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1.
Eur J Endocrinol ; 180(6): 387-396, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30991359

RESUMO

Objective Many patients with adrenocortical carcinoma (ACC) suffer from tumor recurrence despite radical surgery. Evidence on the post-operative use of mitotane is controversial and no predictors of response are available. We aimed to assess whether adjuvant mitotane treatment may prolong survival in patients with non-metastatic ACC following complete resection and whether ACC patients at high risk of recurrence may benefit from treatment. Design and methods We retrospectively reviewed data from 152 non-metastatic ACC patients followed at the San Luigi Gonzaga Hospital: 100 patients were treated with adjuvant mitotane and 52 patients were left untreated following surgery. We assessed a number of potential predictive factors of recurrence and death. Mitotane effect was explored stratifying patients by staging (stage I-II vs stage III), hormone secretion (yes vs no) and Ki67 index. Results The non-treated group had a higher risk of recurrence (HR: 2.79, 95%CI: 1.58-4.91; P < 0.001) than mitotane-treated group, while overall survival was not significantly different between groups. Hormone secretion, elevated Weiss score and elevated Ki67 index confer a higher risk of both recurrence and death and stage III ACC of death. Adjuvant mitotane treatment reduced significantly the risk of death in patients with elevated Ki67 index (P = 0.005) and in patients with stage III ACC (P = 0.02). Conclusions Adjuvant mitotane may prolong recurrence-free survival in radically resected ACC patients with acceptable toxicity and may also prolong overall survival in a subgroup of ACC patients at high risk of recurrence.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mitotano/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Adolescente , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/mortalidade , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/mortalidade , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
2.
J Chemother ; 31(2): 105-108, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30831058

RESUMO

A 43-years old woman was diagnosed an adrenocortical carcinoma (AC) that was excised, whereas two lung metastases were un-operable. Mitotane 6 g/day was started as standard therapy but it was responsible for severe central nervous system (CNS) and gastrointestinal toxicities associated with a 10 kg body weight loss. A therapeutic drug monitoring (TDM) protocol demonstrated that mitotane plasma concentrations (>30 mg/L) exceeded the therapeutic range (14-20 mg/L) and increased even when drug daily dose was reduced by 50%. The increase in drug plasma concentrations was probably due to body slimming. Under continuous TDM control, a reduced mitotane dose (1.5 g/day) was definitively administered and it proved to be tolerable and effective. Indeed, lung metastases were excised and two years later there was no evidence of other neoplastic lesions. In conclusion, the adoption of therapeutic mitotane monitoring allowed the treatment of an AC patient with a reduced, tolerable and effective dose.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/administração & dosagem , Monitoramento de Medicamentos/normas , Mitotano/administração & dosagem , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Adulto , Relação Dose-Resposta a Droga , Feminino , Humanos , Prognóstico
3.
Ann Surg Oncol ; 25(12): 3453-3459, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30218246

RESUMO

This is the second of a two-part review on adrenocortical carcinoma (ACC) management. While margin-negative resection provides the only potential cure for ACC, recurrence rates remain high. Furthermore, many patients present with locally advanced, unresectable tumors and/or diffuse metastases. As a result, selecting patients for adjuvant therapy and understanding systemic therapy options for advanced ACC is important. Herein, we detail the current literature supporting the use of adjuvant mitotane therapy, consideration of adjuvant radiation therapy, and utility of cytotoxic chemotherapy in patients with advanced disease. Ongoing investigation into molecular targeted agents, immunotherapy, and inhibitors of steroidogenesis for the treatment of ACC are also highlighted. Lastly, the importance of genetic counseling in patients with ACC is addressed as up to 10% of patients will have an identifiable hereditary syndrome.


