment with any chemotherapy and multiagent chemotherapy. RESULTS: Among 8410 patients, 3566 (42.4%) received any pelvic radiotherapy, of which 2516 (70.6%) were treated with preoperative radiotherapy. Factors associated with receipt of radiotherapy included male sex, white race, younger age, positive clinical nodes and positive margins (P<0.001). Among patients with clinically positive nodes, 1980 (48.6%) received any radiotherapy and among those with pathologically positive nodes, 1532 (37.9%) received radiotherapy. A total of 5708 patients (67.9%) received any chemotherapy including 3020 (52.9%) with multiagent chemotherapy. A total of 2579 (30.7%) of the cohort was treated with surgery alone and among patients who were T3N0, this proportion rose to 42.5%. CONCLUSIONS: Less than half of patients with stage II to III rectosigmoid cancers are treated with radiation therapy and approximately one third do not receive chemotherapy. Ongoing and future studies may help to better tailor treatment for rectosigmoid tumors to optimize the therapeutic ratio. Our work may serve as a benchmark on which to compare future practice patterns.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/radioterapia , Neoplasias Colorretais/cirurgia , Terapia Combinada/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Adulto , Idoso , Antineoplásicos/uso terapêutico , Terapia Combinada/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radioterapia/estatística & dados numéricos , Estados Unidos
7.
Cancer Immunol Res ; 8(4): 451-464, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32127391

RESUMO

Colorectal cancer is a major cause of mortality worldwide. Chemotherapy and radiation remain standard treatment for locally advanced disease, with current immune-targeting therapies applying to only a small subset of patients. Expression of the immuno-oncology target indoleamine 2,3 dioxygenase 1 (IDO1) is associated with poor colorectal cancer clinical outcomes but is understudied as a potential treatment target. In this study, we examined the interaction between the IDO1 pathway and radiotherapy in colorectal cancer. We used human and mouse colorectal cancer cell lines, organoids, mouse syngeneic colorectal cancer tumor graft models, and colorectal cancer tissues from patients who received radiotherapy. IDO1 activity was blocked using the clinical IDO1 inhibitor epacadostat and by genetic disruption. We found that radiation induced IDO1 overexpression in colorectal cancer through type I and II IFN signaling. IDO1 enzymatic activity directly influenced colorectal cancer radiation sensitivity. IDO1 inhibition sensitized colorectal cancer to radiation-induced cell death, whereas the IDO1 metabolite kynurenine promoted radioprotection. IDO1 inhibition also potentiated Th1 cytokines and myeloid cell-modulating factors in the tumor microenvironment and promoted an abscopal effect on tumors outside the radiation field. Conversely, IDO1 blockade protected the normal small intestinal epithelium from radiation toxicity and accelerated recovery from radiation-induced weight loss, indicating a role in limiting side effects. These data demonstrated that IDO1 inhibition potentiates radiotherapy effectiveness in colorectal cancer. The findings also provide rationale and mechanistic insight for the study of IDO1 inhibitors as adjuvant therapy to radiation in patients with locally advanced sporadic and colitis-associated colorectal cancer.


Assuntos
Neoplasias Colorretais/radioterapia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Interferons/farmacologia , Oximas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Sulfonamidas/farmacologia , Microambiente Tumoral , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Mucosa Intestinal/efeitos da radiação , Cinurenina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Protetores contra Radiação/farmacologia
8.
J Cancer Res Clin Oncol ; 146(5): 1227-1234, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32056005

