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1.
Cancers (Basel) ; 12(3)2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32245135

RESUMO

Mitotane is the main option of treatment for advanced adrenocortical carcinoma (ACC). However, limited evidence is available regarding the impact of plasma mitotane levels on patient outcome. To address this question, we retrospectively analyzed patients with advanced ACC treated with mitotane for ≥3 months, with ≥3 measurements of plasma mitotane reported in the Lysosafe Online® database (HRA Pharma, France), followed at 12 tertiary centers in Italy from 2005 to 2017. We identified 80 patients, initially treated with mitotane alone (56.2%) or plus chemotherapy (43.8%). The preference toward combination therapy was given to de novo stage IV ACC and younger patients. After the first line of treatment, 25% of valid cases experienced clinical benefit (14.5% objective response, 10.5% stabilization of disease) and 75% progression, without differences between the groups of treatment. Patients with progression had a lower time in the target range (TTR) of plasma mitotane and an unfavorable outcome. Death occurred in 76.2% of cases and multivariate analysis showed that clinical benefit after first treatment and longer TTR were favorable predictors of overall survival (OS). In conclusion, the present findings support the importance of mitotane monitoring and strengthen the concept of a therapeutic window for mitotane.

2.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31665449

RESUMO

CONTEXT: Urine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC). OBJECTIVE, DESIGN, SETTING: This proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for postoperative recurrence detection after microscopically complete (R0) resection of ACC. PATIENTS AND METHODS: 135 patients from 14 clinical centers provided postoperative urine samples, which were analyzed by gas chromatography-mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians or when analyzed by random forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard. RESULTS: Imaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine "steroid fingerprint" at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by 3 blinded experts detected recurrence by the time of radiological diagnosis in 50% to 72% of cases, improving to 69% to 92%, if a preoperative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22% to 39% of patients. Specificities varied considerably, ranging from 61% to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity = specificity = 81%). CONCLUSION: Urine steroid metabolomics is a promising tool for postoperative recurrence detection in ACC; availability of a preoperative urine considerably improves the ability to detect ACC recurrence.

3.
J Clin Med ; 8(11)2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31684071

RESUMO

Mitotane is used as a post-operative adjuvant treatment for patients with adrenocortical carcinoma. Monitoring of plasma mitotane concentrations is recommended, but we do not know what impact target concentrations have on patient outcome. To answer this question, we retrospectively analyzed patient records in the Lysosafe Online® database (HRA Pharma, France) for patients who were treated for ≥6 months and who had ≥3 measurements of plasma mitotane levels during follow-ups at 11 tertiary centers in Italy from 2005 to 2017. We identified 110 patients treated with adjuvant mitotane for a median of 46 months (IQR, interquartile range, 28-62) with a median maintenance dose of 2.0 g/day (IQR 1.5-2.5). Achievement of target mitotane concentrations (≥14 mg/L) required a median of 8 months (IQR 5-19). Female sex was associated inversely with the dose, while body mass index (BMI) was correlated positively. Multivariate analysis showed that the Ki67 index and time to achieve the target range of plasma mitotane were independent predictors of recurrence-free survival (RFS). In a separate multivariate model, considering only the maintenance phase (month 7 to month 36, M7-M36) of treatment, the time in the target range of plasma mitotane was associated with a significantly lower risk of recurrence (Hazard Ratio, HR = 0.93; 0.88-0.98, p < 0.01). The prognostic implications of the time in target range and the time needed to reach target mitotane concentrations support the use of mitotane monitoring and may inform practice.