Assuntos
Neoplasias das Glândulas Suprarrenais/terapia , Carcinoma Adrenocortical/terapia , Aconselhamento Genético , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Adrenalectomia , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/secundário , Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Combinada , Humanos , Mitotano/administração & dosagem , Radioterapia
4.
Horm Cancer ; 9(1): 62-69, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29071575

RESUMO

A partial response (PR) has been proposed as a surrogate for overall survival in advanced adrenocortical carcinoma (ACC). The primary endpoint of the study was to characterize the time until a PR in patients with metastatic ACC treated with a standard therapy is achieved. Long-term survivors were selected to allow evaluation of delayed tumor response to mitotane. Records from patients with metastatic ACC that survived for > 24 months were retrieved. Tumor response was analyzed according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Time until a tumor response, after treatment initiation or therapeutic plasma mitotane level, was analyzed. Sixty-eight patients were analyzed. The first-line systemic therapy was mitotane as a monotherapy (M) (n = 57) or cytotoxic polychemotherapy plus/minus mitotane (PC ± M) (n = 11). The second-line therapy was M (n = 2) or PC ± M (n = 41). Thirty-two PRs occurred in 30/68 patients (44.1%): this was obtained for 13 (40.6%) during M and during PC ± M for 19/32 responders (59.4%). PRs were observed within 6 months of starting M or PC ± M in 76.9 and 94.7% of responses, respectively, within 6 months of therapeutic plasma mitotane being first observed in 88.9% of responses with M and in 53.3% of responses with PC ± M. All PRs (but one) occurred within 1 year after initiating treatment. To conclude, Most patients with metastatic ACC and long survival times had PRs within the first 6 months of standard systemic therapy, and almost all within the first year. The absence of response after that period could be considered as a treatment failure. Maintenance of mitotane therapy in non-responders after 1 year should be questioned in future randomized trials.


Assuntos
Carcinoma Adrenocortical/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mitotano/administração & dosagem , Carcinoma Adrenocortical/sangue , Carcinoma Adrenocortical/patologia , Carcinoma Adrenocortical/radioterapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitotano/efeitos adversos , Mitotano/sangue , Metástase Neoplásica , Sobreviventes , Resultado do Tratamento
6.
Ginekol Pol ; 88(10): 576-577, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29192420

RESUMO

Adrenocortical carcinoma is a rare tumour with high malignancy and poor prognosis. This tumour is rarely diagnosed in the reproductive age. Complete surgical resection is the only curative treatment for adrenal cancer in all stages. After surgery adjuvant chemotherapy is required. Mitotane is the most important drug in adrenal cancer chemotherapy. Mitotane's mode of action is not entirely explained. Animal studies have shown that the substance exerts a direct cytotoxic effect on the cells of the adrenal cortex. This activity is selective, progressive and affects only the zona reticularis and fasciculata of the adrenal cortex. Mitotane inhibits cortisol synthesis by disrupting the chain of cholesterol. It has been suggested, that mitotane also affects the peripheral metabolism of steroids, especially of transcortin (CBG). This results in an increase of CBG blood concentration and a reduction of the amount of free hormones.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/uso terapêutico , Dispositivos Intrauterinos Medicados , Levanogestrel/uso terapêutico , Menorragia/diagnóstico , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/cirurgia , Adulto , Antineoplásicos Hormonais/administração & dosagem , Quimioterapia Adjuvante , Diagnóstico Diferencial , Feminino , Humanos , Levanogestrel/administração & dosagem , Menorragia/diagnóstico por imagem , Menorragia/tratamento farmacológico , Mitotano/administração & dosagem , Mitotano/uso terapêutico
7.
J Pharm Pharmacol ; 69(11): 1524-1530, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28809444

