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1.
Clin Cancer Res ; 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38809262

RESUMO

On November 8, 2023, the FDA approved fruquintinib, an inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine­, oxaliplatin­, and irinotecan­based chemotherapy, an anti­VEGF therapy, and, if RAS wild­type and medically appropriate, an anti EGFR therapy. Approval was based on Study FRESCO-2, a globally-conducted, double-blind, placebo-controlled randomized trial. The primary endpoint was overall survival (OS). The key secondary endpoint was progression-free survival (PFS). A total of 691 patients were randomized (461 and 230 into the fruquintinib and placebo arms, respectively). Fruquintinib provided a statistically significant improvement in OS with a hazard ratio (HR) of 0.66 (95% CI: 0.55, 0.80; p<0.001). The median OS was 7.4 months (95% CI: 6.7, 8.2) in the fruquintinib arm and 4.8 months (95% CI: 4.0, 5.8) for the placebo arm. Adverse events observed were generally consistent with the known safety profile associated with inhibition of the VEGFR. The results of FRESCO-2 were supported by the FRESCO study, a double-blind, single country, placebo-controlled, randomized trial in patients with refractory mCRC who have been previously treated with fluoropyrimidine­, oxaliplatin­, and irinotecan­based chemotherapy. In FRESCO, the OS HR was 0.65 (95% CI: 0.51, 0.83; p<0.001). FDA concluded that the totality of the evidence from FRESCO-2 and FRESCO supported an indication for patients with mCRC with prior treatment with fluoropyrimidine, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild­type and medically appropriate, an anti-EGFR therapy.

2.
Regul Toxicol Pharmacol ; 149: 105616, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38561147

RESUMO

Pharmacokinetic (PK) models are increasingly submitted to the FDA to support first-in-human (FIH) dose selection of immune-oncology products. To examine whether a simple PK modeling (SPM) using clearance for scaling was acceptable for dose estimation, FIH(SPM) doses were computed and compared to doses that were safely administered to patients. We concluded that the SPM approach is acceptable in FIH dose estimation, but the variables should be carefully selected for CD3 constructs. For CD3 constructs, use of 60 kg BWh, a clearance exponent of 0.75, and a targeted plasma concentration based on relevant and/or sensitive activity assays was an acceptable approach for FIH dose selection; use of 0.85 as the scaling factor is questionable at this time as it resulted in a FIH dose that was too close to the AHD for one product (7%). Immune activating mAbs were not sensitive to changes in the clearance exponent (0.75-0.85) or body weight (60-70 kg). For PD-1/PD-L1 mAbs, using products' in vitro EC50 in the model resulted in suboptimal FIH doses and clinical data of closely related products informed FIH dose selection. PK models submitted by sponsors were diverse in methods, assumptions, and variables, and the resulting FIH doses were not always optimal.


Assuntos
Modelos Biológicos , Humanos , Relação Dose-Resposta a Droga , Antígeno B7-H1/imunologia , Antineoplásicos Imunológicos/farmacocinética , Antineoplásicos Imunológicos/administração & dosagem , Receptor de Morte Celular Programada 1/imunologia , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Complexo CD3/imunologia , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/sangue
3.
Clin Cancer Res ; 29(20): 4027-4031, 2023 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-37289037

RESUMO

On September 30, 2022, the FDA granted accelerated approval to futibatinib for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions or other rearrangements. Approval was based on Study TAS-120-101, a multicenter open-label, single-arm trial. Patients received futibatinib 20-mg orally once daily. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to RECIST v1.1. ORR was 42% (95% confidence interval, 32%-52%). Median DoR was 9.7 months. Adverse reactions occurring in ≥30% patients were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, and abdominal pain. The most common laboratory abnormalities (≥50%) were increased phosphate, increased creatinine, decreased hemoglobin, and increased glucose. Ocular toxicity (including dry eye, keratitis, and retinal epithelial detachment) and hyperphosphatemia are important risks of futibatinib, which are listed under Warnings and Precautions. This article summarizes the FDA's thought process and data supporting the approval of futibatinib.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Pirazóis , Pirróis , Adulto , Humanos , Pirimidinas/efeitos adversos , Colangiocarcinoma/tratamento farmacológico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos , Aprovação de Drogas , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética
4.
Nat Rev Drug Discov ; 22(8): 625-640, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37344568

