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1.
Urology ; 137: 84-90, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31877313

RESUMO

OBJECTIVE: To investigate the influence of CYP2D6 polymorphisms on outcomes and health-related quality of life of patients with retroperitoneal fibrosis (RPF) receiving tamoxifen (TMX). TMX is an effective alternative to corticosteroids for patients with RPF. Conversion of TMX to more potent endoxifen is dependent on enzyme activity of CYP2D6. MATERIALS AND METHODS: CYP2D6 genotyping and phenotype prediction of all patients treated with TMX between 02/2007 and 01/2018 was assessed using multiplex polymerase chain reaction (PCR). Groups were classified by phenotype: extensive (EM) vs poor and intermediate (PM + IM) vs ultrarapid metabolizer (UM). Retrospective evaluation of outcome (including magnetic resonance imaging and positron emission tomography-computed tomography) and health-related quality of life using the SF-36 was performed. RESULTS: A total of 63/194 patients received TMX, 40/63 with complete follow-up were sequenced: Twenty-nine patients with EM phenotype, 8 PM + IM and 3 UM. The median therapy duration was 364.5 days with a mean follow-up of 62.9 months. Seven therapy terminations occurred due to lack of response (17.5%), including all UM patients (P <.001). Magnetic resonance imagings showed a regression of fibrosis for EM and PM + IM in 69% and 62.5% of cases and a progression for UM in 100% (P = .004). In positron emission tomography-computed tomography, glucose utilization of RPF decreased significantly for EM and PM + IM. The physical sum-score of SF-36 improved for EM and PM + IM and decreased for UM (P <.05). The removal of DJ-stents was successful for EM, PM + IM, and UM in 48.3%, 75%, and 0% of cases (P = .0581). CONCLUSION: Contrary to expectations, UM showed the lowest success rate, which concludes that genotyping of RPF-patients may be useful in the sense of a tailored-therapy.


Assuntos
Citocromo P-450 CYP2D6/genética , Qualidade de Vida , Fibrose Retroperitoneal , Tamoxifeno , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos/métodos , Polimorfismo de Nucleotídeo Único , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Fibrose Retroperitoneal/diagnóstico por imagem , Fibrose Retroperitoneal/tratamento farmacológico , Fibrose Retroperitoneal/genética , Fibrose Retroperitoneal/psicologia , Espaço Retroperitoneal/diagnóstico por imagem , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Resultado do Tratamento
2.
Zhonghua Zhong Liu Za Zhi ; 41(12): 953-958, 2019 Dec 23.
Artigo em Chinês | MEDLINE | ID: mdl-31874555

RESUMO

Aromatase inhibitors (AIs) directly applies to postmenopausal breast cancer patients. Patients underwent bilateral ovariectomy or ≥60 years were acknowledged as postmenopausal.Alternatively, for <60 years breast cancer patients, sex hormone detection to evaluate menopause is recommended by National Comprehensive Cancer Network (NCCN) guideline, textbooks, and AIs clinical trials.However, series of clinical trial found that, a broad overlap region of follicle stimulating hormone and estradiol appeared between premenopausal and postmenopausal patients, which unable to determine the menopause even with sensitivity promotion of detection equipment or manners.We have abandon this detection in clinical treatment, and decision making was only according to the relapse risk and disease status. We recommend bilateral ovariectomy resection accompanied with AIs for breast cancer patients with high recurrence risk (e.g. T3-4 or LNM≥4) or patients with advanced metastatic disease.However, patients with low or moderate recurrence risk can be treated with tamoxifen.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Tamoxifeno/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Humanos , Menopausa , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Ovariectomia , Tamoxifeno/administração & dosagem
3.
Int J Pharm ; 570: 118691, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31518632