RESUMO

INTRODUCTION: Liver and lung are common sites of metastases from colorectal cancer (CRC). Stereotactic body radiation therapy (SBRT) represents a valid treatment, with high rates of local control (LC). In this study, we applied recursive partitioning model-based analysis (RPA) to define class risks for overall survival (OS) and progression free survival (PFS) in oligometastatic CRC patients. MATERIALS AND METHODS: In this monocentric analysis, we included patients with lung or liver metastases. Patients were candidate to SBRT if a maximum of 5 metastases. End points of the present analysis were LC, PFS, and OS. The binary classification tree approach with RPA was applied to stratify the patients into risk groups based on OS and PFS. RESULTS: 218 patients were treated with SBRT on 371 metastases. Majority of patients (56%) was treated on single lesion, followed by 2 (26.1%) and 3 lesions (14.7%). Median follow-up was 22.7 months. Rates of LC were 84.2% at 1 year and 73.8% at 3 years. Rates of PFS at 1 and 3 years were 42.2% and 14.9%, respectively. RPA identified 3 classes for PFS, according to age and number of metastases with 3-year PFS of 30.6%, 13.5% and 8.4%. Overall survival was 87.2% at 1 year, 51.9% at 3 years, and 36.8% at 5 years. RPA identified 3 nodes. Class 1 included patients with liver metastases (3-year OS 35.2%). Class 2 included patients with lung metastases and DFI ≤ 48 months (3-year OS 65%). Class 3 included patients with lung metastases and DFI > 48 months (3-year OS 73.5%). CONCLUSIONS: Stereotactic body radiation therapy can be considered an effective treatment for the management of liver and lung metastases from CRC. With RPA, we identified prognostic risk class to define patients who could benefit the most from SBRT.


Assuntos
Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/radioterapia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/radioterapia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/radioterapia , Modelos Estatísticos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Feminino , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Radiocirurgia
9.
Clin Nucl Med ; 45(3): 202-203, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31977487

RESUMO

A 66-year-old man with colorectal carcinoma and liver-only metastases underwent radioembolization using Y-loaded, resin-based microspheres. One day after radioembolization, the patient experienced severe hypertension and multiple seizures. On MRI, symmetric edematous areas in the cerebellum and the parietal and occipital lobe were observed, a typical finding for posterior reversible encephalopathy syndrome (PRES). The PRES is associated with, for example, renal failure or blood pressure fluctuations leading to cerebral endothelial dysfunction. Antihypertensive and antiepileptic therapies led to normotensive blood pressure and neurological remission. Therefore, newly developed neurological symptoms accompanied by high blood pressure fluctuations after radioembolization should lead to PRES as differential diagnosis.


Assuntos
Braquiterapia/efeitos adversos , Neoplasias Colorretais/radioterapia , Neoplasias Hepáticas/radioterapia , Microesferas , Síndrome da Leucoencefalopatia Posterior/diagnóstico por imagem , Convulsões/diagnóstico por imagem , Idoso , Neoplasias Colorretais/patologia , Diagnóstico Diferencial , Humanos , Neoplasias Hepáticas/secundário , Imagem por Ressonância Magnética , Masculino , Síndrome da Leucoencefalopatia Posterior/etiologia , Compostos Radiofarmacêuticos/uso terapêutico , Convulsões/etiologia , Radioisótopos de Ítrio/uso terapêutico
10.
Cancer Radiother ; 23(6-7): 496-499, 2019 Oct.
Artigo em Francês | MEDLINE | ID: mdl-31471251

RESUMO

Stereotactic radiotherapy of oligometastases, mono- or hypofractionated, represents a fundamental change in the practice of the specialty as it was developed for a century. Despite the great heterogeneity of sites, techniques, and doses, most studies found a high local control rate, around 70 to 90% at 2 years, and reduced toxicity, around 5% of grade 3 at 2 years. Four main phase II and III trials are underway in France. Future research concerns the association of stereotactic radiotherapy with immunotherapy or different conventional chemotherapy protocols, the identification of the best clinical presentations, and optimization of fractionation and biological dose for poor prognosis localizations.