RESUMO

The cancer treatment landscape has changed dramatically since the turn of the century, resulting in substantial improvements in outcomes for patients. This Review summarizes trends in the approval of oncology therapeutic products by the United States Food and Drug Administration (FDA) from January 2000 to October 2022, based on a categorization of these products by their mechanism of action and primary target. Notably, the rate of oncology indication approvals has increased in this time, driven by approvals for targeted therapies, as has the rate of introduction of new therapeutic approaches. Kinase inhibitors are the dominant product class by number of approved products and indications, yet immune checkpoint inhibitors have the second most approvals despite not entering the market until 2011. Other trends include a slight increase in the share of approvals for biomarker-defined populations and the emergence of tumour-site-agnostic approvals. Finally, we consider the implications of the trends for the future of oncology therapeutic product development, including the impact of novel therapeutic approaches and technologies.


Assuntos
Antineoplásicos , Neoplasias , Estados Unidos , Humanos , United States Food and Drug Administration , Neoplasias/tratamento farmacológico , Biomarcadores , Oncologia , Aprovação de Drogas/métodos , Antineoplásicos/uso terapêutico
5.
Clin Cancer Res ; 29(11): 2020-2024, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36485007

RESUMO

On May 15, 2020, the FDA approved ripretinib for adult patients with advanced gastrointestinal stromal tumor who have received prior treatment with three or more kinase inhibitors, including imatinib. The approval was based on results from INVICTUS (NCT03353753), an international, multi-center, double-blind, placebo-controlled trial. Patients were randomly allocated (2:1) to receive either ripretinib 150 mg once daily (n = 85) or matching placebo (n = 44). The trial demonstrated a statistically significant improvement in progression-free survival (PFS) as assessed by modified RECIST v1.1 by blinded independent central review for patients randomized to ripretinib, with a median PFS of 6.3 months [95% confidence interval (CI): 4.6-6.9] compared with 1.0 month (95% CI: 0.9-1.7) for placebo [HR: 0.15 (95% CI: 0.09-0.25); P < 0.0001, stratified log-rank test]. There was no statistically significant difference in objective response rate in the ripretinib arm, 9% (95% CI: 4.2-18) compared with placebo 0% [(95% CI: 0-8); P = 0.0504, Fisher exact test]. The median overall survival (OS) in the ripretinib arm was 15.1 months (95% CI: 12.3-15.1) compared with 6.6 months (95% CI: 4.1-11.6) in the placebo arm. A formal statistical comparison of OS was not made due to the prespecified hierarchical analysis plan. The most common (≥20%) adverse events with ripretinib, in order of decreasing frequency, were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia, and vomiting. Other important risks of ripretinib include new primary cutaneous malignancies, hypertension, and cardiac dysfunction.


Assuntos
Tumores do Estroma Gastrointestinal , Adulto , Humanos , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/uso terapêutico , Naftiridinas/uso terapêutico , Ureia/uso terapêutico
6.
Mol Omics ; 17(5): 677-691, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34142686

