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1.
Biomed Pharmacother ; 171: 116105, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38171245

RESUMEN

Breast cancer prevention only requires local exposure of the breast to active drug. However, oral preventive agents entail systemic exposure, causing adverse effects that limit acceptance by high-risk women. Drug-delivery through the breast skin is an attractive option, but requires demonstration of dermal safety and drug distribution throughout the breast. We formulated the tamoxifen metabolite (E/Z)-endoxifen for transdermal delivery and tested it in a placebo-controlled, double-blinded Phase I trial with dose escalation from 10 to 20 mg daily. The primary endpoint was dermal toxicity. Thirty-two women planning mastectomy were randomized (2:1) to endoxifen-gel or placebo-gel applied to both breasts for 3-5 weeks. Both doses of endoxifen-gel incurred no dermal or systemic toxicity compared to placebo. All endoxifen-treated breasts contained the drug at each of five sampling locations; the median per-person tissue concentration in the treated participants was 0.6 ng/g (IQR 0.4-1.6), significantly higher (p < 0.001) than the median plasma concentration (0.2 ng/mL, IQR 0.2-0.2). The median ratio of the more potent (Z)-isomer to (E)-isomer at each breast location was 1.50 (IQR 0.96-2.54, p < 0.05). No discernible effects of breast size or adiposity on tissue concentrations were observed. At the endoxifen doses and duration used, and the tissue concentration achieved, we observed a non-significant overall reduction of tumor proliferation (Ki67 LI) and significant downregulation of gene signatures known to promote cancer invasion (FN1, SERPINH1, PLOD2, PDGFA, ITGAV) (p = 0.03). Transdermal endoxifen is an important potential breast cancer prevention agent but formulations with better dermal penetration are needed.


Asunto(s)
Productos Biológicos , Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Mastectomía , Tamoxifeno/farmacología , Antineoplásicos Hormonales
2.
JAMA Surg ; 158(12): 1265-1273, 2023 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-37870954

RESUMEN

Importance: Oral tamoxifen citrate benefits women with ductal carcinoma in situ (DCIS), but concern about toxic effects has limited acceptance. Previous pilot studies have suggested transdermal 4-hydroxytamoxifen gel has equivalent antiproliferative efficacy to oral tamoxifen, with low systemic exposure. Objective: To demonstrate that 4-hydroxytamoxifen gel applied to the breast skin is noninferior to oral tamoxifen in its antiproliferative effect in DCIS lesions. Design, Setting, and Participants: This randomized, double-blind, phase 2 preoperative window trial was performed at multicenter breast surgery referral practices from May 31, 2017, to January 27, 2021. Among 408 women with estrogen receptor-positive DCIS who were approached, 120 consented and 100 initiated study treatment. The most common reasons for nonparticipation were surgical delay, disinterest in research, and concerns about toxic effects. Data were analyzed from January 26, 2021, to October 5, 2022. Intervention: Random assignment to oral tamoxifen citrate, 20 mg/d, and gel placebo or 4-hydroxytamoxifen gel, 2 mg/d per breast, and oral placebo, for 4 to 10 weeks, followed by DCIS resection. Main Outcomes and Measures: The primary end point was absolute change in DCIS Ki-67 labeling index (Ki67-LI). Secondary end points included 12-gene DCIS Score, breast tissue tamoxifen metabolite concentrations, tamoxifen-responsive plasma protein levels, and patient-reported symptoms. Noninferiority of Ki67-LI reduction by 4-hydroxytamoxifen gel was tested using analysis of covariance; within- and between-arm comparisons were performed with paired t tests for mean values or the Wilcoxon rank sum test for medians. Results: Of 90 participants completing treatment (mean [SD] age, 55 [11] years; 8 [8.9%] Asian, 16 [17.8%] Black, 8 [8.9%] Latina, and 53 [58.9%] White), 15 lacked residual DCIS in the surgical sample, leaving 75 evaluable for the primary end point analysis (40 in the oral tamoxifen group and 35 in the 4-hydroxytamoxifen gel group). Posttreatment Ki67-LI was 3.3% higher (80% CI, 2.1%-4.6%) in the 4-hydroxytamoxifen gel group compared with the oral tamoxifen group, exceeding the noninferiority margin (2.6%). The DCIS Score decreased more with oral tamoxifen treatment (-16 [95% CI, -22 to -9.4]) than with 4-hydroxytamoxifen gel (-1.8 [95% CI, -5.8 to 2.3]). The median 4-hydroxytamoxifen concentrations deep in the breast were nonsignificantly higher in the oral tamoxifen group (5.7 [IQR, 4.0-7.9] vs 3.8 [IQR, 1.3-7.9] ng/g), whereas endoxifen was abundant in the oral tamoxifen group and minimal in the 4-hydroxytamoxifen gel group (median, 13.0 [IQR, 8.9-20.6] vs 0.3 [IQR, 0-0.3] ng/g; P < .001). Oral tamoxifen caused expected adverse changes in plasma protein levels and vasomotor symptoms, with minimal changes in the transdermal group. Conclusions and Relevance: In this randomized clinical trial, antiproliferative noninferiority of 4-hydroxytamoxifen gel to oral tamoxifen was not confirmed, potentially owing to endoxifen exposure differences. New transdermal approaches must deliver higher drug quantities and/or include the most potent metabolites. Trial Registration: ClinicalTrials.gov Identifier: NCT02993159.