Assuntos
Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Neoplasias/radioterapia , Radiocirurgia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/radioterapia , Terapia Combinada/métodos , Previsões , França , Humanos , Imunoterapia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Masculino , Metástase Neoplásica , Neoplasias/patologia , Neoplasias/terapia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia
11.
Biomed Pharmacother ; 118: 109202, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545232

RESUMO

BACKGROUND: IFC-305, an adenosine derivative, has been proved to exert a therapeutic effect on radiation-induced intestinal toxicity in colon cancer (CC). The aim of the present study was to investigate the underlying molecular mechanism of protective role of IFC-305 in CC by modifying the methylation of peroxisome proliferator-activated receptor (PPAR)-r promoter. METHOD: Peripheral blood and cancerous tissues samples were collected from the CC patients. Irradiation (IR) mice models were established in comparison with control mice accordingly. Bisulfite sequencing, real-time PCR, Western-blot analysis, immunohistochemistry (IHC) and hematoxylin eosin (HE) staining were performed upon both human and animal samples. RESULT: The results upon the human CC samples demonstrated that the level of methylation of PPAR-r promoter in methylated patients was increased, while the risk of radiation-induced intestinal toxicity in methylated patients was also increased compared with unmethylated patients. Also, the PPAR-r mRNA/protein expression was lower in methylated patients compared with unmethylated patients, thus indicating the presence of PPAR-r promoter methylation repressed PPAR-r expression in vivo. Moreover, in the mice models, IFC-305 treatment partially alleviated radiation-induced toxicity in the columnar epithelia and tubular glands of IR mice, and villus height and the number/circumference of crypts were also increased while the relative number of inflammatory cells was decreased in IR + IFC-305 mice group compared with the control mice. Compared with the control group, the levels of PPAR-r mRNA/protein expression were significantly decreased in IR mice, while the presence of IFC-305 exerted therapeutic effect upon IR rats via elevating the PPAR-r mRNA/protein expression to a certain extent. CONCLUSION: In this study, we demonstrated the relationship between PPAR-r promoter methylation and the risk of radiation-induced intestinal toxicity via studying the clinical samples collected from CC patients. And the study upon mice models suggested that the administration of IFC-305 could alleviate radiation-induced intestinal toxicity through decreasing the methylation of PPAR-r promoter and enhancing the expression of PPAR-r in IR mice.


Assuntos
Adenosina/análogos & derivados , Neoplasias Colorretais/radioterapia , Metilação de DNA/efeitos dos fármacos , PPAR gama/genética , Lesões por Radiação/prevenção & controle , Protetores contra Radiação/farmacologia , Adenosina/farmacologia , Idoso , Animais , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Lesões por Radiação/genética , Lesões por Radiação/metabolismo , Lesões Experimentais por Radiação/genética , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/prevenção & controle
12.
J Biosci ; 44(4)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31502570

RESUMO

Radioresistance is a material obstacle for effective treatment of colorectal cancer (CRC). Thus, the discovery of a novel biomarker for determining the CRC radiosensitivity is necessary. Recent studies have confirmed that miR-183-3p regulates cell phenotypes and tumor growth in various cancers. However, the role and mechanism of this micro-ribonucleic acid in CRC radiosensitivity remains unclear. Here, the abundances of miR-183-5p and ATG5 mRNAwere detected by a real-time quantitative reverse transcription polymerase chain reaction. Kaplan-Meier survival analysis was carried out to explore the correlation between miR-183-5p and patient prognosis. Cell viability was evaluated by the MTT assay. Survival fraction analysis through colony formation was performed to assess the cell radiation response. Bioinformatic, luciferase and western blot assays were employed to verify the targeted interaction between miR-183-5p and ATG5. The results showed that an elevated abundance of miR-183-5p and a reduced ATG5 level in CRC were associated with the poor prognosis. The knockdown of miR-183-5p enhanced the sensitivity of CRC cells to radiation, inflected by the decreased cell viability and survival fraction. Mechanically, ATG5 was targeted by miR-183-5p. The addition of ATG5 conferred the radiosensitivity of the CRC cells, which was revered by miR-183-5p restoration. Furthermore, miR-183-5p knockdown hindered the tumor growth by repressing ATG5 in vivo after radiation treatment. In summary, the output data indicated that miR-183-5p heightened the radiation response of the CRC cells by targeting ATG5, promising a novel therapeutic target for CRC patients with radioresistance.