RESUMO

Triple negative breast cancer (TNBC) is an aggressive type of breast cancer with very little treatment options. TNBC is very heterogeneous with large alterations in the genomic, transcriptomic, and proteomic landscapes leading to various subtypes with differing responses to therapeutic treatments. We applied a multi-omics data integration method to evaluate the correlation of important regulatory features in TNBC BRCA1 wild-type MDA-MB-231 and TNBC BRCA1 5382insC mutated HCC1937 cells compared with non-tumorigenic epithelial breast MCF10A cells. The data includes DNA methylation, RNAseq, protein, phosphoproteomics, and histone post-translational modification. Data integration methods identified regulatory features from each omics method that had greater than 80% positive correlation within each TNBC subtype. Key regulatory features at each omics level were identified distinguishing the three cell lines and were involved in important cancer related pathways such as TGFß signaling, PI3K/AKT/mTOR, and Wnt/beta-catenin signaling. We observed overexpression of PTEN, which antagonizes the PI3K/AKT/mTOR pathway, and MYC, which downregulates the same pathway in the HCC1937 cells relative to the MDA-MB-231 cells. The PI3K/AKT/mTOR and Wnt/beta-catenin pathways are both downregulated in HCC1937 cells relative to MDA-MB-231 cells, which likely explains the divergent sensitivities of these cell lines to inhibitors of downstream signaling pathways. The DNA methylation and RNAseq data is freely available via GEO GSE171958 and the proteomics data is available via the ProteomeXchange PXD025238.


Assuntos
Transdução de Sinais , Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Humanos , Proteômica , Neoplasias de Mama Triplo Negativas/genética
7.
Regul Toxicol Pharmacol ; 110: 104511, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31678263

RESUMO

A systematic analysis of new commercial investigational new drug applications (IND) submitted to the FDA's Office of Hematology and Oncology Products (OHOP) in the Center for Drug Evaluation and Research was conducted to quantify the most common reasons INDs for oncology indications go on clinical hold. In OHOP, less than 10% of INDs went on hold or were withdrawn within the 30-day safety review period. Of INDs that were placed on hold, deficiencies were mainly clinical, followed by concerns related to pharmaceutical quality and nonclinical development. INDs were also characterized based on phase of development, product type, sponsors' regulatory experience, and occurrence of a pre-IND meeting. INDs that were placed on hold were mostly for first-in-human trials or submitted by sponsors with limited regulatory experience. INDs that went on hold or were safe-to-proceed had pre-IND meetings with comparable rates but sponsors with substantial experience appeared to benefit more from pre-IND meetings compared to those with limited experience. The time interval between the pre-IND meeting and the IND submission was longer for INDs that went on hold. To obtain useful FDA feedback on product development, it is essential to provide focused questions and supporting information in pre-IND meeting packages.


Assuntos
Antineoplásicos , Aplicação de Novas Drogas em Teste/estatística & dados numéricos , Estados Unidos , United States Food and Drug Administration
8.
Oncol Lett ; 14(3): 3480-3486, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28927103

RESUMO

Metformin is a biguanide employed in treating type II diabetes. Its potential efficacy for treating cancer has been demonstrated epidemiologically (lower cancer incidence in metformin users compared with users of sulfonylureas or insulin) and mechanistically, primarily in cell culture. Metformin decreases the levels of insulin-like growth factor 1 and secondarily inhibits the mammalian target of rapamycin pathway to exhibit anticancer effects. The current study examined its cancer preventive efficacy in multiple standard in situ arising cancer models. Metformin was administered orally by gavage or in the diet, at human equivalent doses, in numerous cancer models. In the hydroxybutyl(butyl)nitrosamine-induced model of invasive urinary bladder cancer, metformin (50 or 150 mg/kg body weight/day, intragastric) was ineffective despite high urinary concentrations of metformin. Metformin (250 or 500 ppm in diet) failed to decrease the incidence or invasiveness of squamous cell cancer of the tongue in a 4-nitroquinoline-1-(4NQO)-induced model. Finally, in the Min mouse model of gastrointestinal cancer, metformin (400 or 1,200 ppm in diet) was ineffective. Notably, a slight increase in intestinal tumor multiplicity was observed at the higher dose. Therefore, metformin lacked efficacy in multiple standard cancer models in non-diabetic rodents. This lack of efficacy may discourage any large phase clinical cancer trials in non-diabetic individuals in the absence of clear phase-II studies.