4.
Eur J Endocrinol ; 181(6): 681-689, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639772

RESUMO

Objective: Temozolomide has shown a significant anti-proliferative activity on adrenocortical cancer (ACC) cells in vitro. Design: On the basis of these results the drug was prescribed as second/third line in advanced metastatic ACC patients in four referral centers in Italy. Methods: We retrospectively collected anagraphic, clinical and pathological data of patients with advanced ACC with disease progression to standard chemotherapy plus mitotane who were treated with temozolomide at the dose of 200 mg/m2/die given for 5 consecutive days every 28 days. The primary endpoint was the disease control rate, defined as objective response or disease stabilization after 3 months. Secondary endpoints were overall survival (OS), progression-free survival (PFS) and drug safety. Results: Twenty-eight patients have been included in the study. Ten patients (35.8%, 95% CI: 17.8-53.8) obtained a disease control from temozolomide treatment. In particular, 1 patient had a complete response, 5 patients a partial response and 4 patients stable disease. Median PFS was 3.5 months and median OS was 7.2 months. Disease response was more frequently observed in patients with methylation of O6-methylguanine-DNA methyltransferase (MGMT) gene. Temozolomide therapy was well tolerated and most toxicities were limited to grade G1-2 according to WHO criteria. Conclusion: Temozolomide was found active in the management of advanced ACC patients. The disease control rate obtained, however, was short-lived and the prognosis of treated patients was poor.


Assuntos
Carcinoma Adrenocortical/tratamento farmacológico , Temozolomida/efeitos adversos , Temozolomida/uso terapêutico , Carcinoma Adrenocortical/metabolismo , Adulto , Idoso , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Proteínas Supressoras de Tumor/metabolismo
5.
Eur J Intern Med ; 68: 66-70, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31399330

RESUMO

BACKGROUND: The value of salivary cortisol measurement to study stress-related adrenal response is controversial. The study aim was to assess the role of salivary cortisol measurement to detect time-related changes of adrenal response in critically ill patients. PATIENTS AND METHODS: Patients with organ failure, sepsis or trauma were prospectively recruited in the Emergency Department. Serum and salivary cortisol were measured at baseline (T0) and after 48 h (T48). In 33 patients ACTH test was also done. RESULTS: Fifty-five patients were studied and classified as septic (22) or non-septic (33). We found a significant correlation between serum and salivary cortisol at T0 and T48. No patient had baseline serum cortisol < 276 nmol/L and salivary cortisol significantly decreased at T48 in almost all patients. A delta serum cortisol < 250 nmol/L after ACTH was found in only 4 patients who showed elevated baseline cortisol levels. CONCLUSION: We found that reduced baseline and post-ACTH cortisol levels are uncommon in our samples. In patients able to provide adequate saliva samples, salivary cortisol may be used to check the degree of stress-induced response and appears as a suitable tool for multiple measurements over time.

6.
Endocr Connect ; 7(12): E5-E8, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30400026

RESUMO

Immunotherapy is widely used in the treatment of different cancer types, including metastatic melanoma, non-small cell lung cancer, renal cell carcinoma and urothelial cancer. The results of the phase I JAVELIN study failed to demonstrate a substantial activity of the PDL-1 inhibitor Avelumab in advanced adrenocortical carcinoma (ACC). This editorial focus on the possible mechanisms of ACC immunoevasion and suggests strategies to overcome the intrinsic immunotherapy resistance of this disease.

7.
Endocr Connect ; 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30352400

RESUMO

OBJECTIVE: Metyrapone has been approved for the treatment of patients with Cushing's syndrome (CS), but only few retrospective clinical studies are available. The aim of our study was the prospective assessment of metyrapone as pre-operative treatment. DESIGN AND METHODS: Before adrenalectomy, 7 patients with ACTH-independent CS due to adrenal adenoma were prospectively treated with metyrapone for 3 months in 3 tertiary academic centers, with endocrine work-up and clinical evaluation at screening and at predefined evaluation time points (Day 14, 31, 48, 65, 82). RESULTS: In all patients, UFC levels decreased up to normal range from baseline to Day 82 [609 (188 - 1476) vs 69 (28 - 152) nmol/24 h, p <0.02], with a reduction of serum and salivary cortisol levels, and no significant increase of plasma ACTH and serum DHEAS levels. Clinical improvement was reported on quality of life [+16.7 (+4.2; +52.00) points, p <0.04) and pressure control [systolic pressure, -25 (-52;-10) mmHg, p <0.01; diastolic pressure, -16 (-50; +2 mmHg), p <0.03)]. No significant change in weight, electrolytes, glycemic and lipid profile was reported. Although in women a significant increase of testosterone and androstenedione was reported, no worsening of clinical hyperandrogenism was observed. All drug-related adverse events (nausea, fatigue, low grade fever, edema of lower limbs and facial rash) were grade 1 or 2 and generally transient. CONCLUSIONS: This prospective pilot study demonstrated that metyrapone is effective in normalizing biochemical and clinical parameters in patients with CS due to adrenal adenoma before surgical intervention, with minimal side effects.