Assuntos
Proteína 5 Relacionada à Autofagia/genética , Neoplasias Colorretais/radioterapia , MicroRNAs/genética , Tolerância a Radiação/genética , Idoso , Sobrevivência Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células HCT116 , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Exp Clin Cancer Res ; 38(1): 399, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511084

RESUMO

BACKGROUND: Radiotherapy (RT) is a highly effective multimodal nonsurgical treatment that is essential for patients with advanced colorectal cancer (CRC). Nevertheless, cell subpopulations displaying intrinsic radioresistance survive after RT. The reactivation of their proliferation and successful colonization at local or distant sites may increase the risk of poor clinical outcomes. Recently, radioresistant cancer cells surviving RT were reported to exhibit a more aggressive phenotype than parental cells, although the underlying mechanisms remain unclear. METHODS: By investigating public databases containing CRC patient data, we explored potential radioresistance-associated signaling pathways. Then, their mechanistic roles in radioresistance were investigated through multiple validation steps using patient-derived primary CRC cells, human CRC cell lines, and CRC xenografts. RESULTS: Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling was activated in radioresistant CRC tissues in correlation with local and distant metastases. JAK2 was preferentially overexpressed in the CRC stem cell subpopulation, which was accompanied by the phosphorylation of STAT proteins, especially STAT3. JAK2/STAT3 signaling played an essential role in promoting tumor initiation and radioresistance by limiting apoptosis and enhancing clonogenic potential. Mechanistically, the direct binding of STAT3 to the cyclin D2 (CCND2) promoter increased CCND2 transcription. CCND2 expression was required for persistent cancer stem cell (CSC) growth via the maintenance of an intact cell cycle and proliferation with low levels of DNA damage accumulation. CONCLUSION: Herein, we first identified JAK2/STAT3/CCND2 signaling as a resistance mechanism for the persistent growth of CSCs after RT, suggesting potential biomarkers and regimens for improving outcomes among CRC patients.


Assuntos
Neoplasias Colorretais/metabolismo , Ciclina D2/metabolismo , Janus Quinase 2/metabolismo , Células-Tronco Neoplásicas/metabolismo , Tolerância a Radiação , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/radioterapia , Técnicas de Inativação de Genes , Humanos , Receptores de Hialuronatos/metabolismo , Modelos Biológicos , Tolerância a Radiação/genética
14.
Oncol Res Treat ; 42(10): 497-505, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31352448

RESUMO

BACKGROUND: Randomized trials have shown a lower efficacy of postoperative chemotherapy in rectal cancer patients having received preoperative radiotherapy than in nonirradiated colorectal cancer (CRC) patients. We hypothesized that preoperative radio(chemo)therapy impairs the relative dose intensity (RDI) of further chemotherapy because of long-term radiation damage. This retrospective study aimed to test this hypothesis. METHODS: The analysis was conducted on 220 consecutive patients with CRC who received FOLFOX-4 postoperatively or because of cancer relapse. Of these, 41 patients with rectal cancer had preoperatively received radio(chemo)therapy (study group) and the remaining 179 with CRC had not (control group). The RDI of oxaliplatin at 8 and 16 weeks was calculated. RESULTS: The median RDI of oxaliplatin at 8 weeks was 95.91% in the study group and 96.15% in the control group (p = 0.79). The corresponding percentages at 16 weeks were 87.6 and 86.5%, respectively (p = 0.55). It was found that within 0-8 weeks, 26.9% of the patients in the study group and 26.3% in the control group had grade 3+ toxicity, hypersensitivity reactions, or granulocyte colony-stimulating factor administration (p = 0.94). The corresponding percentages for 0-16 weeks were 44.8 and 43.9%, respectively (p = 0.92). CONCLUSIONS: We found no association between preoperative radio(chemo)therapy and the RDI of FOLFOX-4. We failed to explain the inferior efficacy of postoperative chemotherapy in patients with rectal cancer who had preoperatively received irradiation compared to those with CRC who had not.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pelve/efeitos da radiação , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Quimiorradioterapia/normas , Quimioterapia Adjuvante , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/radioterapia , Neoplasias Colorretais/cirurgia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Oxaliplatina/administração & dosagem , Oxaliplatina/uso terapêutico , Oxaliplatina/toxicidade , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Estudos Retrospectivos
15.
Nanoscale ; 11(29): 13947-13960, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31305836