9.
Clin Cancer Res ; 23(17): 5302-5310, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28450405

RESUMO

Purpose: Adrenal incidentalomas must be differentiated from adrenocortical cancer (ACC). Currently, size, growth, and imaging characteristics determine the potential for malignancy but are imperfect. The aim was to evaluate whether urinary small molecules (<800 Da) are associated with ACC.Experimental Design: Preoperative fasting urine specimens from patients with ACC (n = 19) and benign adrenal tumors (n = 46) were analyzed by unbiased ultraperformance liquid chromatography/mass spectrometry. Creatinine-normalized features were analyzed by Progenesis, SIMCA, and unpaired t test adjusted by FDR. Features with an AUC >0.8 were identified through fragmentation patterns and database searches. All lead features were assessed in an independent set from patients with ACC (n = 11) and benign adrenal tumors (n = 46) and in a subset of tissue samples from patients with ACC (n = 15) and benign adrenal tumors (n = 15) in the training set.Results: Sixty-nine features were discovered and four known metabolites identified. Urinary creatine riboside was elevated 2.1-fold (P = 0.0001) in patients with ACC. L-tryptophan, Nε,Nε,Nε-trimethyl-L-lysine, and 3-methylhistidine were lower 0.33-fold (P < 0.0001), 0.56-fold (P < 0.0001), and 0.33-fold (P = 0.0003) in patients with ACC, respectively. Combined multivariate analysis of the four biomarkers showed an AUC of 0.89 [sensitivity 94.7% (confidence interval {CI}, 73.9%-99.1%), specificity 82.6% (CI, 68.6%-92.2%), PPV 69.2% (CI, 48.2%-85.6%), and NPV 97.4% (CI, 86.5%-99.6%)] for distinguishing ACC from benign tumors. Of the four, creatine riboside and four unknown features were validated. Creatine riboside, Nε,Nε,Nε-trimethyl-L-lysine, and two unknown features were elevated in ACC tumors.Conclusions: There are unique urinary metabolic features in patients with ACC with some metabolites present in patient tumor samples. Urinary creatine riboside can differentiate benign adrenal neoplasms from ACC. Clin Cancer Res; 23(17); 5302-10. ©2017 AACR.


Assuntos
Neoplasias das Glândulas Suprarrenais/urina , Biomarcadores Tumorais/urina , Creatina/análogos & derivados , Neoplasias/urina , Ribonucleosídeos/urina , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Creatina/urina , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia
10.
Cancer Epidemiol Biomarkers Prev ; 25(6): 978-86, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27013655

RESUMO

BACKGROUND: Lung cancer is a major health burden causing 160,000 and 1.6 million deaths annually in the United States and worldwide, respectively. METHODS: While seeking to identify stable and reproducible biomarkers in noninvasively collected biofluids, we assessed whether previously identified metabolite urinary lung cancer biomarkers, creatine riboside (CR), N-acetylneuraminic acid (NANA), cortisol sulfate, and indeterminate metabolite 561+, were elevated in the urines of subjects prior to lung cancer diagnosis in a well-characterized prospective Southern Community Cohort Study (SCCS). Urine was examined from 178 patients and 351 nondiseased controls, confirming that one of four metabolites was associated with lung cancer risk in the overall case-control set, whereas two metabolites were associated with lung cancer risk in European-Americans. RESULTS: OR of lung cancer associated with elevated CR levels, and adjusted for smoking and other potential confounders, was 2.0 [95% confidence interval (CI), 1.2-3.4; P= 0.01]. In European-Americans, both CR and NANA were significantly associated with lung cancer risk (OR = 5.3; 95% CI, 1.6-17.6; P= 0.006 and OR=3.5; 95% CI, 1.5-8.4; P= 0.004, respectively). However, race itself did not significantly modify the associations. ROC analysis showed that adding CR and NANA to a model containing previously established lung cancer risk factors led to a significantly improved classifier (P= 0.01). Increasing urinary levels of CR and NANA displayed a positive association with increasing tumor size, strengthening a previously established link to altered tumor metabolism. CONCLUSION AND IMPACT: These replicated results provide evidence that identified urinary metabolite biomarkers have a potential utility as noninvasive, clinical screening tools for early diagnosis of lung cancer. Cancer Epidemiol Biomarkers Prev; 25(6); 978-86. ©2016 AACR.