RESUMO

Vaginally delivered tamoxifen is being developed as alternative to estrogen-based therapies for the treatment of vulvar and vaginal atrophy (VVA) symptoms in subjects at high risk for breast cancer, undergoing treatment for breast cancer with aromatase inhibitors or are breast cancer survivors. Tamoxifen (1 or 20 mg) was administered intra-vaginally to female rabbits once-daily over a 28-day period to assess its pharmacokinetics, systemic exposure and local vaginal tolerance. Plasma samples were taken to assess concentrations of tamoxifen and its metabolites 4-hydroxytamoxifen and N-desmethyltamoxifen over the first day of vaginal administration and following the last dose on Day 28. In-life observations included evaluation of the vaginal region for signs of irritation. At necropsy, vaginal irritation was assessed by the method of Eckstein which reflect collective histopathological grading of four parameters within the vagina including epithelial morphology, leukocytic infiltration, congestion, and edema. Uterine effects of vaginal tamoxifen were also assessed. Plasma concentrations of tamoxifen were higher following administration of 20 mg tamoxifen compared to 1 mg tamoxifen at both Day 1 and Day 28. The metabolite 4-hydroxytamoxifen could not be detected on Day 1 and concentrations were low at Day 28 at the 1 mg tamoxifen dose. 4-Hydroxytamoxifen concentrations were low, but detectable at Day 1 and 28 following administration of 20 mg tamoxifen. The metabolite N-desmethyltamoxifen was undetectable at the 1 mg and 20 mg doses on Day 1; it remained undetectable at the 1 mg tamoxifen dose at Day 28. N-desmethyltamoxifen was detected over the first 8 h of Day 28 then fell below the quantitation limits. There was little to no vaginal or systemic accumulation of tamoxifen following once-daily dosing for 28 days. Tamoxifen accounted for more than 85% of the total systemic exposure compared to its metabolites, 4-hydroxytamoxifen, and N-desmethyltamoxifen. There was essentially no detectable vaginal irritation evident over the course of the study. At necropsy the individual Eckstein scores (maximum score of 16) of the proximal, mid, and distal vagina of females in the 1 mg and 20 mg dose groups were generally comparable in both groups and ranged from minimal to mild magnitude (1 mg dose group: ranging from 1 to 3 in the proximal vagina, 4 to 5 in the mid vagina, and 3 to 7 in the distal vagina; 20 mg dose group: ranging from 3 to 5 in the proximal vagina, 4 to 7 in the mid vagina, and 4 to 5 in the distal vagina). Overall, tamoxifen was absorbed and metabolized following vaginal administration and vaginal irritation was minimal to none at both doses.


Assuntos
Atrofia/tratamento farmacológico , Tamoxifeno/administração & dosagem , Vagina/efeitos dos fármacos , Administração Intravaginal , Animais , Neoplasias da Mama/tratamento farmacológico , Feminino , Coelhos , Tamoxifeno/análogos & derivados , Tamoxifeno/metabolismo
4.
Pak J Pharm Sci ; 32(3): 1121-1128, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31278729

RESUMO

There has been a number of studies looking into an alternative mode of therapy for the treament of breast cancer via 4-hydroxytamoxifen (4-OHT) transdermal administration.This systematic review aims to compare the safety and efficacy of a transdermal 4-OHT local therapy and oral tamoxifen (oral-T) on the treatment of ductal carcinoma in situ breast cancer. Through a systematic search of health science databases, eligible trials were located and the end points assessed were Ki-67 labeling index, concentration of 4-OHT in breast adipose tissue (ng/g) and plasma (ng/ml). Revman 5.3 version was used to perfom the meta-analysis. Three trials were identified (n=103), while only two were included for meta analysis. The mean difference between the two studies included were 0.40 and -10.58. Overall the I2 value was 89.0%, (Tau2 =53.86) and the differences between the two trials were statistically significant p=0.002. The meta analysis of the randomized controlled trials showed that the use of local transdermal therapy of 4-OHT gel is more safer than oral-T. However, due to the limited number of studies, the potential use of 4-OHT topical transdermal therapy for the treatment of breast cancer could not be concluded for healthcare professionals.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Tamoxifeno/análogos & derivados , Tamoxifeno/administração & dosagem , Administração Cutânea , Administração Oral , Antineoplásicos/farmacocinética , Carcinoma Intraductal não Infiltrante/tratamento farmacológico , Feminino , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tamoxifeno/farmacocinética , Tamoxifeno/farmacologia
5.
Life Sci ; 232: 116656, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31306658

RESUMO

AIMS: Tamoxifen-induced liver-specific Dicer1 deletion (iDicer1-/-) in mature mice may provide clues demonstrating the genuine effects of acute loss of Dicer1 and miRNAs in the liver regeneration process. MAIN METHODS: In this study, mice with tamoxifen-induced Dicer1 deletion through the Cre/LoxP system were constructed and then underwent classic 70% partial hepatectomy or CCl4-induced liver injury. To rescue the inhibitory effect of Dicer1 ablation on liver regeneration, miR-21 agomir was injected into the tail vein of iDicer1-/- mice. KEY FINDINGS: Unlike constitutive embryonic deletion of Dicer1, tamoxifen-induced Dicer1 deletion did not result in severe liver injury or lesions, providing an ideal model for investigating acute loss of Dicer1 and miRNAs in liver regeneration. Dicer1 deletion led to impaired liver regeneration through the inhibitory effect of miR-21 on PTEN and Rhob expression. SIGNIFICANCE: In our previous study, we found that embryonic loss of Dicer1 impairs hepatocyte survival and leads to chronic inflammation and progenitor cell activation, while the role of Dicer1 in liver regeneration remains largely unknown. We clearly identified the promotion effect of Dicer1 on liver regeneration by increasing miR-21 expression, which inhibits the expression of two negative cell proliferation regulators, Pten and Rhob.