Asunto(s)
Carcinoma Intraductal no Infiltrante , Humanos , Femenino , Persona de Mediana Edad , Carcinoma Intraductal no Infiltrante/tratamiento farmacológico , Carcinoma Intraductal no Infiltrante/cirugía , Antígeno Ki-67 , Método Doble Ciego , Tamoxifeno/uso terapéutico , Tamoxifeno/efectos adversos , Proteínas Sanguíneas/uso terapéutico
3.
Front Immunol ; 14: 1162669, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37207208

RESUMEN

Background: Recent clinical trial data from Lynch Syndrome (LS) carriers demonstrated that naproxen administered for 6-months is a safe primary chemoprevention that promotes activation of different resident immune cell types without increasing lymphoid cellularity. While intriguing, the precise immune cell types enriched by naproxen remained unanswered. Here, we have utilized cutting-edge technology to elucidate the immune cell types activated by naproxen in mucosal tissue of LS patients. Methods: Normal colorectal mucosa samples (pre- and post-treatment) from a subset of patients enrolled in the randomized and placebo-controlled 'Naproxen Study' were obtained and subjected to a tissue microarray for image mass cytometry (IMC) analysis. IMC data was processed using tissue segmentation and functional markers to ascertain cell type abundance. Computational outputs were then used to quantitatively compare immune cell abundance in pre- and post-naproxen specimens. Results: Using data-driven exploration, unsupervised clustering identified four populations of immune cell types with statistically significant changes between treatment and control groups. These four populations collectively describe a unique cell population of proliferating lymphocytes within mucosal samples from LS patients exposed to naproxen. Conclusions: Our findings show that daily exposure of naproxen promotes T-cell proliferation in the colonic mucosa, which paves way for developing combination of immunoprevention strategies including naproxen for LS patients.


Asunto(s)
Antineoplásicos , Vacunas contra el Cáncer , Neoplasias Colorrectales Hereditarias sin Poliposis , Humanos , Naproxeno/farmacología , Inmunoterapia , Linfocitos , Mucosa Intestinal , Quimioprevención
4.
Cancer Prev Res (Phila) ; 16(1): 47-55, 2023 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-36228112

RESUMEN

PREVENTION RELEVANCE: Bexarotene is a rexinoid that has been shown to prevent mammary tumors in mouse models but oral dosing has toxicities. This phase I study evaluates topical bexarotene, as a potential chemoprevention agent, for safety and toxicity in high-risk women for breast cancer.


Asunto(s)
Bexaroteno , Neoplasias , Femenino , Bexaroteno/administración & dosificación , Bexaroteno/efectos adversos , Neoplasias/tratamiento farmacológico , Humanos , Administración Tópica , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos
5.
Clin Pharmacol Ther ; 109(3): 728-738, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32996592

