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1.
PLoS One ; 17(2): e0264266, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35196351

RESUMO

BACKGROUND: According to the World Health Organization, more than 250 million people worldwide are chronically infected with the hepatitis B virus, and almost 800.000 patients die annually of mediated liver disorders. Therefore, adequate biological test systems are needed that could fully simulate the course of chronic hepatitis B virus infection, including in patients with hepatocellular carcinoma. METHODS: In this study, we will assess the effectiveness of existing protocols for isolation and cultivation of primary cells derived from patients with hepatocellular carcinoma in terms of the yield of viable cells and their ability to replicate the hepatitis B virus using isolation and cultivation methods for adhesive primary cells, flow cytometry and quantitative polymerase chain reaction. Another part of our study will be devoted to evaluating the effectiveness of hepatocellular carcinoma grafting methods to obtain patient-derived heterotopic and orthotopic xenograft mouse avatars using animal X-ray irradiation and surgery procedures and in vivo fluorescent signals visualization and measurements. Our study will be completed by histological methods. DISCUSSION: This will be the first extensive comparative study of the main modern methods and protocols for isolation and cultivation primary hepatocellular carcinoma cells and tumor engraftment to the mice. All protocols will be optimized and characterized using the: (1) efficiency of the method for isolation cells from removed hepatocellular carcinoma in terms of their quantity and viability; (2) efficiency of the primary cell cultivation protocol in terms of the rate of monolayer formation and hepatitis B virus replication; (3) efficiency of the grafting method in terms of the growth rate and the possibility of hepatitis B virus persistence and replication in mice. The most effective methods will be recommended for use in translational biomedical research.


Assuntos
Modelos Animais de Doenças , Hepatite C Crônica/patologia , Cultura Primária de Células/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/normas , Animais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Células Cultivadas , Hepatite C Crônica/virologia , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
2.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361027

RESUMO

The experimental animal model is still essential in the development of new anticancer drugs. We characterized mouse tumors derived from two-dimensional (2D) monolayer cells or three-dimensional (3D) spheroids to establish an in vivo model with highly standardized conditions. Primary cancer-associated fibroblasts (CAFs) were cultured from head and neck squamous cell carcinoma (HNSCC) tumor tissues and co-injected with monolayer cancer cells or spheroids into the oral mucosa of mice. Mice tumor blood vessels were stained, followed by tissue clearing and 3D Lightsheet fluorescent imaging. We compared the effect of exosomes secreted from 2D or 3D culture conditions on the angiogenesis-related genes in HNSCC cells. Our results showed that both the cells and spheroids co-injected with primary CAFs formed tumors. Interestingly, vasculature was abundantly distributed inside the spheroid-derived but not the monolayer-derived mice tumors. In addition, cisplatin injection more significantly decreased spheroid-derived but not monolayer-derived tumor size in mice. Additionally, exosomes isolated from co-culture media of FaDu spheroid and CAF upregulated angiogenesis-related genes in HNSCC cells as compared to exosomes from FaDu cell and CAF co-culture media under in vitro conditions. The mouse tumor xenograft model derived from 3D spheroids of HNSCC cells with primary CAFs is expected to produce reliable chemotherapy drug screening results given the robust angiogenesis and lack of necrosis inside tumor tissues.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias Bucais/patologia , Neovascularização Patológica/patologia , Esferoides Celulares/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinoma de Células Escamosas/metabolismo , Exossomos/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Bucais/metabolismo , Neovascularização Patológica/metabolismo , Cultura Primária de Células/métodos , Esferoides Celulares/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto/normas
3.
FASEB J ; 35(2): e21231, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33428275

