RESUMO
Broccoli sprout extract containing sulforaphane (BSE-SFN) has been shown to inhibit ultraviolet radiation-induced damage and tumor progression in skin. This study evaluated the toxicity and potential effects of oral BSE-SFN at three dosages. Seventeen patients who each had at least 2 atypical nevi and a prior history of melanoma were randomly allocated to 50, 100, or 200 µmol oral BSE-SFN daily for 28 days. Atypical nevi were photographed on days 1 and 28, and plasma and nevus samples were taken on days 1, 2, and 28. Endpoints assessed were safety, plasma and skin sulforaphane levels, gross and histologic changes, IHC for phospho-STAT3(Y705), Ki-67, Bcl-2, HMOX1, and TUNEL, plasma cytokine levels, and tissue proteomics. All 17 patients completed 28 days with no dose-limiting toxicities. Plasma sulforaphane levels pooled for days 1, 2, and 28 showed median postadministration increases of 120 ng/mL for 50 µmol, 206 ng/mL for 100 µmol, and 655 ng/mL for 200 µmol. Median skin sulforaphane levels on day 28 were 0.0, 3.1, and 34.1 ng/g for 50, 100, and 200 µmol, respectively. Plasma levels of proinflammatory cytokines decreased from day 1 to 28. The tumor suppressor decorin was increased from day 1 to 28. Oral BSE-SFN is well tolerated at daily doses up to 200 µmol and achieves dose-dependent levels in plasma and skin. A larger efficacy evaluation of 200 µmol daily for longer intervals is now reasonable to better characterize clinical and biological effects of BSE-SFN as chemoprevention for melanoma. Cancer Prev Res; 11(7); 429-38. ©2018 AACR.
Assuntos
Brassica/química , Isotiocianatos/administração & dosagem , Melanoma/prevenção & controle , Nevo/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Administração Oral , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Biópsia , Cápsulas , Estudos de Viabilidade , Feminino , Humanos , Isotiocianatos/efeitos adversos , Isotiocianatos/farmacocinética , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Nevo/patologia , Extratos Vegetais/efeitos adversos , Extratos Vegetais/farmacocinética , Gravidez , Pele/efeitos dos fármacos , Pele/patologia , Neoplasias Cutâneas/patologia , Sulfóxidos , Distribuição Tecidual , Resultado do Tratamento , Adulto JovemRESUMO
Background: A nontoxic chemopreventive intervention efficacious against different subtypes of breast cancer is still a clinically unmet need. The present study was undertaken to determine the efficacy of an Ayurvedic medicine phytochemical (Withaferin A, [WA]) for chemoprevention of breast cancer and to elucidate its mode of action. Methods: Chemopreventive efficacy of WA (4 and 8 mg/kg body weight) was determined using a rat model of breast cancer induced by N-methyl-N-nitrosourea (MNU; n = 14 for control group, n = 15 for 4 mg/kg group, and n = 18 for 8 mg/kg group). The mechanisms underlying breast cancer chemoprevention by WA were elucidated by immunoblotting, biochemical assays, immunohistochemistry, and cytokine profiling using plasma and tumors from the MNU-rat (n = 8-12 for control group, n = 7-11 for 4 mg/kg group, and n = 8-12 for 8 mg/kg group) and/or mouse mammary tumor virus-neu (MMTV-neu) models (n = 4-11 for control group and n = 4-21 for 4 mg/kg group). Inhibitory effect of WA on exit from mitosis and leptin-induced oncogenic signaling was determined using MCF-7 and/or MDA-MB-231 cells. All statistical tests were two-sided. Results: Incidence, multiplicity, and burden of breast cancer in rats were decreased by WA administration. For example, the tumor weight in the 8 mg/kg group was lower by about 68% compared with controls (8 mg/kg vs control, mean = 2.76 vs 8.59, difference = -5.83, 95% confidence interval of difference = -9.89 to -1.76, P = .004). Mitotic arrest and apoptosis induction were some common determinants of breast cancer chemoprevention by WA in the MNU-rat and MMTV-neu models. Cytokine profiling showed suppression of plasma leptin levels by WA in rats. WA inhibited leptin-induced oncogenic signaling in cultured breast cancer cells. Conclusions: WA is a promising chemopreventative phytochemical with the ability to inhibit at least two different subtypes of breast cancer.