Assuntos
RNA Helicases DEAD-box/fisiologia , Regeneração Hepática/fisiologia , MicroRNAs/fisiologia , PTEN Fosfo-Hidrolase/metabolismo , Ribonuclease III/fisiologia , Proteína rhoB de Ligação ao GTP/metabolismo , Animais , RNA Helicases DEAD-box/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Camundongos , Camundongos Knockout , Ribonuclease III/genética , Tamoxifeno/administração & dosagem
6.
Mol Pharmacol ; 96(2): 272-296, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31221824

RESUMO

Tamoxifen is used to prevent and treat estrogen receptor-positive (ER+) breast cancer (BC); however, its chronic use can increase uterine cancer risk and induce tamoxifen resistance. Novel melatonin-tamoxifen drug conjugates may be promising to treat BC and may help offset the adverse effects of tamoxifen usage alone due to the presence of melatonin. We synthesized and screened five drug conjugates (C2, C4, C5, C9, and C15 linked) for their effects on BC cell (MCF-7, tamoxifen-resistant MCF-7, mouse mammary carcinoma, MDA-MB-231, and BT-549) viability, migration, and binding affinity to melatonin receptor 1 (MT1R) and estrogen receptor 1 (ESR1). C4 and C5 demonstrated the most favorable pharmacological characteristics with respect to binding profiles (affinity for ESR1 and MT1R) and their potency/efficacy to inhibit BC cell viability and migration in four phenotypically diverse invasive ductal BC cell lines. C4 and C5 were further assessed for their actions against tamoxifen-resistant MCF-7 cells and a patient-derived xenograft triple-negative BC cell line (TU-BcX-4IC) and for their mechanisms of action using selective mitogen-activated protein kinase kinase MEK1/2, MEK5, and phosphoinositide 3-kinase (PI3K) inhibitors. C4 and C5 inhibited tamoxifen-resistant MCF-7 cells with equal potency (IC50 = 4-8 µM) and efficacy (∼90% inhibition of viability and migration) but demonstrated increased potency (IC50 = 80-211 µM) and efficacy (∼140% inhibition) to inhibit migration versus cell viability (IC50 = 181-304 mM; efficacy ∼80% inhibition) in TU-BcX-4IC cells. Unique pharmacokinetic profiles were observed, with C4 having greater bioavailability than C5. Further assessment of C4 and C5 demonstrates that they create novel pharmacophores within each BC cell that is context specific and involves MEK1/2/pERK1/2, MEK5/pERK5, PI3K, and nuclear factor κB. These melatonin-tamoxifen drug conjugates show promise as novel anticancer drugs and further preclinical and clinical evaluation is warranted.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/metabolismo , Melatonina/administração & dosagem , Receptor MT1 de Melatonina/metabolismo , Tamoxifeno/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células MCF-7 , Melatonina/farmacocinética , Melatonina/farmacologia , Camundongos , Tamoxifeno/farmacocinética , Tamoxifeno/farmacologia
7.
Ren Fail ; 41(1): 507-520, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31216906

RESUMO

Menopause is an important physiological event associated with structural and functional changes in the kidneys. An animal model of bilateral ovariectomy was used to study the effects of estrogen depletion, replacement and antiestrogen on renal structure and endocrine function. Sixty female rats were divided into six groups; group I was the control group, the remaining five groups underwent ovariectomy: group II received no treatment. The other groups received estradiol in group III, tamoxifen in group IV, estradiol followed by tamoxifen in group V and tamoxifen followed by estradiol in group VI. Serum creatinine, blood urea nitrogen, and endocrine functions of kidney were measured. Tissue samples were examined both microscopically for beta estrogen receptors and ultrastructurally for cell changes. Groups II, IV & VI showed a significant increase in creatinine, blood urea nitrogen, renal malondialdehyde, renal erythropoietin, plasma renin and plasma prostaglandin E2 and a significant decrease in renal antioxidants and serum vitamin D3. Groups III &V had a significant decrease in creatinine, blood urea nitrogen, renal malondialdehyde and renal erythropoietin with an increase in renal antioxidants, plasma prostaglandin E2 and serum vitamin D3. Histopathological and ultrastructural examinations revealed atrophic tubular changes in group II. The changes were less marked in groups III &V and more extensive in groups IV & VI. Estrogen receptor beta staining showed progressively increased expression in the absence of estrogen. Structural and most endocrine functions of the kidney were significantly affected by estradiol deficiency. Estradiol replacement exhibited a protective effect on renal tissue and endocrine functions.