RESUMO

Tumors of the nervous system including glioblastoma multiforme (GBM) are the most frequent and aggressive form of brain tumors; however, little is known about the impact of the circadian timing system on the formation, growth, and treatment of these tumors. We investigated day/night differences in tumor growth after injection of A530 glioma cells isolated from malignant peripheral nerve sheath tumor (MPNSTs) of NPcis (Trp53+/- ; Nf1+/- ) mice. Synchronized A530 cell cultures expressing typical glial markers were injected at the beginning of the day or night into the sciatic nerve zone of C57BL/6 mice subject to a 12:12 hours light/dark (LD) cycle or after being released to constant darkness (DD). Tumors generated in animals injected early at night in the LD cycle or in DD showed higher growth rates than in animals injected diurnally. No differences were found when animals were injected at the same time with cultures synchronized 12 hours apart. Similar experiments performed with B16 melanoma cells showed higher tumor growth rates in animals injected at the beginning of the night compared to those injected in the daytime. A higher tumor growth rate than that in controls was observed when mice were injected with knocked-down clock gene Bmal1 cells. Finally, when we compared day/night administration of different doses of the proteasome inhibitor Bortezomib (0.5-1.5 mg/kg) in tumor-bearing animals, we found that low-dose chemotherapy displayed higher efficacy when administered at night. Results suggest the existence of a precise temporal control of tumor growth and of drug efficacy in which the host state and susceptibility are critical.


Assuntos
Neoplasias Encefálicas/patologia , Ritmo Circadiano , Glioblastoma/patologia , Fotoperíodo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Fatores de Transcrição ARNTL/genética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Bortezomib/administração & dosagem , Bortezomib/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Esquema de Medicação , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Camundongos , Camundongos Endogâmicos C57BL , Neurofibromina 1/genética , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto/normas
4.
PLoS One ; 15(10): e0240169, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33027304

RESUMO

We have created the immunodeficient SRG rat, a Sprague-Dawley Rag2/Il2rg double knockout that lacks mature B cells, T cells, and circulating NK cells. This model has been tested and validated for use in oncology (SRG OncoRat®). The SRG rat demonstrates efficient tumor take rates and growth kinetics with different human cancer cell lines and PDXs. Although multiple immunodeficient rodent strains are available, some important human cancer cell lines exhibit poor tumor growth and high variability in those models. The VCaP prostate cancer model is one such cell line that engrafts unreliably and grows irregularly in existing models but displays over 90% engraftment rate in the SRG rat with uniform growth kinetics. Since rats can support much larger tumors than mice, the SRG rat is an attractive host for PDX establishment. Surgically resected NSCLC tissue from nine patients were implanted in SRG rats, seven of which engrafted and grew for an overall success rate of 78%. These developed into a large tumor volume, over 20,000 mm3 in the first passage, which would provide an ample source of tissue for characterization and/or subsequent passage into NSG mice for drug efficacy studies. Molecular characterization and histological analyses were performed for three PDX lines and showed high concordance between passages 1, 2 and 3 (P1, P2, P3), and the original patient sample. Our data suggest the SRG OncoRat is a valuable tool for establishing PDX banks and thus serves as an alternative to current PDX mouse models hindered by low engraftment rates, slow tumor growth kinetics, and multiple passages to develop adequate tissue banks.


Assuntos
Subunidade gama Comum de Receptores de Interleucina/genética , Neoplasias Experimentais/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Deleção de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Experimentais/genética , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto/normas
5.
Cancer Res ; 80(11): 2286-2297, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32152150

RESUMO

Patient-derived xenografts (PDX) are tumor-in-mouse models for cancer. PDX collections, such as the NCI PDXNet, are powerful resources for preclinical therapeutic testing. However, variations in experimental and analysis procedures have limited interpretability. To determine the robustness of PDX studies, the PDXNet tested temozolomide drug response for three prevalidated PDX models (sensitive, resistant, and intermediate) across four blinded PDX Development and Trial Centers using independently selected standard operating procedures. Each PDTC was able to correctly identify the sensitive, resistant, and intermediate models, and statistical evaluations were concordant across all groups. We also developed and benchmarked optimized PDX informatics pipelines, and these yielded robust assessments across xenograft biological replicates. These studies show that PDX drug responses and sequence results are reproducible across diverse experimental protocols. In addition, we share the range of experimental procedures that maintained robustness, as well as standardized cloud-based workflows for PDX exome-sequencing and RNA-sequencing analyses and for evaluating growth. SIGNIFICANCE: The PDXNet Consortium shows that PDX drug responses and sequencing results are reproducible across diverse experimental protocols, establishing the potential for multisite preclinical studies to translate into clinical trials.