8.
Expert Rev Anticancer Ther ; 18(11): 1125-1133, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30117750

RESUMO

INTRODUCTION: Adrenocortical carcinoma (ACC) is a rare tumor characterized by poor prognosis in most cases. Moreover, in most cases ACC produces an excess of adrenal steroid hormones with relevant clinical consequences. Areas covered: After an extensive literature search, this narrative review addresses diagnostic management, including hormonal, radiological and pathological assessment, and treatment, which should be directed toward both cancer and hormone related problems. While surgery is the first option in ACC without evidence of metastatic disease, and the only possibility of cure, the therapeutic management of metastatic patients is centered on systemic therapy including mitotane alone or in combination with chemotherapy. Mitotane is also used in the adjuvant setting, because up to 80% of patients with nonmetastatic ACC show locoregional or distant metastases after an apparent complete surgical excision. Expert commentary: Management of ACC patients is fraught with many difficulties and should be limited to experienced physicians. Each step of clinical management, such as diagnosis, prognostication, treatment (both surgical and medical) is challenging and carries the possibility of severe mistakes. For this reason, each step of the management strategy should be decided in the setting of a multidisciplinary team including different expertise (endocrinology, radiology, pathology, oncology), in expert centers.


Assuntos
Neoplasias do Córtex Suprarrenal/terapia , Carcinoma Adrenocortical/terapia , Tomada de Decisões , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Antineoplásicos Hormonais/uso terapêutico , Quimioterapia Adjuvante/métodos , Humanos , Mitotano/uso terapêutico , Equipe de Assistência ao Paciente/organização & administração , Prognóstico
9.
PLoS One ; 13(5): e0196931, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29734384

RESUMO

Mitotane is the reference drug for adrenocortical carcinoma (ACC) and the metabolic activation of the drug is considered as essential for its activity. The aim of this study was to assess the role of CYP11B1 on mitotane action and metabolism in H295R ACC cells to understand whether this enzyme may influence mitotane action. The simultaneous incubation with mitotane and metyrapone, an adrenolytic molecule targeting 11-beta-hydroxylase, did not influence mitotane-mediated cytotoxic effect and metabolism in H295R ACC cells. CYP11B1 silencing confirmed the lack of a significant metyrapone effect on mitotane action. The present findings do not support the view that CYP11B1 catalyzes a crucial step in the metabolic activation of mitotane and that CYP11B1 confers the adrenal specificity to mitotane.


Assuntos
Carcinoma Adrenocortical/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Mitotano/farmacologia , Esteroide 11-beta-Hidroxilase/genética , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/patologia , Antineoplásicos Hormonais/farmacologia , Linhagem Celular Tumoral , Humanos , Metirapona/farmacologia , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores , Esteroide 11-beta-Hidroxilase/metabolismo
10.
Endocrinol Metab Clin North Am ; 47(2): 395-407, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29754640

RESUMO

Adrenocortical carcinoma (ACC) is a rare and aggressive tumor. ACC may be associated with different syndromes of hormone excess, most frequently Cushing's syndrome with or without hypersecretion of androgens. Recent data suggest that cortisol excess is a negative prognostic factor in advanced and localized ACC. Surgery with radical intent, when feasible, is the most effective treatment for ACC with hypercortisolism. Mitotane is the medical treatment of choice, both postoperatively and in inoperable or metastatic cases. Because of its slow onset of action, combination with other antisecretory agents (ie, metyrapone) is helpful to achieve more rapid and effective control of hypercortisolism.