Assuntos
Estradiol/administração & dosagem , Terapia de Reposição de Estrogênios/métodos , Rim/metabolismo , Menopausa/efeitos dos fármacos , Animais , Antagonistas de Estrogênios/administração & dosagem , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Menopausa/metabolismo , Modelos Animais , Ovariectomia/efeitos adversos , Ratos , Tamoxifeno/administração & dosagem
8.
Gulf J Oncolog ; 1(30): 22-28, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31242978

RESUMO

INTRODUCTION: Paediatric soft tissue sarcoma treatments and outcomes have improved significantly in the last few decades. However, a significant number of patients still succumb to the disease. In low-middle income countries there are dual problems of advanced disease at presentation and financial burden leading to poor compliance to therapy. Hence, we designed a low-cost oral metronomic chemotherapy protocol for these patients and studied the responses and toxicities to therapy in a tertiary referral hospital. PATIENTS AND METHODS: This is retrospective, single institutional, observational study. We retrospectively reviewed data of patients with relapsed, refractory or metastatic soft tissue sarcoma (STS) [ Ewing Sarcoma (ES); Rhabdomyosarcoma (RMS) or other STS] who were treated with the metronomic protocol of oral Tamoxifen, Etoposide and Cyclophosphamide (TEC) during the period April 1998 to September 2013, at the Tata Memorial Hospital, Parel, Mumbai. Patients with ES and RMS were primarily treated on our Institutional protocols. The patients included in the analysis were those who had relapsed after the primary protocols and then treated with metronomic TEC protocol; or those with primary refractory or metastatic disease (RMS, ES) and received metronomic TEC therapy. RESULTS: 49 patients were enrolled. Among the 49 patients, 32 were diagnosed ES, 13 RMS and 4 other STS. For the whole cohort response rates (RR) were 59% and clinical benefit rate (CBR) was 79%. Patients in the study were grouped into the following subgroups. Systemic recurrent/relapsed disease (N=24), metastatic disease at presentation (N=15) and local disease (refractory/recurrent) (N=10). None of the patients required blood or platelet support or admission for supportive care. The PFS for the above groups were 16.8 months, 12.5 months and 126.68 months respectively. This compares favorably with other historical cohorts in a similar setting. CONCLUSIONS: This study provides a preliminary evidence efficacy and tolerability of metronomic chemotherapy in poor risk ES and RMS. It also demonstrates that with this low-cost low risk treatment few patients could go into long term remissions despite high disease burden.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Recidiva Local de Neoplasia/mortalidade , Rabdomiossarcoma/mortalidade , Terapia de Salvação , Sarcoma de Ewing/mortalidade , Sarcoma/mortalidade , Administração Metronômica , Adolescente , Adulto , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/secundário , Sarcoma/tratamento farmacológico , Sarcoma/secundário , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/secundário , Taxa de Sobrevida , Tamoxifeno/administração & dosagem , Adulto Jovem
9.
N Engl J Med ; 381(4): 307-316, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31166679

RESUMO

BACKGROUND: An earlier analysis of this phase 3 trial showed that the addition of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor to endocrine therapy provided a greater benefit with regard to progression-free survival than endocrine therapy alone in premenopausal or perimenopausal patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Here we report the results of a protocol-specified interim analysis of the key secondary end point of overall survival. METHODS: We randomly assigned patients to receive either ribociclib or placebo in addition to endocrine therapy (goserelin and either a nonsteroidal aromatase inhibitor or tamoxifen). Overall survival was evaluated with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods. RESULTS: A total of 672 patients were included in the intention-to-treat population. There were 83 deaths among 335 patients (24.8%) in the ribociclib group and 109 deaths among 337 patients (32.3%) in the placebo group. The addition of ribociclib to endocrine therapy resulted in significantly longer overall survival than endocrine therapy alone. The estimated overall survival at 42 months was 70.2% (95% confidence interval [CI], 63.5 to 76.0) in the ribociclib group and 46.0% (95% CI, 32.0 to 58.9) in the placebo group (hazard ratio for death, 0.71; 95% CI, 0.54 to 0.95; P = 0.00973 by log-rank test). The survival benefit seen in the subgroup of 495 patients who received an aromatase inhibitor was consistent with that in the overall intention-to-treat population (hazard ratio for death, 0.70; 95% CI, 0.50 to 0.98). The percentage of patients who received subsequent antineoplastic therapy was balanced between the groups (68.9% in the ribociclib group and 73.2% in the placebo group). The time from randomization to disease progression during receipt of second-line therapy or to death was also longer in the ribociclib group than in the placebo group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.55 to 0.87). CONCLUSIONS: This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone-receptor-positive, HER2-negative breast cancer. No new concerns regarding toxic effects emerged with longer follow-up. (Funded by Novartis; MONALEESA-7 ClinicalTrials.gov number, NCT02278120.).