Assuntos
Transplante de Neoplasias/normas , Medicina de Precisão/métodos , Medicina de Precisão/normas , Transplante Heterólogo/normas , Ensaios Antitumorais Modelo de Xenoenxerto/normas , Animais , Humanos , Camundongos , Transplante de Neoplasias/métodos , Distribuição Aleatória , Transplante Heterólogo/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
6.
Hepatology ; 72(3): 1085-1101, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-31899548

RESUMO

BACKGROUND AND AIMS: Several major factors limit our understanding of hepatocellular carcinoma (HCC). First, human HCCs are infrequently biopsied for diagnosis and thus are not often biologically interrogated. Second, HCC initiation and progression are strongly influenced by the cirrhotic microenvironment, and the exact contributions of intrinsic and extrinsic tumor factors are unclear. A powerful approach to examine the personalized biology of liver cancers and the influence of host tissues is with patient-derived xenograft (PDX) models. In Asia, HCCs from patients with hepatitis B virus have been efficiently converted into PDXs, but few parallel efforts from the west have been reported. APPROACH AND RESULTS: In a large-scale analysis, we implanted 93 HCCs and 8 cholangiocarcinomas (CCAs) to systematically analyze host factors and to define an optimized platform for PDX development from both surgical and biopsy samples. NOD Scid IL-2Rγ-/- (NSG) mice that had undergone partial hepatectomy (PHx) represented the best combination of engraftability, growth, and passageability, but overall rates were low and indicative of a unique intrinsic biology for HCCs in the United States. PDX models preserved the histology and genetic features of parental tumors, and ultimately, eight models were usable for preclinical studies. Intriguingly, HCC PDXs were differentially sensitive to regorafenib and sorafenib, and CCA PDXs were also highly sensitive to regorafenib. CONCLUSIONS: PDX models functionalize early and advanced stage HCCs and revealed unique biological features of liver cancers from the United States.


Assuntos
Antineoplásicos/farmacologia , Biópsia/métodos , Carcinoma Hepatocelular , Hepatectomia/métodos , Neoplasias Hepáticas , Fígado/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Feminino , Expressão Gênica , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/normas
7.
Int J Mol Sci ; 20(22)2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31717935

RESUMO

BACKGROUND: Considering the positive or negative potential effects of adipocytes, depending on their lipid composition, on breast tumor progression, it is important to evaluate whether adipose tissue (AT) harvesting procedures, including epinephrine infiltration, may influence breast cancer progression. METHODS: Culture medium conditioned with epinephrine-infiltrated adipose tissue was tested on human Michigan Cancer Foundation-7 (MCF7) breast cancer cells, cultured in monolayer or in oncospheres. Lipid composition was evaluated depending on epinephrine-infiltration for five patients. Epinephrine-infiltrated adipose tissue (EI-AT) or corresponding conditioned medium (EI-CM) were injected into orthotopic breast carcinoma induced in athymic mouse. RESULTS: EI-CM significantly increased the proliferation rate of MCF7 cells Moreover EI-CM induced an output of the quiescent state of MCF7 cells, but it could be either an activator or inhibitor of the epithelial mesenchymal transition as indicated by gene expression changes. EI-CM presented a significantly higher lipid total weight compared with the conditioned medium obtained from non-infiltrated-AT of paired-patients. In vivo, neither the EI-CM or EI-AT injection significantly promoted MCF7-induced tumor growth. CONCLUSIONS: Even though conditioned media are widely used to mimic the secretome of cells or tissues, they may produce different effects on tumor progression, which may explain some of the discrepancy observed between in vitro, preclinical and clinical data using AT samples.


