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1.
JCI Insight ; 6(17)2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34255745

RESUMO

BACKGROUNDThe aberrant activation of the PI3K/mTOR signaling circuitry is one of the most frequently dysregulated signaling events in head and neck squamous cell carcinoma (HNSCC). Here, we conducted a single-arm, open-label phase IIa clinical trial in individuals with oral premalignant lesions (OPLs) to explore the potential of metformin to target PI3K/mTOR signaling for HNSCC prevention.METHODSIndividuals with OPLs, but who were otherwise healthy and without diabetes, underwent pretreatment and posttreatment clinical exam and biopsy. Participants received metformin for 12 weeks (week 1, 500 mg; week 2, 1000 mg; weeks 3-12, 2000 mg daily). Pretreatment and posttreatment biopsies, saliva, and blood were obtained for biomarker analysis, including IHC assessment of mTOR signaling and exome sequencing.RESULTSTwenty-three participants were evaluable for response. The clinical response rate (defined as a ≥50% reduction in lesion size) was 17%. Although lower than the proposed threshold for favorable clinical response, the histological response rate (improvement in histological grade) was 60%, including 17% complete responses and 43% partial responses. Logistic regression analysis revealed that when compared with never smokers, current and former smokers had statistically significantly increased histological responses (P = 0.016). Remarkably, a significant correlation existed between decreased mTOR activity (pS6 IHC staining) in the basal epithelial layers of OPLs and the histological (P = 0.04) and clinical (P = 0.01) responses.CONCLUSIONTo our knowledge this is the first phase II trial of metformin in individuals with OPLs, providing evidence that metformin administration results in encouraging histological responses and mTOR pathway modulation, thus supporting its further investigation as a chemopreventive agent.TRIAL REGISTRATIONNCT02581137FUNDINGNIH contract HHSN261201200031I, grants R01DE026644 and R01DE026870.


Assuntos
Regulação Neoplásica da Expressão Gênica , Leucoplasia Oral/prevenção & controle , Metformina/administração & dosagem , Mucosa Bucal/metabolismo , Lesões Pré-Cancerosas , Serina-Treonina Quinases TOR/genética , Administração Oral , Biópsia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Leucoplasia Oral/patologia , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/patologia , RNA Neoplásico/genética , Transdução de Sinais/efeitos dos fármacos , Método Simples-Cego , Serina-Treonina Quinases TOR/biossíntese
2.
J Transl Med ; 12: 223, 2014 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-25115686

RESUMO

BACKGROUND: Breast cancer risk is partially determined by several hormone-related factors. Preclinical and clinical studies suggested that resveratrol may modulate these hormonal factors. METHODS: We conducted a pilot study in postmenopausal women with high body mass index (BMI ≥ 25 kg/m2) to determine the clinical effect of resveratrol on systemic sex steroid hormones. Forty subjects initiated the resveratrol intervention (1 gm daily for 12 weeks) with six withdrawn early due to adverse events (AEs). Thirty-four subjects completed the intervention. RESULTS: Resveratrol intervention did not result in significant changes in serum concentrations of estradiol, estrone, and testosterone but led to an average of 10% increase in the concentrations of sex steroid hormone binding globulin (SHBG). Resveratrol intervention resulted in an average of 73% increase in urinary 2-hydroxyestrone (2-OHE1) levels leading to a favorable change in urinary 2-OHE1/16α-OHE1 ratio. One participant had asymptomatic Grade 4 elevation of liver enzymes at the end of study intervention. Two subjects had Grade 3 skin rashes. The remaining adverse events were Grade 1 or 2 events. The most common adverse events were diarrhea and increased total cholesterol, reported in 30% and 27.5% of the subjects, respectively. CONCLUSION: We conclude that among overweight and obese postmenopausal women, daily 1 gm dose of resveratrol has favorable effects on estrogen metabolism and SHBG. Further placebo-controlled studies are needed to confirm our findings on these hormone-related breast cancer risk factors and the attribution of the adverse effects observed in the study population. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01370889.


Assuntos
Índice de Massa Corporal , Hormônios Esteroides Gonadais/sangue , Pós-Menopausa/efeitos dos fármacos , Estilbenos/farmacologia , Adulto , Demografia , Estrogênios/sangue , Feminino , Humanos , Pessoa de Meia-Idade , Projetos Piloto , Pós-Menopausa/sangue , Resveratrol , Estilbenos/efeitos adversos , Estilbenos/sangue
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