Assuntos
Biomarcadores Tumorais/urina , Neoplasias Pulmonares/urina , Modelos Biológicos , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Fatores de Risco
11.
Cancer Prev Res (Phila) ; 8(6): 518-27, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25804611

RESUMO

Metformin is a widely prescribed drug for the treatment of type II diabetes. Although epidemiologic data have provided a strong rationale for investigating the potential of this biguanide for use in cancer prevention and control, uncertainty exists whether metformin should be expected to have an impact in nondiabetic patients. Furthermore, little attention has been given to the possibility that other biguanides may have anticancer activity. In this study, the effects of clinically relevant doses of metformin (9.3 mmol/kg diet), buformin (7.6 mmol/kg diet), and phenformin (5.0 mmol/kg diet) were compared with rats fed control diet (AIN93-G) during the post-initiation stage of 1-methyl-1-nitrosourea-induced (50 mg/kg body weight) mammary carcinogenesis (n = 30/group). Plasma, liver, skeletal muscle, visceral fat, mammary gland, and mammary carcinoma concentrations of the biguanides were determined. In comparison with the control group, buformin decreased cancer incidence, multiplicity, and burden, whereas metformin and phenformin had no statistically significant effect on the carcinogenic process relative to the control group. Buformin did not alter fasting plasma glucose or insulin. Within mammary carcinomas, evidence was obtained that buformin treatment perturbed signaling pathways related to energy sensing. However, further investigation is needed to determine the relative contributions of host systemic and cell autonomous mechanisms to the anticancer activity of biguanides such as buformin.


Assuntos
Buformina/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Metformina/farmacologia , Fenformin/farmacologia , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Carcinógenos/toxicidade , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Feminino , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/patologia , Ratos , Ratos Sprague-Dawley
12.
Cancer Prev Res (Phila) ; 8(3): 231-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25681088

RESUMO

Epidemiologic studies have shown that diabetics receiving the biguanide metformin, as compared with sulfonylureas or insulin, have a lower incidence of breast cancer. Metformin increases levels of activated AMPK (AMP-activated protein kinase) and decreases circulating IGF-1; encouraging its potential use in both cancer prevention and therapeutic settings. In anticipation of clinical trials in nondiabetic women, the efficacy of metformin in nondiabetic rat and mouse mammary cancer models was evaluated. Metformin was administered by gavage or in the diet, at a human equivalent dose, in standard mammary cancer models: (i) methylnitrosourea (MNU)-induced estrogen receptor-positive (ER(+)) mammary cancers in rats, and (ii) MMTV-Neu/p53KO ER(-) (estrogen receptor-negative) mammary cancers in mice. In the MNU rat model, metformin dosing (150 or 50 mg/kg BW/d, by gavage) was ineffective in decreasing mammary cancer multiplicity, latency, or weight. Pharmacokinetic studies of metformin (150 mg/kg BW/d, by gavage) yielded plasma levels (Cmax and AUC) higher than humans taking 1.5 g/d. In rats bearing small palpable mammary cancers, short-term metformin (150 mg/kg BW/d) treatment increased levels of phospho-AMPK and phospho-p53 (Ser20), but failed to reduce Ki67 labeling or expression of proliferation-related genes. In the mouse model, dietary metformin (1,500 mg/kg diet) did not alter final cancer incidence, multiplicity, or weight. Metformin did not prevent mammary carcinogenesis in two mammary cancer models, raising questions about metformin efficacy in breast cancer in nondiabetic populations.