Assuntos
Tecido Adiposo/metabolismo , Proliferação de Células/efeitos dos fármacos , Epinefrina/farmacologia , Metabolismo dos Lipídeos , Neoplasias Mamárias Experimentais/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Meios de Cultivo Condicionados/farmacologia , Feminino , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto/normas
8.
AAPS J ; 21(2): 16, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30627814

RESUMO

A single efficacy metric quantifying anti-tumor activity in xenograft models is useful in evaluating different tumors' drug sensitivity and dose-response of an anti-tumor agent. Commonly used metrics include the ratio of tumor volume in treated vs. control mice (T/C), tumor growth inhibition (TGI), ratio of area under the curve (AUC), and growth rate inhibition (GRI). However, these metrics have some limitations. In particular, for biologics with long half-lives, tumor volume (TV) of treated xenografts displays a delay in volume reduction (and in some cases, complete regression) followed by a growth rebound. These observed data cannot be described by exponential functions, which is the underlying assumption of TGI and GRI, and the fit depends on how long the tumor volumes are monitored. On the other hand, T/C and TGI only utilizes information from one chosen time point. Here, we propose a new metric called Survival Prolongation Index (SPI), calculated as the time for drug-treated TV to reach a certain size (e.g., 600 mm3) divided by the time for control TV to reach 600mm3 and therefore not dependent on the chosen final time point tf. Simulations were conducted under different scenarios (i.e., exponential vs. saturable growth, linear vs. nonlinear kill function). For all cases, SPI is the most linear and growth-rate independent metric. Subsequently, a literature analysis was conducted using 11 drugs to evaluate the correlation between pre-clinically obtained SPI and clinical overall response. This retrospective analysis of approved drugs suggests that a predicted SPI of 2 is necessary for clinical response.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/normas , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto/estatística & dados numéricos , Humanos , Camundongos , Modelos Biológicos , Neoplasias/mortalidade , Neoplasias/patologia , Estudos Retrospectivos , Análise de Sobrevida , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto/estatística & dados numéricos
9.
Methods Mol Biol ; 1884: 297-315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30465212

RESUMO

The efficacy of cancer therapies strongly relies on their ability to reinstate cancer immunosurveillance. Numerous biomedical approaches with immunotherapeutic activity have been developed to reeducate the host immune system to detect and clear tumor cells. Cytotoxicants have been primarily designed to slow down malignant cell proliferation and to induce programmed cell death. Some cytotoxic stimuli are able to activate a particular type of apoptosis, which is referred to as immunogenic cell death (ICD), that de facto convert cancer cells into their own vaccine. This effect ultimately facilitates the establishment of an antitumor immune response that potentially annihilates spared malignant cells, as well as an immune memory that prevents cancer recurrence. Based on the characteristic hallmarks of ICD, protocols have been developed to validate ICD induction in vitro, ex vivo, and in vivo. These methods may contribute to identify novel ICD inducers and to design multimodal regimens with superior therapeutic efficacy. Moreover, their translation into clinical research could have prognostic or predictive value. This chapter will introduce the "gold standard" protocol for the in vivo assessment of ICD in mice. The procedure relies on vaccination with treated cancer cells, followed by rechallenge with living entities of the same type, in syngeneic immunocompetent animals.


Assuntos
Apoptose/imunologia , Vigilância Imunológica , Imunoterapia/métodos , Neoplasias/terapia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Técnicas de Cultura de Células/instrumentação , Técnicas de Cultura de Células/métodos , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias/imunologia , Neoplasias/patologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/instrumentação , Ensaios Antitumorais Modelo de Xenoenxerto/normas
11.
PLoS Biol ; 15(6): e2002212, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28662052

RESUMO

There is vigorous debate about the reproducibility of research findings in cancer biology. Whether scientists can accurately assess which experiments will reproduce original findings is important to determining the pace at which science self-corrects. We collected forecasts from basic and preclinical cancer researchers on the first 6 replication studies conducted by the Reproducibility Project: Cancer Biology (RP:CB) to assess the accuracy of expert judgments on specific replication outcomes. On average, researchers forecasted a 75% probability of replicating the statistical significance and a 50% probability of replicating the effect size, yet none of these studies successfully replicated on either criterion (for the 5 studies with results reported). Accuracy was related to expertise: experts with higher h-indices were more accurate, whereas experts with more topic-specific expertise were less accurate. Our findings suggest that experts, especially those with specialized knowledge, were overconfident about the RP:CB replicating individual experiments within published reports; researcher optimism likely reflects a combination of overestimating the validity of original studies and underestimating the difficulties of repeating their methodologies.