RESUMO

OBJECTIVES: Mitotane is the reference drug for the adrenocortical carcinoma treatment; its pharmacological activity seems to depend on drug transformation in two active metabolites: o,p'-DDE (dichlorodiphenylethene) and o,p'-DDA (dichlorodiphenylacetate). Mitotane and metabolites are lipophilic agents; thus, they tend to accumulate into adipose tissues (white and brown), which change their prevalence seasonally. Aim of the work was to evaluate mitotane and metabolites plasma levels variation over the year, in adrenocortical cancer patients treated with Lysodren® for at least 6 months. METHODS: We enrolled a group of 86 adrenocortical carcinoma diagnosed patients, who underwent radical surgery and started mitotane as adjuvant treatment. For drug and metabolites plasma level (from samples collected ~12 h after the dose administration of mitotane, just before the subsequent administration) determination, a validated chromatographic method was used. KEY FINDINGS: Results showed an evidence of a seasonal trend for the three substance (o,p'-DDD, o,p'-DDE and o,p'-DDA) plasma levels, in terms of acrophases and lower values. Furthermore, it came out that male patients need a higher significant mitotane drug dose than female patients to reach mitotane therapeutic window. CONCLUSIONS: In conclusion, this is the first study assessing a mitotane plasma level variation over the year, but further studies in larger cohorts are required.


Assuntos
Neoplasias do Córtex Suprarrenal/terapia , Carcinoma Adrenocortical/terapia , Antineoplásicos Hormonais/administração & dosagem , Mitotano/administração & dosagem , Tecido Adiposo/metabolismo , Adulto , Antineoplásicos Hormonais/farmacocinética , Quimioterapia Adjuvante/métodos , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitotano/análogos & derivados , Mitotano/farmacocinética , Estações do Ano , Fatores Sexuais , Fatores de Tempo , Adulto Jovem
8.
Medwave ; 17(6): e7007, 2017 Jul 31.
Artigo em Espanhol | MEDLINE | ID: mdl-28777782

RESUMO

There are no approved therapeutic regimes for adrenal carcinoma following progression to a first line of chemotherapy/mitotane although a high percentage of patients are candidates to receive them. In the present article we review the possible therapeutic alternatives after the progression to a first line of treatment in patients with adrenal carcinoma and we report a case in which a prolonged overall survival is achieved, much higher than expected, probably in relation to the multidisciplinary management of the case and the use of most of the therapeutic arsenal available.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Adulto , Humanos , Masculino , Mitotano/administração & dosagem , Cuidados Paliativos/métodos , Equipe de Assistência ao Paciente/organização & administração , Taxa de Sobrevida
9.
Endocr Relat Cancer ; 24(7): 319-327, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28432084

RESUMO

Topoisomerase II alpha (TOP2A) and thymidylate synthase (TS) are known prognostic parameters in several tumors and also predictors of efficacy of anthracyclines, topoisomerase inhibitors and fluoropirimidines, respectively. Expression of TOP2A and TS mRNA was assessed in 98 patients with adrenocortical carcinoma (ACC) and protein expression was assessed by immunohistochemistry in a subset of 39 tumors. Ninety-two patients were radically resected for stage II-III disease and 38 of them received adjuvant mitotane. Twenty-six patients with metastatic disease received the EDP-M (etoposide, doxorubicin, Adriamycin, cisplatin plus mitotane). TOP2A and TS expression in ACC tissue was directly correlated with the clinical data. Both markers were not associated with either disease free survival (DFS) or overall survival (OS) in multivariate analyses and failed to be associated to mitotane efficacy. Disease response or stabilization to EDP-M treatment was observed in 12/17 (71%) and 1/9 (11%) patients with high and low TOP2A expressing tumors (P = 0.0039) and 9/13 (69%) and 4/13 (31%) patients with high and low TS expressing ACC, respectively (P = 0.049). High TOP2A expression was significantly associated with longer time to progression (TTP) after EDP-M. TOP2A and TS proteins assessed by immunohistochemistry significantly correlated with mRNA expression. Immunohistochemical TOP2A expression was associated with a non-significant better response and longer TTP after EDP-M. TOP2A and TS were neither prognostic nor predictive of mitotane efficacy in ACC patients. The predictive role of TOP2A expression of EDP-M activity suggests a significant contribution of Adriamycin and etoposide for the efficacy of the EDP scheme.