RESUMEN

Oral breast cancer prevention medications entail systemic exposure, limiting acceptance by high-risk women. Delivery through the breast skin, although an attractive alternative, requires demonstration of drug distribution throughout the breast. We conducted a randomized double-blind, placebo-controlled phase II clinical trial comparing telapristone acetate, a progesterone receptor antagonist, administered orally (12 mg/day) or transdermally (12 mg/breast) for 4 ± 1 weeks to women planning mastectomy. Plasma and tissue concentrations, measured at five locations in the mastectomy specimen using liquid chromatography tandem mass spectrometry were compared. In 60 evaluable subjects, median drug concentration (ng/g tissue) was 103 (interquartile range (IQR): 46.3-336) in the oral vs. 2.82 (IQR: 1.4-5.5) in the transdermal group. Despite poor dermal permeation, within-breast drug distribution pattern was identical in both groups (R2  = 0.88, P = 0.006), demonstrating that transdermally and orally delivered drug is distributed similarly through the breast, and is strongly influenced by tissue adiposity (P < 0.0001). Other skin-penetrant drugs should be tested for breast cancer prevention.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Terapia Neoadyuvante , Norpregnadienos/administración & dosificación , Absorción Cutánea , Adiposidad , Administración Cutánea , Administración Oral , Adulto , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Neoplasias de la Mama/sangre , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Cromatografía Liquida , Método Doble Ciego , Monitoreo de Drogas , Femenino , Humanos , Mastectomía , Persona de Mediana Edad , Norpregnadienos/efectos adversos , Norpregnadienos/sangre , Espectrometría de Masas en Tándem , Factores de Tiempo , Distribución Tisular , Resultado del Tratamiento , Estados Unidos
6.
Gut ; 70(3): 555-566, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32641470

RESUMEN

OBJECTIVE: Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS. DESIGN: We conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs). RESULTS: Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control. CONCLUSIONS: Naproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity. TRIAL REGISTRATION NUMBER: gov Identifier: NCT02052908.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Quimioprevención , Neoplasias Colorrectales Hereditarias sin Poliposis/tratamiento farmacológico , Neoplasias Colorrectales Hereditarias sin Poliposis/inmunología , Naproxeno/farmacología , Adulto , Anciano , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Mucosa Intestinal/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Naproxeno/administración & dosificación
7.
Oncotarget ; 8(16): 26312-26322, 2017 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-28412747

RESUMEN

According to the Nutritional Prevention of Cancer (NPC) trial, a selenized yeast supplement containing selenium, 200 mcg/day, decreased the incidence of total cancer, cancers of the prostate, colon and lung, and cancer mortality. The active agent in the selenized yeast supplement was assumed to be selenomethionine (SEMET), although the supplement had not been well speciated. The SELECT study, largely motivated by the NPC trial, enrolling nearly 40 times as many subjects, showed unequivocally that selenium 200 mcg/day, with selenium in the form of SEMET, does not protect selenium-replete men against prostate or other major cancer. The agent tested by SELECT, pure SEMET, could have been different from the selenized yeast tested in NPC. One of the selenium forms suspected of having chemopreventive effects, and which may have been present in the NPC agent, is methyl selenocysteine (MSC). This study, with 29 selenium-replete patients enrolled in a randomized, double-blind trial, compared the multiple-dose toxicity, pharmacokinetics and pharmacodynamics of MSC and SEMET. Patients were on trial for 84 days. No toxicity was observed. Although SEMET supplementation increased blood selenium concentration more than MSC did, neither form had a more than minimal impact on the two major selenoproteins: selenoprotein P(SEPP1) and glutathione peroxidase(GPX).


Asunto(s)
Suplementos Dietéticos , Selenocisteína/análogos & derivados , Selenometionina/administración & dosificación , Selenometionina/farmacocinética , Adulto , Anciano , Estudios de Casos y Controles , Quimioprevención , Monitoreo de Drogas , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Neoplasias/prevención & control , Selenocisteína/administración & dosificación , Selenocisteína/farmacocinética , Factores de Tiempo
9.
Cancer Prev Res (Phila) ; 9(2): 142-8, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26667449