Assuntos
Pesquisa Biomédica/normas , Julgamento , Neoplasias/terapia , Pesquisadores/normas , Relatório de Pesquisa/normas , Ciência/normas , Animais , Pesquisa Biomédica/métodos , Coleta de Dados/métodos , Coleta de Dados/estatística & dados numéricos , Prova Pericial/métodos , Humanos , Camundongos , Neoplasias/diagnóstico , Competência Profissional/normas , Reprodutibilidade dos Testes , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/normas
12.
Stem Cell Reports ; 8(5): 1340-1353, 2017 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-28494940

RESUMO

The ability to form teratomas in vivo containing multiple somatic cell types is regarded as functional evidence of pluripotency for human pluripotent stem cells (hPSCs). Since the Teratoma assay is animal dependent, laborious, and only qualitative, the PluriTest and the hPSC ScoreCard assay have been developed as in vitro alternatives. Here we compared normal hPSCs, induced hPSCs (hiPSCs) with reactivated reprogramming transgenes, and human embryonal carcinoma cells (hECs) in these assays. While normal hPSCs gave rise to typical teratomas, the xenografts of the hECs and the hiPSCs with reactivated reprogramming transgenes were largely undifferentiated and malignant. The hPSC ScoreCard assay confirmed the line-specific differentiation propensities in vitro. However, when undifferentiated cells were analyzed by the PluriTest, only hECs were identified as abnormal whereas all other cell lines were indistinguishable and resembled normal hPSCs. Our results indicate that pluripotency assays are best selected on the basis of intended downstream applications.


Assuntos
Testes de Carcinogenicidade/normas , Diferenciação Celular , Células-Tronco Pluripotentes Induzidas/citologia , Teratoma/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/normas , Animais , Testes de Carcinogenicidade/efeitos adversos , Testes de Carcinogenicidade/métodos , Linhagem Celular , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
13.
AAPS J ; 18(5): 1262-1272, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27329303

RESUMO

The purpose of this study was to explore the impact of censoring due to animal sacrifice on parameter estimates and tumor volume calculated from two diameters in larger tumors during tumor growth experiments in preclinical studies. The type of measurement error that can be expected was also investigated. Different scenarios were challenged using the stochastic simulation and estimation process. One thousand datasets were simulated under the design of a typical tumor growth study in xenografted mice, and then, eight approaches were used for parameter estimation with the simulated datasets. The distribution of estimates and simulation-based diagnostics were computed for comparison. The different approaches were robust regarding the choice of residual error and gave equivalent results. However, by not considering missing data induced by sacrificing the animal, parameter estimates were biased and led to false inferences in terms of compound potency; the threshold concentration for tumor eradication when ignoring censoring was 581 ng.ml(-1), but the true value was 240 ng.ml(-1).


Assuntos
Animais de Laboratório , Eutanásia Animal , Modelos Teóricos , Ensaios Antitumorais Modelo de Xenoenxerto/normas , Animais , Simulação por Computador
16.
Cancer Res ; 74(4): 1272-83, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24356420

RESUMO

Standardized and reproducible preclinical models that recapitulate the dynamics of prostate cancer are urgently needed. We established a bank of transplantable patient-derived prostate cancer xenografts that capture the biologic and molecular heterogeneity currently confounding prognostication and therapy development. Xenografts preserved the histopathology, genome architecture, and global gene expression of donor tumors. Moreover, their aggressiveness matched patient observations, and their response to androgen withdrawal correlated with tumor subtype. The panel includes the first xenografts generated from needle biopsy tissue obtained at diagnosis. This advance was exploited to generate independent xenografts from different sites of a primary site, enabling functional dissection of tumor heterogeneity. Prolonged exposure of adenocarcinoma xenografts to androgen withdrawal led to castration-resistant prostate cancer, including the first-in-field model of complete transdifferentiation into lethal neuroendocrine prostate cancer. Further analysis of this model supports the hypothesis that neuroendocrine prostate cancer can evolve directly from adenocarcinoma via an adaptive response and yielded a set of genes potentially involved in neuroendocrine transdifferentiation. We predict that these next-generation models will be transformative for advancing mechanistic understanding of disease progression, response to therapy, and personalized oncology.