RESUMO

Combined modality therapy incorporating raltitrexed (RTX), a thymidylate synthase inhibitor, and radiation can lead to improved outcome for rectal cancer patients. To increase delivery and treatment efficacy, we formulated a hyaluronic acid (HA) coated nanoparticle encapsulating RTX (HARPs) through layer-by-layer assembly. These particles were determined to have a diameter of ∼115 nm, with a polydispersity index of 0.112 and a zeta potential of -22 mV. Cell uptake in CT26 cells determined through flow cytometry showed a ∼5-fold increase between untargeted and HA-coated particles. Through viability and DNA damage assays, we assessed the potency of the free RTX and HARPs, and found increased DNA damage in cells treated with the RTX-loaded nanoparticles administered concurrently with radiation. In vivo efficacy through tumor growth inhibition was investigated in a syngeneic murine colorectal cancer model. Nanoparticle treatment showed no acute toxicity in vivo, and all treatments showed survival benefits for their respective groups compared to controls. HARPs alone slowed tumor growth, although not significantly. Radiation alone and in combination with the HARPs showed significant growth delay. Notably, the combination treatment significantly hindered tumor progression relative to the HARPs highlighting the benefit of this multipronged treatment. These results provide a foundation for loading RTX in a nanoparticle formulation, and establish a combined radiation and drug dosing schedule to determine optimal tumor growth delay and subsequent treatment efficacy.


Assuntos
Antimetabólitos Antineoplásicos/química , Portadores de Fármacos/química , Ácido Hialurônico/química , Nanopartículas/química , Quinazolinas/química , Tiofenos/química , Animais , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/radioterapia , Dano ao DNA/efeitos dos fármacos , Portadores de Fármacos/metabolismo , Histonas/metabolismo , Humanos , Estimativa de Kaplan-Meier , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/metabolismo , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Radiação Ionizante , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Transplante Heterólogo
16.
Clin Exp Metastasis ; 36(4): 331-342, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31165360

RESUMO

To evaluate the local control (LC), progression free survival (PFS), out-field PFS, overall survival (OS), toxicity and failure predictors of SRT in a series of various sites oligometastatic CRC patients. Patients with oligometastatic CRC disease were analyzed retrospectively. The SRT prescribed dose was dependent on the lesion volume and its location. 102 consecutive oligometastatic CRC patients (150 lesions) were included. They underwent SRT between 2012 and 2015. Median prescription dose was 45 Gy (median dose/fraction was 15 Gy/3 fractions biological equivalent dose (BED10) 112.5 Gy). Median follow-up was 11.4 months. No patients experienced G3 and G4 toxicity. No progression was found in 82% (radiological response at 3 months) and 85% (best radiological response) out of 150 evaluable lesions. At 1 and 2 years: LC was 70% and 55%; OS was 90% and 90%; PFS was 37% and 27%; out-field PFS was 37% and 23% respectively. Progressive disease was correlated with BED10 (better LC when BED10 was ≥ 75 Gy (p < 0.0001)). In multivariate analysis, LC was higher in lesions with a Plpnning target volume (PTV) volume < 42 cm3 and BED10 ≥ 75 Gy. Patients with Karnofsky performance status < 90 showed higher out-field progression. SRT is an effective treatment for patients with oligometastases from CRC. Its low treatment-associated morbidity and acceptable LC make of SRT an option not only in selected cases. Further studies should be focused to clarify which patient subgroup will benefit most from this treatment modality and to define the optimal dose to improve LC while maintaining low toxicity profile.