RESUMEN

Aromatase inhibitors (AI) profoundly suppress estrogen levels in postmenopausal women and are effective in breast cancer prevention among high-risk postmenopausal women. Unfortunately, AI treatment is associated with undesirable side effects that limit patient acceptance for primary prevention of breast cancer. A double-blind, randomized trial was conducted to determine whether low and intermittent doses of letrozole can achieve effective estrogen suppression with a more favorable side-effect profile. Overall, 112 postmenopausal women at increased risk for breast cancer were randomized to receive letrozole at 2.5 mg once daily (QD, standard dose arm), 2.5 mg every Monday, Wednesday, and Friday (Q-MWF), 1.0 mg Q-MWF, or 0.25 mg Q-MWF for 24 weeks. Primary endpoint was suppression in serum estradiol levels at the end of letrozole intervention. Secondary endpoints included changes in serum estrone, testosterone, C-telopeptide (marker of bone resorption), lipid profile, and quality-of-life measures (QoL) following treatment. Significant estrogen suppression was observed in all dose arms with an average of 75% to 78% and 86% to 93% reduction in serum estradiol and estrone levels, respectively. There were no differences among dose arms with respect to changes in C-telopeptide levels, lipid profile, adverse events (AE), or QoL measures. We conclude that low and intermittent doses of letrozole are not inferior to standard dose in estrogen suppression and resulted in a similar side-effect profile compared with standard dose. Further studies are needed to determine the feasibility of selecting an effective AI dosing schedule with better tolerability.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma in Situ/tratamiento farmacológico , Carcinoma Lobular/tratamiento farmacológico , Nitrilos/uso terapéutico , Triazoles/uso terapéutico , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma in Situ/patología , Carcinoma in Situ/cirugía , Carcinoma Lobular/patología , Carcinoma Lobular/cirugía , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Letrozol , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Posmenopausia , Pronóstico
10.
Cancer Prev Res (Phila) ; 8(12): 1131-7, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26471236

RESUMEN

This study was conducted to determine the safety and efficacy of the green tea-derived Polyphenon E (Poly E) in patients with Barrett's Esophagus (BE). Subjects were randomized to a 6-month, twice daily (BID) oral treatment of placebo or Poly E (200, 400, or 600 mg). Endoscopic evaluation, including biopsies, was performed before and after treatment. The primary objective was to demonstrate safety; secondary objectives investigated catechin accumulation and effects in clinical specimens. Of the 44 enrolled subjects, 11 received placebo, and 33 received Poly E. No dose-limiting toxicities were encountered, and a maximum tolerated dose (MTD) was not reached. The recommended phase II dose was 600 mg twice daily. The most common treatment-related adverse events (AE) in Poly E-treated subjects were grade I and II nausea, grade I belching, and grade I lactate dehydrogenase (LDH) elevation. No treatment-related AEs were reported in placebo-treated subjects, aside from grade I laboratory abnormalities. Pill counts and subject diaries were not consistently collected, and compliance was difficult to determine. However, on the basis of an intention-to-treat analysis, there was a significant relationship between Poly E dose and esophageal EGCG level--mean changes (pmol/g) of 0.79 (placebo), 6.06 (200 mg), 35.67 (400 mg), and 34.95 (600 mg); P = 0.005. There was a possible relationship between Poly E dose and urine PGE-M concentration. In conclusion, Poly E was well-tolerated, and treatment with Poly E (400 and 600 mg) but not Poly E (200 mg) or placebo resulted in clinically relevant and detectable EGCG accumulation in the target organ, esophageal mucosa.


Asunto(s)
Esófago de Barrett/tratamiento farmacológico , Catequina/análogos & derivados , Fitoterapia/métodos , Anciano , Anciano de 80 o más Años , Biopsia , Catequina/administración & dosificación , Catequina/efectos adversos , Catequina/análisis , Catequina/metabolismo , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esofagoscopía , Femenino , Humanos , Masculino , Persona de Mediana Edad
11.
Cancer Prev Res (Phila) ; 6(5): 410-8, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23639862

RESUMEN

Oral premalignancy serves as an ideal model for study of chemopreventive agents. Although 13-cis-retinoic acid showed reversal of oral premalignancy, toxicity, and reversal of clinical response after cessation of therapy obviated its widespread use. A search for nontoxic agents with cancer preventive activity led us to evaluate Bowman Birk Inhibitor (BBI) formulated as BBI Concentrate (BBIC). We previously reported encouraging results in a phase IIa trial of BBIC in patients with oral leukoplakia with measurable clinical responses and favorable biomarker changes. On the basis of these results, we undertook a randomized, placebo controlled phase IIb trial with patients receiving BBIC or placebo for 6 months, with assessment of clinical response and change in lesion area as primary end point and an intent-to-treat analysis. One hundred and thirty two subjects were randomized; and 89 subjects completed six months on study drug or placebo. Both placebo and BBIC showed a statistically significant decrease in mean lesion area of 17.1% and 20.6%, respectively, and partial or greater clinical responses of 30% and 28% respectively. No significant difference between placebo and study drug arms was observed. Histologic review, review of photographs of lesions, and comparison of serum neu protein and oral mucosal cell protease activity also did not show significant differences between study arms. Probable reasons for these negative results were considered, are discussed, and include a placebo with non-BBIC clinical activity and reduced pharmacokinetic availability of the second batch of BBIC. This experience should be a strong cautionary note to those considering "Green" chemoprevention.