Assuntos
Adenocarcinoma/diagnóstico , Adenocarcinoma/tratamento farmacológico , Antineoplásicos/isolamento & purificação , Descoberta de Drogas/métodos , Detecção Precoce de Câncer/métodos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Transplante de Neoplasias/normas , Obtenção de Tecidos e Órgãos/normas , Ensaios Antitumorais Modelo de Xenoenxerto/normas
17.
Mol Cell Endocrinol ; 351(1): 71-7, 2012 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-22056412

RESUMO

Adrenocortical carcinoma (ACC) is a very rare but aggressive tumor, whose biological and cellular features and processes underlying the development, progression and metastatic evolution are still obscure. Despite many attempts to use general cytostatic and cytotoxic drugs, the only available drug therapy for advanced ACC is still represented by mitotane (MTT). However, the mechanism of action of this adrenolytic derivative of the pesticide DDT has still been poorly characterized. In this context, the development of more specific drugs for ACC treatment is based on the knowledge of the molecular pathways involved in the tumor growth. Xenograft models for the screening of such drugs at preclinical levels is mandatory. In the first part of this review, we will summarize the "pro" and "con" of the different xenograft models available for anticancer drug testing in different types of tumors in general and in the last part, we will focus on the preclinical evidence obtained so far with the use of such models applied to drug screening for anticancer effects in ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/farmacologia , Mitotano/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/normas , Animais , Antineoplásicos Hormonais/uso terapêutico , Humanos , Camundongos , Mitotano/uso terapêutico
18.
AAPS PharmSciTech ; 12(2): 665-72, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21584856

RESUMO

Hydroxypropyl-sulfobutyl-ß-cyclodextrin (HP-SBE-ß-CD) inclusion complex was developed and used as a drug delivery system for DTX (DTX/HP-SBE-ß-CD). The objective of the present study was to evaluate and compare the biological properties of DTX/HP-SBE-Β-CD with Taxotere®. The pharmacokinetics, biodistribution, antitumor efficacy in vivo and in vitro, and safety evaluation of DTX/HP-SBE-ß-CD were studied. The most significant finding was that it was possible to prepare a Polysorbate-80-free inclusion complex for DTX. Studies based on pharmacokinetics, biodistribution, and antitumor efficacy indicated that DTX/HP-SBE-ß-CD had similar pharmacokinetic properties and antitumor efficacy both in vitro and in vivo as Taxotere®. Fortunately, this new drug delivery system attenuated the side effects when used in vivo. As a consequence, DTX/HP-SBE-ß-CD may be a promising alternative to Taxotere® for cancer chemotherapy treatment with reduced side effects. The therapeutic potential against a variety of human tumors and low toxicity demonstrated in a stringent study clearly warrant clinical investigation of DTX/HP-SBE-ß-CD for possible use against human tumors.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Taxoides/administração & dosagem , Taxoides/farmacocinética , beta-Ciclodextrinas/administração & dosagem , beta-Ciclodextrinas/farmacocinética , Animais , Docetaxel , Sistemas de Liberação de Medicamentos/normas , Células HCT116 , Células Hep G2 , Humanos , Masculino , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Coelhos , Distribuição Aleatória , Ratos , Ratos Wistar , Taxoides/efeitos adversos , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/normas , beta-Ciclodextrinas/efeitos adversos
19.
Surg Neurol ; 70(3): 295-307; discussion 307, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18261772