Assuntos
Carcinoma Adrenocortical , Antineoplásicos Hormonais/uso terapêutico , Síndrome de Cushing , Carcinoma Adrenocortical/complicações , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/cirurgia , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/tratamento farmacológico , Síndrome de Cushing/etiologia , Síndrome de Cushing/cirurgia , Humanos
12.
J Clin Endocrinol Metab ; 102(11): 4323-4332, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29092062

RESUMO

Context: Adrenocortical carcinoma (ACC) is rare and confers an unfavorable prognosis in advanced stages. Other than combination chemotherapy with cisplatin, etoposide, doxorubicin, and mitotane, the second- and third-line regimens are not well-established. Gemcitabine (GEM)-based chemotherapy was suggested in a phase 2 clinical trial with 28 patients. In other solid tumors, human equilibrative nucleoside transporter type 1 (hENT1) and/or ribonucleotide reductase catalytic subunit M1 (RRM1) expression have been associated with resistance to GEM. Objective: To assess the efficacy of GEM-based chemotherapy in ACC in a real-world setting and the predictive role of molecular parameters. Design: Retrospective multicenter study. Setting: Referral centers of university hospitals. Patients and Materials: A total of 145 patients with advanced ACC were treated with GEM-based chemotherapy (132 with concomitant capecitabine). Formalin-fixed paraffin-embedded tumor material was available for 70 patients for immunohistochemistry. Outcome Measures: The main outcome measures were progression-free survival (PFS) and an objective response to GEM-based chemotherapy. The secondary objective was the predictive role of hENT1 and RRM1. Results: The median PFS for the patient population was 12 weeks (range, 1 to 94). A partial response or stable disease was achieved in 4.9% and 25.0% of cases, with a median duration of 26.8 weeks. Treatment was generally well tolerated, with adverse events of grade 3 or 4 occurring in 11.0% of cases. No substantial effect of hENT1 and/or RRM1 expression was observed in response to GEM-based chemotherapy. Conclusions: GEM-based chemotherapy is a well-tolerated, but modestly active, regimen against advanced ACC. No reliable molecular predictive factors could be identified. Owing to the scarce alternative therapeutic options, GEM-based chemotherapy remains an important option for salvage treatment for advanced ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias do Córtex Suprarrenal/diagnóstico , Carcinoma Adrenocortical/diagnóstico , Adulto , Idoso , Biomarcadores Tumorais/análise , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
13.
Eur J Endocrinol ; 177(4): 361-367, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28780517

RESUMO

OBJECTIVE: Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency. Recent studies in vitro have also documented a direct inhibitory effect of mitotane at the pituitary level. The present study was aimed to assess the hypothalamic-pituitary-adrenal axis in patients with ACC receiving mitotane. DESIGN AND METHODS: We prospectively enrolled 16 patients on adjuvant treatment with mitotane after radical surgical resection of ACC, who underwent standard hormone evaluation and h-CRH stimulation. A group of 10 patients with primary adrenal insufficiency (PAI) served as controls for the CRH test. RESULTS: We demonstrated a close correlation between cortisol-binding globulin (CBG) and plasma mitotane levels, and a non-significant trend between mitotane dose and either serum or salivary cortisol in ACC patients. We did not find any correlation between the dose of cortisone acetate and either ACTH or cortisol levels. ACTH levels were significantly higher in patients with PAI than that in patients with ACC, both in baseline conditions (88.99 (11.04-275.00) vs 24.53 (6.16-121.88) pmol/L, P = 0.031) and following CRH (158.40 (34.32-275.00) vs 67.43 (8.8-179.52) pmol/L P = 0.016). CONCLUSIONS: The observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels. In conclusion, the present study shows that mitotane affects the HPA axis at multiple levels and no single biomarker may be used for the assessment of adrenal insufficiency.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/uso terapêutico , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Mitotano/uso terapêutico , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Neoplasias do Córtex Suprarrenal/sangue , Carcinoma Adrenocortical/sangue , Hormônio Adrenocorticotrópico/sangue , Adulto , Idoso , Antineoplásicos Hormonais/sangue , Antineoplásicos Hormonais/farmacologia , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Pessoa de Meia-Idade , Mitotano/sangue , Mitotano/farmacologia , Sistema Hipófise-Suprarrenal/metabolismo , Estudos Prospectivos , Resultado do Tratamento
14.
PLoS One ; 11(9): e0162437, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27649075