Asunto(s)
Leucoplasia Bucal/tratamiento farmacológico , Inhibidor de la Tripsina de Soja de Bowman-Birk/uso terapéutico , Inhibidores de Tripsina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Leucoplasia Bucal/patología , Masculino , Persona de Mediana Edad , Pronóstico
12.
Cancer Prev Res (Phila) ; 6(5): 379-83, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23466485

RESUMEN

Chemoprevention is the administration of agents (drugs, biologics, dietary supplements, or nutrients) to reduce the risk of developing cancer or prevent the recurrence of cancer. The National Cancer Institute, Division of Cancer Prevention (NCI, DCP), is a major sponsor of cancer preventive preclinical and clinical research. As such, it has developed a comprehensive drug development program specifically designed to meet the requirements needed for cancer preventive drugs to achieve initial regulatory approval. Clinical development of cancer prevention agents presents unique challenges that are not encountered with most cancer therapeutic agents. To meet these challenges, NCI, DCP has implemented new approaches and programs, including phase 0 clinical trial designs and microdose studies. In addition, the PREVENT Cancer Program was recently implemented by NCI, DCP to offer a formalized structure for moving drugs forward in the prevention pipeline using a continue/not continue decision process. Likewise, DCP has implemented a Clinical Trials Consortium to further develop these agents. These and other approaches will be discussed in this commentary.


Asunto(s)
Antineoplásicos/uso terapéutico , Diseño de Fármacos , Neoplasias/prevención & control , Humanos , National Cancer Institute (U.S.) , Estados Unidos
13.
Cancer Prev Res (Phila) ; 4(11): 1938-44, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21846796

RESUMEN

The recently published report of the SELECT evaluation of selenium and vitamin E provided strong evidence that selenium 200 µg per day in the form of selenomethionine does not protect selenium-replete men against prostate or any other cancer. This seems to refute the result of the much smaller Nutritional Prevention of Cancer (NPC) trial of selenium. Because SELECT did not test the NPC agent, it is possible that the difference between the two trials stems partly from the use of different agents: selenomethionine in SELECT, and selenized yeast in the NPC trial. One of the organic selenium forms suspected of having strong chemopreventive effects, and which may have been present in the NPC agent, is methyl selenocysteine. This study characterizes the single-dose pharmacokinetics of methyl selenocysteine.


Asunto(s)
Cisteína/análogos & derivados , Compuestos de Organoselenio/farmacocinética , Adulto , Estudios de Cohortes , Cisteína/administración & dosificación , Cisteína/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Masculino , Dosis Máxima Tolerada , Compuestos de Organoselenio/administración & dosificación , Selenocisteína/análogos & derivados , Resultado del Tratamiento
14.
Cancer Prev Res (Phila) ; 4(3): 347-53, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21372034

RESUMEN

SR13668, an orally active Akt pathway inhibitor, has demonstrated cancer chemopreventive potential in preclinical studies. To accelerate the clinical development of this promising agent, we designed and conducted the first-ever phase 0 chemoprevention trial to evaluate and compare the effects of food and formulation on SR13668 bioavailability. Healthy adult volunteers were randomly assigned to receive a single, 38-mg oral dose of SR13668 in one of five different formulations, with or without food. On the basis of existing animal data, SR13668 in a PEG400/Labrasol oral solution was defined as the reference formulation. Blood samples were obtained pre- and post-agent administration for pharmacokinetic analyses. Area under the plasma concentration-time curve (AUC(0-∞)) was defined as the primary endpoint. Data were analyzed and compared using established statistical methods for phase 0 trials with a limited sample size. Participants (n = 20) were rapidly accrued over a 5-month period. Complete pharmacokinetic data were available for 18 randomized participants. AUC(0-∞) values were highest in the fed state (range = 122-439 ng/mL × hours) and were statistically significantly different across formulations (P = 0.007), with Solutol HS15 providing the highest bioavailability. SR13668 time to peak plasma concentration (3 hours; range, 2-6 hours) and half-life were (11.2 ± 3.1 hours) were not formulation-dependent. Using a novel, highly efficient study design, we rapidly identified a lead formulation of SR13668 for further clinical testing. Our findings support application of the phase 0 trial paradigm to accelerate chemoprevention agent development.