Assuntos
Aminopiridinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Purinas/administração & dosagem , Adulto , Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/mortalidade , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Análise de Intenção de Tratamento , Pessoa de Meia-Idade , Perimenopausa , Pré-Menopausa , Inibidores de Proteínas Quinases/efeitos adversos , Purinas/efeitos adversos , Receptor ErbB-2 , Receptores Estrogênicos , Receptores de Progesterona , Análise de Sobrevida , Tamoxifeno/administração & dosagem
10.
PLoS Genet ; 15(5): e1007687, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31059499

RESUMO

The transcription factor Oct1/Pou2f1 promotes poised gene expression states, mitotic stability, glycolytic metabolism and other characteristics of stem cell potency. To determine the effect of Oct1 loss on stem cell maintenance and malignancy, we deleted Oct1 in two different mouse gut stem cell compartments. Oct1 deletion preserved homeostasis in vivo and the ability to establish organoids in vitro, but blocked the ability to recover from treatment with dextran sodium sulfate, and the ability to maintain organoids after passage. In a chemical model of colon cancer, loss of Oct1 in the colon severely restricted tumorigenicity. In contrast, loss of one or both Oct1 alleles progressively increased tumor burden in a colon cancer model driven by loss-of-heterozygosity of the tumor suppressor gene Apc. The different outcomes are consistent with prior findings that Oct1 promotes mitotic stability, and consistent with differentially expressed genes between the two models. Oct1 ChIPseq using HCT116 colon carcinoma cells identifies target genes associated with mitotic stability, metabolism, stress response and malignancy. This set of gene targets overlaps significantly with genes differentially expressed in the two tumor models. These results reveal that Oct1 is selectively required for recovery after colon damage, and that Oct1 has potent effects in colon malignancy, with outcome (pro-oncogenic or tumor suppressive) dictated by tumor etiology.


Assuntos
Carcinogênese/genética , Colo/metabolismo , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Fator 1 de Transcrição de Octâmero/genética , Animais , Azoximetano/administração & dosagem , Carcinogênese/metabolismo , Carcinogênese/patologia , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Sulfato de Dextrana/administração & dosagem , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Células HCT116 , Humanos , Integrases/genética , Integrases/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Camundongos , Camundongos Knockout , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fator 1 de Transcrição de Octâmero/deficiência , Organoides/efeitos dos fármacos , Organoides/metabolismo , Organoides/patologia , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Regeneração , Transdução de Sinais , Análise de Sobrevida , Tamoxifeno/administração & dosagem
12.
Breast ; 46: 52-57, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31082762

RESUMO

OBJECTIVES: Severe hot flash (HF) toxicity due to tamoxifen can compromise compliance. We previously found that HFs did not correlate with endoxifen level or CYP2D6 genotype. In this study, we reduced tamoxifen dose in patients with severe HFs to determine whether HFs were ameliorated whilst maintaining a purported therapeutic endoxifen level of >15 nM. MATERIALS AND METHODS: Twenty patients with severe HFs on 20 mg TAM had CYP2D6genotype, trough level tamoxifen and metabolites measured with Loprinzi HF scores (HFS) derived before and after DR of tamoxifen to 10 mg. Other data collected included demographics, smoking, alcohol, menstrual and breast cancer history, previous chemotherapies, concurrent medications, BMI and other tamoxifen toxicities. RESULTS: At the 20 mg tamoxifen dose, endoxifen levels were 25.6, 0-91.9 nM (median, range) with HFS 131, 22-1482 (median, range). Upon DR to 10 mg, median endoxifen level fell to 14.1, 0.6-71.9 nM (difference in means p = 0.11, two-tailed T test) with HFS 47, 5-864 (difference in means p = 0.24, two-tailed T test). Despite lacking statistical significance, 85% of patients reported subjective improvement of HFs with DR. After DR, the proportion of patients with endoxifen level <15 nM increased from 20% to 50%. HFS did not correlate with any other parameter. CONCLUSION: DR of tamoxifen from 20 mg to 10 mg daily resulted in halving of endoxifen levels and subjective improvement of HF. While half the dose-reduced patients were below a potential therapeutic level of endoxifen, other recent studies suggest that low endoxifen levels may not indicate reduced effectiveness of tamoxifen.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Fogachos/induzido quimicamente , Tamoxifeno/análogos & derivados , Tamoxifeno/efeitos adversos , Adulto , Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/genética , Citocromo P-450 CYP2D6 , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Tamoxifeno/administração & dosagem , Tamoxifeno/sangue , Resultado do Tratamento
13.
Breast ; 46: 19-24, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31051411