RESUMO

CONTEXT: Patients with adrenal incidentalomas (AI) may experience detrimental consequences due to a minimal cortisol excess sustained by adrenal adenoma. SNPs of the glucocorticoid receptor gene (NR3C1) modulate individual sensitivity to glucocorticoids and may interfere with the clinical presentation. OBJECTIVE: To compare the frequency of N363S, ER22/23EK and BclI SNPs in patients with AI with the general population and to evaluate whether these SNPs are linked to consequences of cortisol excess. SETTING: Multicentric, retrospective analysis of patients referred from 2010 to 2014 to 4 centers (Orbassano, Milano, Messina [Italy] and Zagreb [Croatia]). PATIENTS: 411 patients with AI; 153 males and 258 females and 186 from blood donors. MAIN OUTCOMES MEASURES: All patients and controls were genotyped for BclI, N363S and ER22/23EK and SNPs frequency was associated with clinical and hormonal features. RESULTS: SNP frequency was: SNP frequency was: N363S 5.4% (MAF 0.027), BclI 54.7% (MAF 0.328), ER22/23EK 4.4% (MAF 0.022), without any significant difference between patients and controls. N363S was more frequent in hypertensive patients (p = 0.03) and was associated with hypertension (p = 0.015) in patients with suppressed cortisol after the 1-mg DST. CONCLUSIONS: Our results demonstrate that SNPs of the glucocorticoid receptor gene do not play a pathogenetic role for AI. The impact of any single SNP on the phenotypic expression of minimal cortisol excess is limited and their analysis does not provide additional data that may be exploited for patient management.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Glândulas Suprarrenais/patologia , Polimorfismo de Nucleotídeo Único , Receptores de Glucocorticoides/genética , Neoplasias das Glândulas Suprarrenais/sangue , Neoplasias das Glândulas Suprarrenais/complicações , Glândulas Suprarrenais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hidrocortisona/sangue , Hipertensão/sangue , Hipertensão/complicações , Hipertensão/genética , Masculino , Pessoa de Meia-Idade
15.
Eur J Endocrinol ; 166(3): 451-8, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22189997

RESUMO

BACKGROUND: There is a strong rationale in the use of antiangiogenic therapy in the management of adrenocortical carcinoma (ACC). Metronomic administration of chemotherapy and antiangiogenic drugs can be synergistic in targeting endothelial cells. OBJECTIVE: We assessed the activity of sorafenib plus metronomic paclitaxel as second/third-line therapy in advanced ACC patients. We also tested the activity of sorafenib and paclitaxel against NCI-H295R in vitro. DESIGN: Multicenter, prospective phase II trial. Setting Referral centers for ACC. METHODS: Twenty-five consecutive metastatic ACC patients who progressed after mitotane plus one or two chemotherapy lines were planned to be enrolled. The patients received a combination of i.v. paclitaxel (60 mg/m(2) every week) and oral sorafenib (400 mg twice a day) till progression. The primary aim was to measure the progression-free survival rate after 4 months and the secondary aims were to assess the objective response rate and toxicity. RESULTS: Tumor progression was observed in nine evaluable patients at the first assessment. These results led to the premature interruption of the trial. The treatment was well tolerated. The most relevant toxicities were fatigue, being grade 2 or 3 in four patients, and hypophosphatemia, being grade 3 in three patients. In the in vitro study, sorafenib impaired the viability of H295R cells with dose-response and time-response relationships. The in vitro sorafenib activity was not increased in combination with paclitaxel. CONCLUSIONS: Despite the in vitro activity, sorafenib plus weekly paclitaxel is an inactive salvage treatment in patients with advanced ACC and should not be recommended.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Adulto , Idoso , Benzenossulfonatos/administração & dosagem , Linhagem Celular Tumoral , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Paclitaxel/administração & dosagem , Compostos de Fenilureia , Estudos Prospectivos , Piridinas/administração & dosagem , Sorafenibe
16.
Horm Cancer ; 2(6): 378-84, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21971765