Asunto(s)
Anticarcinógenos/farmacología , Anticarcinógenos/uso terapéutico , Carbazoles/farmacología , Quimioprevención/métodos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Adulto , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Masculino , Oncología Médica/métodos , Persona de Mediana Edad , Neoplasias/metabolismo , Neoplasias/prevención & control , Resultado del Tratamiento
15.
Front Biosci (Landmark Ed) ; 16(3): 980-96, 2011 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-21196213

RESUMEN

Breast cancer remains a major cause of death in the United States as well as the rest of the world. In view of the limited treatment options for patients with advanced breast cancer, preventive and novel therapeutic approaches play an important role in combating this disease. The plant-derived triterpenoids, commonly used for medicinal purposes in many Asian countries, posses various pharmacological properties. A large number of triterpenoids are known to exhibit cytotoxicity against a variety of tumor cells as well as anticancer efficacy in preclinical animal models. Numerous triterpenoids have been synthesized by structural modification of natural compounds. Some of these analogs are considered to be the most potent antiinflammatory and anticarcinogenic triterpenoids known. This review examines the potential role of natural triterpenoids and their derivatives in the chemoprevention and treatment of mammary tumors. Both in vitro and in vivo effects of these agents and related molecular mechanisms are presented. Potential challenges and future directions involved in the advancement of these promising compounds in the prevention and therapy of human breast cancer are also identified.


Asunto(s)
Anticarcinógenos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/prevención & control , Triterpenos/uso terapéutico , Animales , Anticarcinógenos/química , Antineoplásicos Fitogénicos/uso terapéutico , Quimioprevención , Glicósidos/uso terapéutico , Humanos , Ratones , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/uso terapéutico , Ácido Ursólico
16.
Cancer Res ; 70(22): 9003-11, 2010 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-20935227

RESUMEN

Resveratrol, a naturally occurring polyphenol, has cancer chemopreventive properties in preclinical models. It has been shown to downregulate the levels of insulin-like growth factor-1 (IGF-I) in rodents. The purpose of the study was to assess its safety, pharmacokinetics, and effects on circulating levels of IGF-I and IGF-binding protein-3 (IGFBP-3) after repeated dosing. Forty healthy volunteers ingested resveratrol at 0.5, 1.0, 2.5, or 5.0 g daily for 29 days. Levels of resveratrol and its metabolites were measured by high performance liquid chromatography-UV in plasma obtained before and up to 24 hours after a dose between days 21 and 28. IGF-I and IGFBP-3 were measured by ELISA in plasma taken predosing and on day 29. Resveratrol was safe, but the 2.5 and 5 g doses caused mild to moderate gastrointestinal symptoms. Resveratrol-3-O-sulfate, resveratrol-4'-O-glucuronide, and resveratrol-3-O-glucuronide were major plasma metabolites. Maximal plasma levels and areas under the concentration versus time curve for the metabolites dramatically exceeded those for resveratrol, in the case of areas under the concentration versus time curve, by up to 20.3-fold. Compared with predosing values, the ingestion of resveratrol caused a decrease in circulating IGF-I and IGFBP-3 (P<0.04 for both), respectively, in all volunteers. The decrease was most marked at the 2.5 g dose level. The results suggest that repeated administration of high doses of resveratrol generates micromolar concentrations of parent and much higher levels of glucuronide and sulfate conjugates in the plasma. The observed decrease in circulating IGF-I and IGFBP-3 might contribute to cancer chemopreventive activity.


Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Estilbenos/farmacocinética , Dolor Abdominal/inducido químicamente , Adulto , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/metabolismo , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Diarrea/inducido químicamente , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Glucurónidos/sangre , Glucurónidos/metabolismo , Humanos , Tasa de Depuración Metabólica , Persona de Mediana Edad , Náusea/inducido químicamente , Resveratrol , Estilbenos/efectos adversos , Estilbenos/sangre , Estilbenos/metabolismo , Adulto Joven
17.
Cancer Res ; 70(19): 7392-9, 2010 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-20841478