RESUMO

BACKGROUND: Endocrine treatment with Tamoxifen and aromatase inhibitors (AIs) is a staple in the management of hormone receptor positive breast cancer (HR + BC). It has become clear that HR + BC carries a consistent risk of relapse up to 15 years post-diagnosis. While increasing evidence supports the use of extended adjuvant Tamoxifen over 5 years, controversial data are available on the optimal duration of extended AIs adjuvant treatment. We performed a meta-analysis to assess the real impact of extended adjuvant therapy with AIs on disease-free survival (DFS). METHODS: A literature-based meta-analysis of randomized controlled trials (RCTs) was undertaken. Relevant publications from PubMed, the Cochrane Library, and abstracts from American Society of Clinical Oncology (ASCO) and San Antonio Breast Cancer (SABCS) symposia were searched. Primary and secondary endpoints were Disease Free Survival (DFS) and overall survival (OS) respectively. A subgroup analysis was also performed to elucidate the impact of nodal involvement. RESULTS: The pooled analysis revealed a significant increase in DFS in the extended AIs group (hazard ratio (HR): 0.78, 95% CI: 0.68-0.90; P = 0.0006). The subgroup analysis according to nodal status showed a greater DFS benefit with extended AIs in patients with positive nodes (HR = 0.67 versus 0.80). Our analysis also demonstrated no improvement in OS with extended AIs (HR = 0.99, 95%CI: 0.87-1.12; P = 0.84). CONCLUSION: This work confirmed the efficacy of extended adjuvant treatment with AIs for HR + early breast cancer, with a 22% increase in DFS, but no impact on OS. Greater efficacy was observed in women with positive nodal status.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Tamoxifeno/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/metabolismo , Resultado do Tratamento
14.
Expert Rev Clin Pharmacol ; 12(6): 523-536, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31008668

RESUMO

Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30-100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated. Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed. Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Tamoxifeno/análogos & derivados , Administração Oral , Antineoplásicos Hormonais/farmacocinética , Neoplasias da Mama/patologia , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Feminino , Genótipo , Humanos , Adesão à Medicação , Metástase Neoplásica , Farmacogenética , Tamoxifeno/administração & dosagem , Tamoxifeno/farmacocinética
16.
Breast Cancer Res ; 21(1): 38, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850011