RESUMO

Metronomic chemotherapy is the administration of cytotoxic drugs at low doses, on a frequent or continuous schedule, with no extended interruption. This treatment approach can target tumor cells indirectly since it can affect the endothelium of the growing tumor vasculature and stimulates the anticancer immune response. Both the antiangiogenetic and the immunomodulatory roles of metronomic chemotherapy favor a tumor dormancy, a condition that may improve the patient outcome. Prospective clinical trials conducted in several malignancies have shown that metronomic chemotherapy can obtain disease stabilization or responses in tumors that had been made resistant in vivo to conventional chemotherapeutic regimens. Three prospective phase II trials have been conducted in patients with adrenocortical carcinoma (ACC). In all of them, patients heavily pretreated with conventional chemotherapy and mitotane have been enrolled. One trial tested the activity of the association of gemcitabine and fluoropyrimidines administered on a metronomic schedule. In this trial, 40% of patients attained a disease stabilization or disease response that was long lasting in some of them. In the remaining two trials, metronomic chemotherapy was administered in association with antiangiogenetic drugs, and the results were disappointing since no response or stable disease was obtained. In conclusion, metronomic chemotherapy can delay tumor progression in advanced ACC and deserves to be further tested. The concomitant administration of antiangiogenetic drugs may be detrimental. Several important questions remain to be addressed such as the optimal dose and most effective dosing interval, when to use the metronomic approach in the natural history of the disease, the choice of cytotoxic drugs, and the most efficacious way to integrate metronomic chemotherapy with standard therapy protocols.


Assuntos
Administração Metronômica , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/fisiopatologia , Carcinoma Adrenocortical/patologia , Carcinoma Adrenocortical/fisiopatologia , Animais , Ensaios Clínicos Fase III como Assunto , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Humanos , Imunidade/efeitos dos fármacos , Mitotano/administração & dosagem , Mitotano/efeitos adversos , Neovascularização Patológica , Resultado do Tratamento
17.
J Steroid Biochem Mol Biol ; 116(1-2): 29-36, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19406240

RESUMO

Glucocorticoids (GCs) are widely used for the treatment of hormone refractory prostate cancer. However, few data are available on the expression and regulation of glucocorticoid and mineralocorticoid receptors (GR and MR) and 11beta-hydroxysteroid dehydrogenase (11beta-HSD) 1 and -2 activities in prostate cancer cells. Here we show that GR is expressed in both the androgen-independent PC-3 cell line and, at very low levels, in the androgen-dependent LNCaP cells, and MR is expressed in both cell lines. IL-1beta increased GR expression in both cell lines. In LNCaP cells IL-1beta also increased MR expression. Significant 11beta-HSD oxidase activity and 11beta-HSD2 protein were found in LNCaP cells, but not in PC3 cells, and no ketoreductase activity was detected in either cell lines. GR function was assessed by measuring the inhibitory effect of dexamethasone on constitutive and IL-1beta-inducible IL-6 and osteoprotegerin (OPG) production. In PC-3 cells, IL-1beta stimulated IL-6 and OPG release, and dexamethasone dose-dependently inhibited IL-1beta-inducible IL-6 release, and constitutive and IL-1beta-inducible OPG release. In LNCaP cells, IL-1beta stimulated only OPG release. While dexamethasone was ineffective, cortisol dose-dependently inhibited IL-1beta-inducible OPG release. Eplerenone (Epl), a selective mineralocorticoid antagonist, reverted this effect. We conclude that different patterns of expression of receptors and 11beta-HSD activity were associated with different responsiveness to GCs in terms of regulated gene expression. GR and MR expression may vary as a function not only of the malignant phenotype, but also of local conditions such as the degree of inflammation. Inhibition of IL-6 and OPG release by GCs may contribute to the antitumor efficacy in prostate cancer.