Assuntos
Neoplasias Colorretais/radioterapia , Radiocirurgia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Radiocirurgia/efeitos adversos , Dosagem Radioterapêutica , Estudos Retrospectivos
17.
Gan To Kagaku Ryoho ; 46(4): 705-708, 2019 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-31164511

RESUMO

Primary small bowel cancer is a rare entity; thus, it is often found in progress. Therefore, the prognosis is often poor. Because of its low frequency, there are few reports concerning the treatment for small bowel cancer; hence, it is important to examine individual cases in detail. In this study, we present a case of recurrent small bowel cancer that successfully responded to chemoradiation therapy. Case: A 48-year-old woman had anemia. Colonoscopy showed a tumor in the terminal ileum. Because of invasion in the ovaries and uterus, ileocecal resection, hysterectomy, and bilateral adnexectomy were performed. The pathological diagnosis was small bowel cancer with lymph node metastasis, and CapeOX therapy was administered as postoperative adjuvant chemotherapy. Since local recurrence was detected in the right lower quadrant 6 months after the surgery, IRIS plus BV was initiated. Radiation therapy(2Gy×25 times, total 50 Gy)was also administered within the same period(only S-1 administration during radiation). After radiation therapy, the tumor decreased significantly in size and showed CR. Currently, the patient is under observation without treatment, but she has had no recurrence for 6 years after the confirmation of recurrence(6 years and 6 months after surgery). It is extremely rare for chemoradiation therapy to be effective for recurrent small bowel cancer; we report such a case with literatures.


Assuntos
Neoplasias Colorretais , Neoplasias do Íleo , Quimiorradioterapia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/radioterapia , Feminino , Humanos , Neoplasias do Íleo/tratamento farmacológico , Neoplasias do Íleo/radioterapia , Metástase Linfática , Pessoa de Meia-Idade , Recidiva Local de Neoplasia
18.
Phys Med Biol ; 64(13): 135018, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31117062

RESUMO

Approximately 50% of all colorectal cancer (CRC) patients will develop metastasis to the liver. 90Y selective internal radiation therapy (SIRT) is an established treatment for metastatic CRC. There is still a fundamental lack of understanding regarding the radiobiology underlying the dose response. This study was designed to determine the radiosensitivity of two CRC cell lines (DLD-1 and HT-29) to 90Y ß - radiation exposure, and thus the relative effectiveness of 90Y SIRT in relation to external beam radiotherapy (EBRT). A 90Y-source dish was sandwiched between culture dishes to irradiate DLD-1 or HT-29 cells for a period of 6 d. Cell survival was determined by clonogenic assay. Dose absorbed per 90Y disintegration was calculated using the PENELOPE Monte Carlo code. PENELOPE simulations were benchmarked against relative dose measurements using EBT3 GAFchromic™ film. Statistical regression based on the linear-quadratic model was used to determine the radiosensitivity parameters [Formula: see text] and [Formula: see text] using R. These results were compared to radiosensitivity parameters determined for 6 MV clinical x-rays and 137Cs γ-ray exposure. Equivalent dose of EBRT in 2 Gy ([Formula: see text]) and 10 Gy ([Formula: see text]) fractions were derived for 90Y dose. HT-29 cells were more radioresistant than DLD-1 for all treatment modalities. Radiosensitivity parameters determined for 6 MV x-rays and 137Cs γ-ray were equivalent for both cell lines. The [Formula: see text] ratio for 90Y ß --particle exposure was over an order of magnitude higher than the other two modalities due to protraction of dose delivery. Consequently, an 90Y SIRT absorbed dose of 60 Gy equates to an [Formula: see text] of 28.7 and 54.5 Gy and an [Formula: see text] of 17.6 and 19.3 Gy for DLD-1 and HT-29 cell lines, respectively. We derived radiosensitivity parameters for two CRC cell lines exposed to 90Y ß --particles, 6 MV x-rays, and 137Cs γ-ray irradiation. These radiobiological parameters are critical to understanding the dose response of CRC lesions and ultimately informs the efficacy of 90Y SIRT relative to other radiation therapy modalities.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Colorretais/radioterapia , Embolização Terapêutica , Tolerância a Radiação , Radioisótopos de Ítrio/uso terapêutico , Partículas beta/uso terapêutico , Raios gama/uso terapêutico , Humanos , Método de Monte Carlo , Radiobiologia , Planejamento da Radioterapia Assistida por Computador
19.
Scand J Urol ; 53(2-3): 156-160, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31092116