RESUMEN

Resveratrol is a phytochemical with chemopreventive activity in preclinical rodent models of colorectal carcinogenesis. Antiproliferation is one of the many chemopreventive modes of action it has been shown to engage in. Concentrations of resveratrol, which can be achieved in human tissues after p.o. administration, have not yet been defined. The purpose of this study was to measure concentrations of resveratrol and its metabolites in the colorectal tissue of humans who ingested resveratrol. Twenty patients with histologically confirmed colorectal cancer consumed eight daily doses of resveratrol at 0.5 or 1.0 g before surgical resection. Resveratrol was found to be well tolerated. Normal and malignant biopsy tissue samples were obtained before dosing. Parent compound plus its metabolites resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-O-sulfate, resveratrol sulfate glucuronide, and resveratrol disulfate were identified by high-performance liquid chromatography (HPLC) with UV or mass spectrometric detection in colorectal resection tissue. Quantitation was achieved by HPLC/UV. Cell proliferation, as reflected by Ki-67 staining, was compared in preintervention and postintervention tissue samples. Resveratrol and resveratrol-3-O-glucuronide were recovered from tissues at maximal mean concentrations of 674 and 86.0 nmol/g, respectively. Levels of resveratrol and its metabolites were consistently higher in tissues originating in the right side of the colon compared with the left. Consumption of resveratrol reduced tumor cell proliferation by 5% (P = 0.05). The results suggest that daily p.o. doses of resveratrol at 0.5 or 1.0 g produce levels in the human gastrointestinal tract of an order of magnitude sufficient to elicit anticarcinogenic effects. Resveratrol merits further clinical evaluation as a potential colorectal cancer chemopreventive agent.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Estilbenos/uso terapéutico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Anciano , Anciano de 80 o más Años , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/farmacocinética , Procesos de Crecimiento Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Terapia Combinada , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Resveratrol , Estilbenos/efectos adversos , Estilbenos/farmacocinética
18.
Cancer Prev Res (Phila) ; 3(9): 1168-75, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20716633

RESUMEN

Resveratrol has been shown to exhibit cancer-preventive activities in preclinical studies. We conducted a clinical study to determine the effect of pharmacologic doses of resveratrol on drug- and carcinogen-metabolizing enzymes. Forty-two healthy volunteers underwent baseline assessment of cytochrome P450 (CYP) and phase II detoxification enzymes. CYP1A2, CYP2D6, CYP2C9, and CYP3A4 enzyme activities were measured by the metabolism of caffeine, dextromethorphan, losartan, and buspirone, respectively. Blood lymphocyte glutathione S-transferase (GST) activity and GST-pi level and serum total and direct bilirubin, a surrogate for UDP-glucuronosyl transferase (UGT) 1A1 activity, were measured to assess phase II enzymes. After the baseline evaluation, study participants took 1 g of resveratrol once daily for 4 weeks. Enzyme assessment was repeated upon intervention completion. Resveratrol intervention was found to inhibit the phenotypic indices of CYP3A4, CYP2D6, and CYP2C9 and to induce the phenotypic index of 1A2. Overall, GST and UGT1A1 activities were minimally affected by the intervention, although an induction of GST-pi level and UGT1A1 activity was observed in individuals with low baseline enzyme level/activity. We conclude that resveratrol can modulate enzyme systems involved in carcinogen activation and detoxification, which may be one mechanism by which resveratrol inhibits carcinogenesis. However, pharmacologic doses of resveratrol could potentially lead to increased adverse drug reactions or altered drug efficacy due to inhibition or induction of certain CYPs. Further clinical development of resveratrol for cancer prevention should consider evaluation of lower doses of resveratrol to minimize adverse metabolic drug interactions.


Asunto(s)
Carcinógenos/farmacocinética , Sistema Enzimático del Citocromo P-450/metabolismo , Preparaciones Farmacéuticas/metabolismo , Estilbenos/farmacología , Adulto , Antineoplásicos Fitogénicos/análisis , Antineoplásicos Fitogénicos/sangre , Antineoplásicos Fitogénicos/farmacología , Carcinógenos/análisis , Carcinógenos/metabolismo , Cromatografía Líquida de Alta Presión , Sistema Enzimático del Citocromo P-450/análisis , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Femenino , Salud , Voluntarios Sanos , Humanos , Inactivación Metabólica/genética , Masculino , Persona de Mediana Edad , Preparaciones Farmacéuticas/análisis , Preparaciones Farmacéuticas/sangre , Resveratrol , Estilbenos/análisis , Estilbenos/sangre , Adulto Joven
19.
Cancer Epidemiol Biomarkers Prev ; 16(6): 1246-52, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17548692