Assuntos
Androgênios/fisiologia , Antineoplásicos/farmacologia , Glucocorticoides/farmacologia , Neoplasias da Próstata/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Linhagem Celular Tumoral , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Masculino , Osteoprotegerina/antagonistas & inibidores , Osteoprotegerina/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/genética
18.
Bioinformation ; 2(1): 1-4, 2007 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-18084641

RESUMO

The emerging domain of epigenetics in molecular medicine finds application for a variety of patient populations. Here, we present fundamental neuroendocrine immune evidence obtained in patients with senile dementia of the Alzheimer's type (sDAT), and discuss the implications of these data from the viewpoint of translational epigenetics of Alzheimer's disease. We followed 18 subjects with mild sDAT treated with acetylcholinesterase inhibitors, and 10 control subjects matched for age in a repeated measure design every six months for 18 months. We monitored psychosocial profile (Mini-Mental State Examination, Functional Assessment Staging, Independence in Activities of Daily Living, Depression, Profile of Moods States) in parallel to immunophenotypic parameters of T cell subpopulations by flow cytometry. Based on change in the mini-mental state score at entry and at 18 months, patients with sDAT were assigned to a "fast progression" (delta greater than 2 points) or to a "slow progression" group (delta less than or equal to 2 points). The change in circulating activated T cells (CD3+Dr+) with time in patients with sDAT was significantly inversely correlated with the change in time in natural killer (NK) cytotoxic activity to cortisol modulation in these patients, which was greater in patients with fast progression, compared to slow progression sDAT. These data indicate underlying neuroendocrine immune processes during progression of sDAT. Our observations suggest that psychoimmune measures such as those we have monitored in this study provide relevant information about the evolving physiological modulation in patients with sDAT during progression of Alzheimer's disease, and point to new or improved translational epigenetic treatment interventions.

19.
Bioinformation ; 2(1): 24-7, 2007 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-18084647

RESUMO

Aluminium (Al) has been investigated as a neurotoxic substance. Al ranks among the potential environmental risk factors for Alzheimer's disease (AD). Epidemiological studies tested the relationship between Al in drinking water and AD, showing a significant correlation between elevated levels of monomeric Al in water and AD, although data to date remain inconclusive with respect to total Al. The aim of this study was to test whether or not Al exacerbates cellular toxicity mediated by the amyloid beta (Abeta) peptide. We evaluated the role of Al in modulating programmed cell death (apoptosis) in human cell cultures. We used the osteosarcoma cell line monolayer (SaOs-2) to demonstrate that treatment of SaOs-2 cultures with the Abeta peptide mid-fragment (25 to 35) at nano M, followed by co-incubation with physiological concentrations of aluminium chloride, which release monomeric Al in solution, led to marked expression of caspase 3, but not caspase 9, key markers of the apoptotic process. The same experimental conditions were shown to blunt significantly the proliferative response of normal human peripheral blood mononuclear cells (PBMC) to phytohemagglutinin (PHA) stimulation. Our observations support the hypothesis that Al significantly impairs certain cellular immune responses, and confirm that Al-mediated cell toxicity may play an important role in AD.

20.
Bioinformation ; 1(9): 363-6, 2007 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-17597922

RESUMO

Patients with Alzheimer's disease (AD) are characterized by an altered sensitivity to cortisol-mediated modulation of circulating lymphocytes. Longitudinal studies are needed to address the clinical applicability of these abnormalities as prognostic factors. Therefore, we designed a longitudinal study to address the clinical applicability of physiologic modulation of Natural Killer (NK) cell activity as a prognostic factor in AD. NK activity was assessed as baseline measurement and in response to modulation by cortisol at 10(-6)M. To verify the immunophysiological integrity of the NK cell population, we tested augmentation of NK cytotoxicity by human recombinant interleukin (IL)-2 (100 IU/ml) as control. The response to modulation by cortisol or by IL-2 was significantly greater in patients with AD. Based on change in the Mini-Mental State score at entry and at 18 months, patients with AD could be assigned to a "fast progression" (Delta > 2 points) or to a "slow progression" group (Delta

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