Assuntos
Modelos Animais de Doenças , Neoplasias Mamárias Experimentais/tratamento farmacológico , Metformina/farmacologia , Alquilantes/toxicidade , Animais , Biomarcadores Tumorais/genética , Feminino , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/patologia , Metformina/farmacocinética , Metilnitrosoureia/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Camundongos Transgênicos , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Distribuição Tecidual , Células Tumorais Cultivadas
13.
Curr Drug Targets ; 13(14): 1876-84, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23140331

RESUMO

Metformin, a widely used anti-hyperglycemic drug in the biguanide class, is currently under investigation for the prevention of cancer. Surprisingly however, considering the time and cost of clinical chemoprevention trials and the current scrutiny of cancer chemoprevention, limited attention has been given to integrating available data, identifying the subpopulations most likely to benefit, or to quantitatively understanding the potential pitfalls of biguanide chemoprevention. Herein, a physiologically-based pharmacokinetic (PBPK) and pharmacodynamic framework is proposed for integrating information on physicochemical, cell-based, animal, and human studies of various biguanides to identify gaps in knowledge and to build a systems model that may facilitate the planning of randomized cancer chemoprevention trials of metformin.


Assuntos
Biguanidas/farmacocinética , Metabolismo Energético/fisiologia , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Neoplasias/metabolismo , Estresse Oxidativo/fisiologia , Animais , Biguanidas/farmacologia , Biguanidas/uso terapêutico , Quimioprevenção/métodos , Quimioprevenção/tendências , Metabolismo Energético/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Metformina/farmacologia , Metformina/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos
15.
Carcinogenesis ; 33(1): 226-32, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22072617

RESUMO

Emerging evidence indicates that common bean (Phaseolus vulgaris L.) is associated with reduced cancer risk in human populations and rodent carcinogenesis models. This study sought to identify cancer-associated molecular targets that mediate the effects of bean on cancer burden in a chemically induced rat model for breast cancer. Initial experiments were conducted using a high dietary concentration of bean (60% wt/wt) where carcinoma burden in bean-fed rats was reduced 62.2% (P < 0.001) and histological and western blot analyses revealed that the dominant cellular process associated with reduced burden was induction of apoptosis. Further analysis of mammary carcinomas revealed changes in the phosphorylation states of mammalian target of rapamycin (mTOR) substrates (4E-binding protein 1 and p70S6 kinase) and mTOR regulators adenosine monophosphate-activated protein kinase and protein kinase B (Akt) (P < 0.001). Effects on mTOR signaling in carcinomas were also found at lower dietary concentrations of bean (7.5-30% wt/wt). Liquid chromatography-time of flight-mass spectrometry analysis of plasma provided evidence of altered lipid metabolism consistent with reduced mTOR network activity in the liver (P < 0.001). Plasma concentrations of insulin and insulin-like growth factor-1 were reduced by 36.3 and 38.9%, respectively, (P < 0.001), identifying a link to Akt regulation. Plasma C-reactive protein, a prognostic marker for long-term survival in breast cancer patients, was reduced by 23% (P < 0.001) in bean-fed rats. Identification of a role for the mTOR signaling network in the reduction of cancer burden by dietary bean is highly relevant given that this pathway is deregulated in the majority of human breast cancers.


Assuntos
Neoplasias Mamárias Experimentais/prevenção & controle , Phaseolus , Transdução de Sinais/fisiologia , Animais , Apoptose , Proliferação de Células , Dieta , Feminino , Antígeno Ki-67/análise , Neoplasias Mamárias Experimentais/patologia , Metaboloma , Ratos , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/fisiologia
16.
J Carcinog ; 10: 17, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21799661