RESUMO

BACKGROUND: High background parenchymal uptake (BPU) on molecular breast imaging (MBI) has been identified as a breast cancer risk factor. We explored the feasibility of offering a short-term intervention of low-dose oral tamoxifen to women with high BPU and examined whether this intervention would reduce BPU. METHODS: Women with a history of high BPU and no breast cancer history were invited to the study. Participants had an MBI exam, followed by 30 days of low-dose oral tamoxifen at either 5 mg or 10 mg/day, and a post-tamoxifen MBI exam. BPU on pre- and post-tamoxifen MBI exams was quantitatively assessed as the ratio of average counts in breast fibroglandular tissue vs. average counts in subcutaneous fat. Pre-tamoxifen and post-tamoxifen BPU were compared with paired t tests. RESULTS: Of 47 women invited, 22 enrolled and 21 completed the study (10 taking 5 mg tamoxifen, 11 taking 10 mg tamoxifen). Mean age was 47.7 years (range 41-56 years). After 30 days low-dose tamoxifen, 8 of 21 women (38%) showed a decline in BPU, defined as a decrease from the pre-tamoxifen MBI of at least 15%; 11 of 21 (52%) had no change in BPU (within ± 15%); 2 of 21 (10%) had an increase in BPU of greater than 15%. Overall, the average post-tamoxifen BPU was not significantly different from pre-tamoxifen BPU (1.34 post vs. 1.43 pre, p = 0.11). However, among women taking 10 mg tamoxifen, 5 of 11 (45%) showed a decline in BPU; average BPU was 1.19 post-tamoxifen vs. 1.34 pre-tamoxifen (p = 0.005). In women taking 5 mg tamoxifen, 2 of 10 (20%) showed a decline in BPU; average BPU was 1.51 post-tamoxifen vs.1.53 pre-tamoxifen (p = 0.99). CONCLUSIONS: Short-term intervention with low-dose tamoxifen may reduce high BPU on MBI for some patients. Our preliminary findings suggest that 10 mg tamoxifen per day may be more effective than 5 mg for inducing declines in BPU within 30 days. Given the variability in BPU response to tamoxifen observed among study participants, future study is warranted to determine if BPU response could predict the effectiveness of tamoxifen for breast cancer risk reduction within an individual. TRIAL REGISTRATION: ClinicalTrials.gov NCT02979301 . Registered 01 December 2016.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Mama/diagnóstico por imagem , Mamografia/métodos , Imagem Molecular/métodos , Tamoxifeno/administração & dosagem , Administração Oral , Adulto , Mama/patologia , Densidade da Mama/efeitos dos fármacos , Neoplasias da Mama/patologia , Estudos de Viabilidade , Feminino , Câmaras gama , Humanos , Mamografia/instrumentação , Pessoa de Meia-Idade , Imagem Molecular/instrumentação , Projetos Piloto , Estudos Prospectivos , Cintilografia/instrumentação , Cintilografia/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Tecnécio Tc 99m Sestamibi/administração & dosagem , Fatores de Tempo
17.
Cancer Treat Rev ; 74: 29-34, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30708267

RESUMO

Patients with luminal early breast cancer are at risk of relapse, even after five years of adjuvant endocrine therapy. To date, no biomarkers have been clinically validated to identify those patients at risk of late recurrence, who might benefit from extended adjuvant endocrine therapy. In recent decades, multiple clinical trials have tested the role of extending adjuvant endocrine therapies in patients with luminal disease. However, the data currently at our disposal are conflicting. This article reviews all the major trials concerning extended adjuvant endocrine regimens, and formulates some general conclusions and hypotheses of future study.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Inibidores da Aromatase/administração & dosagem , Esquema de Medicação , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tamoxifeno/administração & dosagem
18.
Breast Cancer Res Treat ; 175(2): 297-303, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30747308

RESUMO

PURPOSE: UGT2B17 gene deletion (UGT2B17*2) has been reported to affect bone health as well as the pharmacokinetics of aromatase inhibitor (AI) drugs such as exemestane. The goal of this study was to assess associations between UGT2B17 gene deletion and bone health prior to and after 24 months of AI treatment in postmenopausal women with hormone receptor positive (HR+) breast cancer. METHODS: Bone health in women with HR+ breast cancer enrolled on the prospective randomized Exemestane and Letrozole Pharmacogenetics (ELPh) trial was determined by measuring bone turnover markers (BTM) and bone mineral density (BMD) pre-treatment and after 3 BTM and 24 BMD months of treatment with either the steroidal AI exemestane or the nonsteroidal AI letrozole. DNA samples were genotyped for UGT2B17*2. RESULTS: Of the 455 subjects included in the analyses, 244 (53.6%) carried at least one copy of UGT2B17*2. UGT2B17*2 was associated with lower pre-treatment BMD at the hip (P = 0.01) and spine (P = 0.0076). Letrozole treatment was associated with a greater decrease in BMD of the hip (P = 0.03) and spine (P = 0.03) than exemestane. UGT2B17 genotype was not associated with changes in BMD from 24 months of AI treatment, though in UGT2B17*2 homozygous patients, there was a trend toward greater decreases in BMD of the spine from treatment with letrozole compared with exemestane (P = 0.05). CONCLUSION: UGT2B17*2 may be associated with lower baseline BMD in women with HR+ breast cancer. Exemestane is less detrimental to bone health than letrozole in postmenopausal women treated with AI, and this effect may be confined to patients carrying UGT2B17*2, though this finding requires independent validation.