Assuntos
Neoplasias da Mama/prevenção & controle , Neoplasias Mamárias Experimentais/prevenção & controle , Vírus do Tumor Mamário do Camundongo , Infecções por Retroviridae/complicações , Infecções Tumorais por Vírus/complicações , Vitanolídeos/uso terapêutico , 8-Hidroxi-2'-Desoxiguanosina , Acetilcoenzima A/sangue , Família Aldeído Desidrogenase 1 , Animais , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/análise , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Citocinas/sangue , Desoxiguanosina/análogos & derivados , Desoxiguanosina/análise , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Fatores de Transcrição Forkhead/análise , Humanos , Antígeno Ki-67/análise , Ácido Láctico/sangue , Leptina/sangue , Células MCF-7 , Malatos/sangue , Neoplasias Mamárias Experimentais/química , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/virologia , Metilnitrosoureia , Camundongos , Mitose/efeitos dos fármacos , Índice Mitótico , Ratos , Receptores de Estrogênio/análise , Retinal Desidrogenase/análise , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral , Vitanolídeos/análise , Vitanolídeos/farmacologiaRESUMO
PURPOSE: Imatinib mesylate (Gleevec(®)/Glivec(®)) has revolutionized the treatment of chronic myeloid leukemias and gastrointestinal stromal tumors, and there is evidence for an exposure response relationship. Calcium carbonate is increasingly used as a calcium supplement and in the setting of gastric upset associated with imatinib therapy. Calcium carbonate could conceivably elevate gastric pH and complex imatinib, thereby influencing imatinib absorption and exposure. We aimed to evaluate whether use of calcium carbonate has a significant effect on imatinib pharmacokinetics. METHODS: Eleven healthy subjects were enrolled in a 2-period, open-label, single-institution, randomized crossover, fixed-schedule study. In one period, each subject received 400 mg of imatinib p.o. In the other period, 4,000 mg calcium carbonate (Tums Ultra(®)) was administered p.o. 15 min before 400 mg of imatinib. Plasma concentrations of imatinib and its active N-desmethyl metabolite CGP74588 were assayed by LC-MS; data were analyzed non-compartmentally and compared after log transformation. RESULTS: Calcium carbonate administration did not significantly affect the imatinib area under the plasma concentration versus time curve (AUC) (41.2 µg/mL h alone vs. 40.8 µg/mL h with calcium carbonate, P = 0.99), maximum plasma concentration (C(max)) (2.35 µg/mL alone vs. 2.39 µg/mL with calcium carbonate, P = 0.89). CONCLUSIONS: Our results indicate that the use of calcium carbonate does not significantly affect imatinib pharmacokinetics.
Assuntos
Antineoplásicos/farmacocinética , Benzamidas/farmacocinética , Carbonato de Cálcio/farmacologia , Piperazinas/farmacocinética , Pirimidinas/farmacocinética , Área Sob a Curva , Estudos Cross-Over , Interações Medicamentosas , Feminino , Humanos , Mesilato de Imatinib , MasculinoRESUMO
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Gastric upset is a common side effect of nilotinib therapy, and calcium carbonate is frequently used concomitantly, either as antacid or as calcium supplementation. With the increasing number of oral agents in cancer therapy, oral drug-drug interactions are becoming more relevant. Nilotinib has already been shown to be absorbed to a much lesser extent when co-administered with proton pump inhibitors. Because exposure to sub-therapeutic concentrations of anticancer drugs such as nilotinib may result in selection of resistant clones and ultimately relapse, we studied the effect of a calcium carbonate supplement (Tums Ultra 1000®) on nilotinib pharmacokinetics. WHAT THIS STUDY ADDS: Calcium carbonate may be co-administered with nilotinib without significantly affecting the pharmacokinetics of nilotinib and potentially impacting efficacy. PURPOSE: Nilotinib is a second-generation oral tyrosine kinase inhibitor with superior efficacy compared with imatinib mesylate in the treatment for chronic phase chronic myelogenous leukemia. Calcium carbonate is commonly used as a source of calcium supplementation or as antacid to ameliorate the gastrointestinal side effects associated with nilotinib, which could have unknown effects on nilotinib absorption. The purpose of this study was to provide information on the effect of calcium carbonate on the PK of nilotinib in healthy volunteers. METHODS: Healthy subjects were enrolled in a two-period, open-label, single-institution, randomized, cross-over, fixed-schedule study. In one period, each subject received 400 mg of nilotinib p.o. In the other period, 4,000 mg of calcium carbonate (4 X Tums Ultra 1000®) was administered p.o. 15 min prior to the nilotinib dose. Plasma samples were collected at specified timepoints, concentrations of nilotinib were quantitated by LC-MS, and data were analyzed non-compartmentally. RESULTS: Eleven subjects were evaluable. Calcium supplementation did not significantly affect nilotinib pharmacokinetic parameters including area under the plasma concentration versus time curve (18.4 µg/mL h alone vs. 16.9 µg/mL h with calcium carbonate, p = 0.83; 80 % power); maximum plasma concentration (C(max)) (0.670 µg/mL alone vs. 6.18 µg/mL with calcium carbonate, p = 0.97); or half-life (18.9 h alone vs. 17.2 h with calcium carbonate, p = 0.18). CONCLUSIONS: Our results indicate that the use of calcium carbonate does not significantly affect nilotinib pharmacokinetics.