RESUMEN

The red grape constituent resveratrol possesses cancer chemopreventive properties in rodents. The hypothesis was tested that, in healthy humans, p.o. administration of resveratrol is safe and results in measurable plasma levels of resveratrol. A phase I study of oral resveratrol (single doses of 0.5, 1, 2.5, or 5 g) was conducted in 10 healthy volunteers per dose level. Resveratrol and its metabolites were identified in plasma and urine by high-performance liquid chromatography-tandem mass spectrometry and quantitated by high-performance liquid chromatography-UV. Consumption of resveratrol did not cause serious adverse events. Resveratrol and six metabolites were recovered from plasma and urine. Peak plasma levels of resveratrol at the highest dose were 539 +/- 384 ng/mL (2.4 micromol/L, mean +/- SD; n = 10), which occurred 1.5 h post-dose. Peak levels of two monoglucuronides and resveratrol-3-sulfate were 3- to 8-fold higher. The area under the plasma concentration curve (AUC) values for resveratrol-3-sulfate and resveratrol monoglucuronides were up to 23 times greater than those of resveratrol. Urinary excretion of resveratrol and its metabolites was rapid, with 77% of all urinary agent-derived species excreted within 4 h after the lowest dose. Cancer chemopreventive effects of resveratrol in cells in vitro require levels of at least 5 micromol/L. The results presented here intimate that consumption of high-dose resveratrol might be insufficient to elicit systemic levels commensurate with cancer chemopreventive efficacy. However, the high systemic levels of resveratrol conjugate metabolites suggest that their cancer chemopreventive properties warrant investigation.


Asunto(s)
Anticarcinógenos/farmacocinética , Estilbenos/farmacocinética , Adulto , Anticarcinógenos/metabolismo , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/prevención & control , Resveratrol , Estilbenos/metabolismo , Espectrometría de Masas en Tándem
20.
Cancer Epidemiol Biomarkers Prev ; 14(4): 892-9, 2005 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15824161

RESUMEN

Cigarette smoking is thought to contribute to carcinogenesis by formation of DNA adducts of tobacco smoke constituents leading to genotoxic damage. The dithiolethione, oltipraz, is a putative cancer chemopreventive agent that induces phase II detoxifying enzymes in preclinical models and reduces aflatoxin adducts in humans living in areas with high dietary levels. To determine if oltipraz could reduce adduct levels of tobacco smoke constituents in the lungs and other target organs, chronic smokers were enrolled to one of three arms: 400 or 200 mg/wk oral oltipraz or placebo. Endobronchial tissue and bronchoalveolar lavage were done before and after 12 weeks of drug treatment; peripheral blood, urine, and oral saline rinse were also collected. Toxicity was assessed every 4 weeks. Fifty-nine of the 77 enrolled subjects completed the study. Of those receiving oltipraz, 15% experienced grade 2/3 toxicity, which was predominantly gastrointestinal. All subject withdrawals occurred in the oltipraz groups. There was no significant difference between pre- and post-polycyclic aromatic hydrocarbon-DNA adduct levels in lung epithelial cells measured by immunoperoxidase staining between treatment and placebo groups. Likewise, no significant differences were found in polycyclic aromatic hydrocarbon or benzo(a)pyrene-7,8-diol-9,10-epoxide adducts measured in blood, oral lining cells, or bladder lining cells. There was also no increase in mRNA or enzymatic activity of phase II enzymes and no change in glutathione levels. Thus, despite moderate drug-related toxicity, there was no significant effect on pharmacodynamic or surrogate risk biomarkers. Other agents with lower toxicity and greater activity to induce phase II enzymes are needed to definitively test the detoxification-induction paradigm in smokers.


Asunto(s)
Anticarcinógenos/uso terapéutico , Neoplasias Pulmonares/prevención & control , Hidrocarburos Policíclicos Aromáticos/sangre , Pirazinas/uso terapéutico , Fumar/efectos adversos , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido/metabolismo , Administración Oral , Adulto , Anciano , Anticarcinógenos/administración & dosificación , Anticarcinógenos/efectos adversos , Líquido del Lavado Bronquioalveolar/química , Esquema de Medicación , Femenino , Humanos , Neoplasias Pulmonares/etiología , Masculino , Persona de Mediana Edad , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , Fumar/metabolismo , Tionas , Tiofenos
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