RESUMO

BACKGROUND: Immortal cell lines and cell lines derived from operative specimens transplanted into animal models are used in meningioma research. We address 2 criticisms of the mouse xenograft flank tumor model: Why are tumor induction rates derived from operative specimens low and inconsistent? Are flank tumors meningiomas? METHODS: Meningioma cell cultures were processed for Giemsa-band karyotyping and flow cytometry. Mouse flank tumors induced subcutaneously were analyzed microscopically, immunohistochemically, and ultrastructurally. Giemsa-band studies identified meningiomas with simple karyotype (< or =1 chromosomal abnormality) or complex karyotype (multiple chromosomal abnormalities). RESULTS: Cell cultures with complex karyotypes (IOMM-Lee, CH-157 MN, 2 operative specimens) grew rapidly in vitro and induced tumors in 49 (98%) of 50 animals. Meningioma cell cultures with simple karyotypes grew slowly in vitro and showed small, nongrowing tumors in mouse flanks (10/10). Meningioma flank tumors were vimentin-positive with ultrastructural features consistent with meningiomas. Cell cultures with complex karyotypes grew faster in cell culture and consistently induced flank tumors, unlike meningiomas with simple karyotypes. CONCLUSIONS: Meningioma cell lines transplanted into flanks of nude mice exhibit microscopic, immunohistochemical, and ultrastructural features of meningiomas. The ease of monitoring tumor growth in the subcutaneous mouse flank model is its primary advantage, although we recognize an intracranial location is more biologically desirable.


Assuntos
Neoplasias Meníngeas/fisiopatologia , Meningioma/fisiopatologia , Ensaios Antitumorais Modelo de Xenoenxerto/estatística & dados numéricos , Adulto , Idoso , Animais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Linhagem Celular Transformada , Linhagem Celular Tumoral , Aberrações Cromossômicas , Modelos Animais de Doenças , Feminino , Genótipo , Sobrevivência de Enxerto/fisiologia , Humanos , Antígeno Ki-67/imunologia , Masculino , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Meningioma/genética , Meningioma/patologia , Camundongos , Camundongos Nus , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Vimentina/análise , Vimentina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/normas
20.
Radiat Res ; 156(1): 28-35, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11418070

RESUMO

Flynn, A. A., Green, A. J., Pedley, R. B., Boxer, G. M., Boden, R. and Begent, R. H. J. A Mouse Model for Calculating the Absorbed Beta-Particle Dose from (131)I- and (90)Y-Labeled Immunoconjugates, Including a Method for Dealing with Heterogeneity in Kidney and Tumor. Radiat. Res. 156, 28-35 (2001). Conventional internal radiation dosimetry methods assume that the beta-particle energy is absorbed uniformly and completely in the source organ and that the radioactivity is distributed uniformly in the source. However, in mice, a considerable proportion of the beta-particle energy can escape the source organ, resulting in large cross-organ doses. Furthermore, the distribution of radioactivity is generally heterogeneous in kidney and tumor. Therefore, a model was developed to account for cross-organ doses and for the effects of heterogeneity in kidney and tumor in mice for two of the most important radionuclides used in therapy, (131)I and (90)Y. Most mouse organs were modeled as single-compartment ellipsoids or cylinders, while heterogeneity in kidney and in tumor was addressed by using two compartments to represent the cortex and the medulla and viable and necrotic cells, respectively. The dimensions of these models were taken from previous studies, with the exception of kidney and tumor, which were defined using radioluminography and mosaics of high-power microscopy images. The absorbed fractions in each compartment were calculated using beta-particle point dose kernels. The self-organ dose was significantly higher for (131)I compared to (90)Y in all compartments, but a considerable amount of beta-particle energy was shown to escape the source organ for both radionuclides, with as much as 85% and 36% escaping the marrow for (90)Y and (131)I, respectively. The cortex was found to occupy a greater proportion of the total kidney volume than the medulla, and consequently the self-dose was higher in the cortex. In addition, the thickness of the viable shell in the tumor increased with tumor size, as did the self-dose fractions in both necrotic and viable areas. This dosimetry model improves dose estimates in mice and gives a conceptual basis for considering dosimetry in humans.


Assuntos
Partículas beta , Neoplasias Colorretais , Imunoconjugados , Radioisótopos do Iodo/normas , Rim/efeitos da radiação , Radioisótopos de Ítrio/normas , Animais , Partículas beta/uso terapêutico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/radioterapia , Modelos Animais de Doenças , Humanos , Imunoconjugados/uso terapêutico , Camundongos , Camundongos Nus , Transplante de Neoplasias , Dosagem Radioterapêutica/normas , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto/normas
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