RESUMO

BACKGROUND: This study examined whether metformin administration inhibited chemically induced mammary carcinogenesis in rats. In cancer prevention, metformin may act (1) indirectly through reducing systemic risk factors; or (2) directly through AMPK-mediated signaling. To begin to delineate clinically relevant mechanisms for breast cancer prevention, metformin was also studied along with dietary energy restriction. MATERIALS AND METHODS: Mammary cancer was induced in female Sprague--Dawley rats (50 mg/kg MNU, i.p.). Metformin was fed alone (AIN93G + 0.05 to 1.0% w/w metformin) or combined with 40% dietary energy restriction. Plasma analytes (e.g., insulin, glucose, IGF-1) and protein expression (e.g., AMPK, mTOR, Akt) in mammary carcinomas and liver were evaluated. Additional studies included (1) aldehyde dehydrogenase flow cytometry, to gauge potential for cancer-initiated cells in mammary carcinomas to respond to metformin; (2) cell culture, to understand dose response (0.02--20 mM) of different cancer cell line molecular subtypes to metformin; and (3) analysis of a rat mammary epithelial cell microarray database, to examine expression of genes related to metformin pharmacokinetics (e.g., organic cation transporters) and pharmacodynamics (e.g., complex I of electron transport). RESULTS: While a dosing regimen of 1.0%/0.25% metformin-reduced palpable mammary carcinoma incidence, multiplicity, and tumor burden and prolonged latency, lower doses of metformin failed to inhibit carcinogenesis despite effects on plasma insulin. Human breast cancer cell growth inhibition in response to metformin was only observed at high concentrations. Poor in vivo and in vitro response to metformin may be the result of pharmacokinetic (OCT-1 expression was low in rat mammary cells; OCT-3 was downregulated in mammary carcinoma) and pharmacodynamic (complex I transcripts were higher in mammary epithelial cells from carcinomas versus uninvolved gland) effects. In combination with dietary energy restriction, metformin offered protection against new tumor occurrence following release from combined treatment. Flow cytometry indicated the presence of cancer-initiated cells in mammary carcinomas. CONCLUSIONS: As a single agent, metformin possessed limited cancer inhibitory activity. However, metformin may be an effective component of multiagent interventions that target cancer-initiated cells. There is a clear need to identify the conditions under which metformin is likely to benefit prevention and control of breast cancer.

17.
Biol Proced Online ; 12(1): 9032, 2010 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-21406072

RESUMO

The use of architectural and morphological characteristics of cells for establishing prognostic indicators by which individual pathologies are assigned grade and stage is a well-accepted practice. Advances in automated micro- and macroscopic image acquisition and digital image analysis have created new opportunities in the field of prognostic assessment; but, one area in experimental pathology, animal models for colon cancer, has not taken advantage of these opportunities. This situation is primarily due to the methods available to evaluate the colon of the rodent for the presence of premalignant and malignant pathologies. We report a new method for the excision and processing of the entire colon of the rat and illustrate how this procedure permitted the quantitative assessment of aberrant crypt foci (ACF), a premalignant colon pathology, for characteristics consistent with progression to malignancy. ACF were detected by methylene blue staining and subjected to quantitative morphometric analysis. Colons were then restained with high iron diamine-alcian blue for assessment of mucin depletion using an image overlay to associate morphometric data with mucin depletion. The subsequent evaluation of ACF for beta-catenin staining is also demonstrated. The methods described are particularly relevant to the screening of compounds for cancer chemopreventive activity.

18.
Nutr Cancer ; 61(4): 510-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19838923

RESUMO

Experiments reported herein tested the hypothesis that cultivars of apple (Malus domestica Borkh.) would demonstrate anticancer activity in vivo as predicted by in vitro measures. Freeze dried powders of Red Delicious (RD), Fuji (FJ), Golden Delicious (GD), and Granny Smith (GS) apple cultivars were evaluated. Significant differences were noted among cultivars in total phenolics (P < 0.0001), flavonoids (P < 0.0003), oxygen radical absorbance capacity (P < 0.0001), and growth inhibition in the MDA-MB-468 human breast cancer cell line relative to vehicle-treated cells (P < 0.0001). These findings were extended to predict inhibition of the postinitiation phase of 1-methyl-1-nitrosourea-induced mammary carcinogenesis by freeze-dried whole apple powders of the same cultivars. Although rats fed apple-containing diets did not have lower incidence or multiplicity of cancers than rats fed control diet, a finding consistent with epidemiological reports on fruit and breast cancer risk, differences among cultivars were noted, with the greatest difference in cancer multiplicity between GS and RD (1.46 vs. 2.47 cancers/rat; P = 0.0159). The rate of cell proliferation in mammary carcinomas differed between GS and RD (P < 0.001), whereas the apoptotic rate did not. These findings suggest altered methodology for screening apples for anticancer activity and that more diverse apple cultivars with higher phytochemical content should be evaluated.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Frutas , Malus , Neoplasias Mamárias Experimentais/tratamento farmacológico , Extratos Vegetais/farmacologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Análise de Variância , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antioxidantes/análise , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/prevenção & controle , Carcinógenos/toxicidade , Linhagem Celular Tumoral , Feminino , Flavonoides/análise , Flavonoides/uso terapêutico , Liofilização , Frutas/química , Humanos , Hidroxibenzoatos/análise , Hidroxibenzoatos/uso terapêutico , Concentração Inibidora 50 , Malus/química , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/patologia , Metilnitrosoureia/toxicidade , Fitoterapia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
19.
J Nutr ; 138(11): 2091-7, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18936203