Assuntos
Androstadienos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Glucuronosiltransferase/genética , Letrozol/administração & dosagem , Antígenos de Histocompatibilidade Menor/genética , Androstadienos/efeitos adversos , Inibidores da Aromatase/administração & dosagem , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/genética , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Deleção de Genes , Estudos de Associação Genética , Genótipo , Humanos , Letrozol/efeitos adversos , Pessoa de Meia-Idade , Farmacogenética , Pós-Menopausa/efeitos dos fármacos , Pós-Menopausa/genética , Tamoxifeno/administração & dosagem
19.
Anticancer Res ; 39(2): 751-758, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30711954

RESUMO

BACKGROUND/AIM: The anti-cancer effect of high doses of intravenous vitamin C (high-dose vitamin C) remains controversial despite growing evidence that high-dose vitamin C exerts anti-tumorigenic activity by increasing the amount of reactive oxygen species in cancer cells without meaningful toxicities. Therefore, this study attempted to demonstrate the in vitro anti-cancer activity of high-dose vitamin C in combination with conventional treatment in breast cancer. MATERIALS AND METHODS: The pro-apoptotic effects of high-dose vitamin C (1.25 to 20 mM) with or without anti-cancer agents (eribulin mesylate, tamoxifen, fulvestrant, or trastuzumab) were estimated using an MTT assay to measure the cell viability of a variety of breast cancer cell lines (MCF7, SK-BR3, and MDA-MB-231), as well as normal breast epithelial cells (MCF10A). RESULTS: High-dose vitamin C (≥10 mM) significantly decreased cell viability of all breast cancer cell lines, particularly of MCF-7 cells. The catalase activities of MCF7 and MDA-MD-231 cells were also lower than those of MCF10A cells. Moreover, cell viability of both MCF7 and MDA-MD-231 cells was decreased further when combining high-dose vitamin C and eribulin mesylate, and this was also true for MCF-7 cells when combining high-dose vitamin C with tamoxifen or fulvestrant and for SK-BR3 cells when combining high-dose vitamin C with trastuzumab in comparison with chemotherapy or endocrine therapy alone. CONCLUSION: Combining high-dose vitamin C with conventional anti-cancer drugs can have therapeutic advantages against breast cancer cells.


Assuntos
Antineoplásicos/farmacologia , Ácido Ascórbico/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Fulvestranto/administração & dosagem , Furanos/administração & dosagem , Cetonas/administração & dosagem , Tamoxifeno/administração & dosagem , Trastuzumab/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Células MCF-7
20.
Support Care Cancer ; 27(4): 1325-1334, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30729333

RESUMO

PURPOSE: Vaginal atrophy is one of the most common side effects of using tamoxifen in women with breast cancer. Hormone therapy for vaginal atrophy is prohibited in these women. The present study was conducted to investigate the effect of vitamin D and E vaginal suppositories on vaginal atrophy in women with breast cancer receiving tamoxifen. METHODS: Women under breast cancer management receiving tamoxifen and showing symptoms of vaginal atrophy were randomized triple-blind to an 8-week trial on vaginal suppository vitamin E or vitamin D or placebo administered every night before bedtime. The genitourinary atrophy self-assessment tool was administered, and pH was measured in all three groups before the intervention and at the end of weeks 2, 4, and 8 of the intervention. The Vaginal Maturation Index (VMI) was also measured before the intervention and at the end of the eighth week. Data were analyzed with paired t tests, repeated measures analysis of variance, and chi-square test. RESULTS: Thirty-two patients were randomized in each group. The results obtained showed an increase in the VMI by the end of the eighth week of the intervention in the groups receiving the vitamin D and E vaginal suppositories compared with the placebo group (P < 0.001). The vaginal pH also reduced in both groups compared with that in the placebo group (P < 0.001). The symptoms of self-reported genitourinary atrophy also improved in the two intervention groups compared with those in the placebo group by the end of the eighth week (P < 0.001). CONCLUSION: These data support that vitamin D and E vaginal suppositories were beneficial in improving vaginal atrophy in women with breast cancer receiving tamoxifen. Given the prohibition on hormone therapy in these women, the suppositories can be used as an alternative therapy to improve these symptoms.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Tamoxifeno/efeitos adversos , Vagina/efeitos dos fármacos , Doenças Vaginais/induzido quimicamente , Doenças Vaginais/tratamento farmacológico , Vitamina D/administração & dosagem , Vitamina E/administração & dosagem , Adulto , Atrofia/induzido quimicamente , Atrofia/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Irã (Geográfico) , Pessoa de Meia-Idade , Pós-Menopausa , Supositórios , Tamoxifeno/administração & dosagem , Vagina/patologia , Vitamina D/farmacologia , Vitamina E/farmacologia
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