RESUMO

Background: Pelvic radiotherapy causes tissue atrophy and fibrosis, leading to urinary tract dysfunction. Tissue ischaemia poses a significant surgical challenge. This study examined the urological sequelae of radiotherapy, types of reconstructive urological surgery (RUS) required and functional outcomes. Methods: A retrospective review was performed of all radiotherapy patients who underwent RUS at a tertiary centre between 2007-2017. Details including time from radiotherapy, pre-operative assessments, type of surgery performed and functional outcome were analysed. Results: Fifty-four patients were identified. The primary malignancy was cervical (32), colorectal (9) and other urogenital/metastatic origins in the remaining cases. Mean time between radiation and RUS was 13 years. Sixty-nine reconstructive surgeries were performed. Twenty-two patients had fistulae, but only 27% were closed and 73% ended with urinary diversion. Eighteen had ureteric strictures, with 56% having associated bladder dysfunction. Twelve (67%) patients had RUS, of whom 83% required bowel interposition, and 33% primary diversion. Nine of 24 patients with contracted bladders were reconstructed and eight remain functionally continent. Renal function stabilised or improved in 87%. Nine patients (17%) had Clavien 3 or 4 complications. Conclusions: A variety of complex, major RUS were required. In 61%, urinary diversion was necessary, with radiotherapy fistulae being a particular challenge and closed in only a third. In total, 37% of patients were reconstructed achieving functional continence and restoration of upper-tract drainage with renal function preservation. This surgery was at a cost of a re-intervention rate of 28% and significant morbidity in 17%. RUS in the radiotherapy field should be performed in centres with experience.


Assuntos
Lesões por Radiação/cirurgia , Radioterapia/efeitos adversos , Procedimentos Cirúrgicos Reconstrutivos/métodos , Doenças Ureterais/cirurgia , Doenças da Bexiga Urinária/cirurgia , Fístula Urinária/cirurgia , Procedimentos Cirúrgicos Urológicos/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/radioterapia , Constrição Patológica , Contratura/etiologia , Contratura/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/radioterapia , Pelve , Lesões por Radiação/etiologia , Estudos Retrospectivos , Retalhos Cirúrgicos , Resultado do Tratamento , Doenças Ureterais/etiologia , Neoplasias Uretrais/radioterapia , Doenças da Bexiga Urinária/etiologia , Derivação Urinária/métodos , Fístula Urinária/etiologia , Neoplasias do Colo do Útero/radioterapia
20.
Anticancer Res ; 39(5): 2569-2574, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092454

RESUMO

BACKGROUND/AIM: Existing survival scores for patients with brain metastases were created in heterogeneously treated cohorts. A new score was developed in 56 patients with brain metastases from colorectal cancer treated with 10×3 Gy of whole-brain radiotherapy (WBRT). PATIENTS AND METHODS: Factors found significantly associated with survival (p<0.05) or showing a trend (p<0.08) were included in the tool. The new WBRT-30-CRC was compared to diagnosis-specific graded prognostic assessment (DS-GPA) classification for gastrointestinal cancers. RESULTS: The WBRT-30-CRC included four prognostic groups: 3-4, 5-6, 7-9 and 10 points. Six-month survival rates were 0%, 15%, 38% and 80%. PPV of the 3-4 points-group predicting death ≤6 months was 100% (91% for DS-GPA of 0.0-1.0). PPV of the 10 points-group predicting survival ≥6 months was 80% (0% DS-GPA of 3.5-4.0, 33% DS-GPA of 3.0-4.0). CONCLUSION: The WBRT-30-CRC appeared very precise in identifying patients with brain metastases from colorectal cancer dying ≤6 months or surviving ≥6 months.


Assuntos
Neoplasias Encefálicas/radioterapia , Neoplasias Colorretais/radioterapia , Irradiação Craniana , Prognóstico , Adulto , Idoso , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Radiocirurgia , Resultado do Tratamento
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