RESUMO

The purpose of this study was to determine whether a dry bean (Phaseolus vulgaris, L.) containing diet exerts an inhibitory effect on mammary carcinogenesis in a well-characterized rodent model for breast cancer. Twenty-one-d-old female Sprague Dawley rats were given an intraperitoneal injection of 1-methyl-1-nitrosourea and 7 d after carcinogen injection were randomized to 1 of 5 groups fed a modification of the AIN-93G diet formulation containing 0, 7.5, 15, 30, or 60% (wt:wt) small red dry bean incorporated as cooked, freeze-dried, and milled powder. All experimental diets had the same macronutrient content based on proximate analysis. Compared with the control group, dry bean consumption resulted in dose-dependent reductions in mammary cancer incidence (P = 0.046), cancer multiplicity (P = 0.001), and tumor burden (P = 0.01). Dry bean consumption was associated with dose-dependent reductions in plasma concentrations of glucose, insulin, insulin-like growth factor-1, C-reactive protein, and interleukin-6 in food-deprived rats. Analysis of mammary adenocarcinomas indicated that a dominant mechanism accounting for reduced tumor burden was the induction of apoptosis. B cell lymphoma 2 and X-linked inhibitor of apoptosis protein levels decreased and BCL-2-associated X protein increased with increasing dry bean consumption, findings consistent with the induction of apoptosis via the mitochondrial pathway. These data demonstrate that a legume without noteworthy content of isoflavones inhibits the development of mammary carcinogenesis and are consistent with a recent report from the Nurses Health Study that bean or lentil intake is associated with a lower risk for breast cancer.


Assuntos
Neoplasias Mamárias Animais/induzido quimicamente , Neoplasias Mamárias Animais/prevenção & controle , Phaseolus/metabolismo , Ração Animal , Animais , Apoptose , Proliferação de Células , Dieta , Relação Dose-Resposta a Droga , Feminino , Metilnitrosoureia/toxicidade , Ratos , Ratos Sprague-Dawley
20.
Child Psychiatry Hum Dev ; 37(4): 307-23, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17136451

RESUMO

This study sought to determine the emotional effects of a major community toxic release on children in the exposed community while controlling for the potential effects of response bias. Controlling for the response bias inherent in litigated contexts is an advance over previous studies of toxic exposure in children. A randomly selected representative sample of Exposed children (n = 31) was compared to a matched Control group (n = 28) from a nearby, unexposed community. Symptoms and complaints were assessed via interview with the children and their guardians, surveys and checklists, and well-established psychological instruments. Even when biased responding was controlled the Exposed children experienced more psychological distress, more physical symptoms, and greater general concern over their physical functioning than the Controls. The Exposed children also reported some concern about their future health and cancer risk but usually only if asked. Limitations and future research directions are discussed.


Assuntos
Exposição Ambiental/efeitos adversos , Substâncias Perigosas/efeitos adversos , Substâncias Perigosas/toxicidade , Transtornos de Estresse Pós-Traumáticos/etiologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Criança , Feminino , Humanos , Masculino , Inquéritos e Questionários
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