Assuntos
Neoplasias do Córtex Suprarrenal/enzimologia , DNA Topoisomerases Tipo II/biossíntese , Timidilato Sintase/biossíntese , Adolescente , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , DNA Topoisomerases Tipo II/genética , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mitotano/administração & dosagem , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Timidilato Sintase/genética , Adulto Jovem
10.
Anticancer Drugs ; 28(6): 634-644, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28410270

RESUMO

Adrenocortical tumor (ACT) is a malignancy with a low incidence rate and the current therapy for advanced disease has a limited impact on overall patient survival. A previous study from our group suggested that elevated expression of aurora-A and aurora-B is associated with poor outcome in childhood ACT. Similar results were also reported for adult ACTs. The present in-vitro study shows that AMG 900 inhibits aurora kinases in adrenocortical carcinoma cells. AMG 900 inhibited cell proliferation in NCI-H295 cells as well as in the ACT primary cultures and caused apoptosis in the cell line NCI-H295. Furthermore, it potentialized the mitotane, doxorubicin, and etoposide effects on apoptosis induction and acted synergistically with mitotane and doxorubicin in the inhibition of proliferation. In addition, we found that AMG 900 activated Notch signaling and rendered the cells sensitive to the combination of AMG 900 and Notch signaling inhibition. Altogether, these data show that aurora kinases inhibition using AMG 900 may be an adjuvant therapy to treat patients with invasive or recurrent adrenocortical carcinomas.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Ftalazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Neoplasias do Córtex Suprarrenal/enzimologia , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/enzimologia , Carcinoma Adrenocortical/patologia , Aurora Quinases/antagonistas & inibidores , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Histonas/metabolismo , Humanos , Mitotano/administração & dosagem , Mitotano/farmacologia , Fosforilação/efeitos dos fármacos , Ftalazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem
11.
Curr Opin Endocrinol Diabetes Obes ; 24(3): 208-214, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28277340

RESUMO

PURPOSE OF REVIEW: To present an update on the management of and future directions in adrenocortical carcinoma (ACC). RECENT FINDINGS: ACC is a rare malignancy with high morbidity and mortality. Surgery remains the mainstay treatment for localized disease, but it is often not feasible in more advanced cases. There is an ongoing controversy about the routine use of adjuvant treatments after surgery. Hormonal overproduction can complicate the management and worsen the prognosis of the disease. Systemic therapy with multiple cytotoxic drugs is often combined with the adrenolytic agent mitotane. Genomic analyses of ACC revealed numerous signal transduction pathway aberrations (insulin-like growth factor 2 overexpression, TP53 mutations and Wnt/ß-catenin pathway activation), but so far, there has been no clinically meaningful breakthrough in targeting these genes. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in ACC is being explored in multiple ongoing trials. SUMMARY: Surgery by experienced team is the key treatment for localized ACC, whereas currently used chemotherapy has limited efficacy in advanced ACC. The improved understanding of the molecular pathways involved in ACC has not been translated into effective therapy. The development of new therapies requires collaborative effort to fight this disease.


Assuntos
Neoplasias do Córtex Suprarrenal/terapia , Carcinoma Adrenocortical/terapia , Endocrinologia/tendências , Oncologia/tendências , Terapias em Estudo/tendências , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/tratamento farmacológico , Humanos , Imunoterapia/métodos , Imunoterapia/tendências , Mitotano/administração & dosagem , Terapia de Alvo Molecular/métodos , Prognóstico , Transdução de Sinais/genética
12.
Oncotarget ; 7(48): 79292-79304, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27764813

RESUMO

In recent years it has been recognized that clinical translation of novel therapeutic strategies for patients with adrenocortical carcinoma (ACC) often fails. These disappointing results indicate that the currently utilized tumor models only poorly reflect relevant pathophysiology and, thereby, do not predict clinical applicability of novel pharmacological approaches. However, also the development of new preclinical ACC models has remained a challenge with only one human cell line (NCI-H295R) and one recently established human pediatric xenograft model (SJ-ACC3) being available for this highly heterogeneous malignancy. Our current study furthermore reveals a poor reproducibility of therapeutic action between different clones of the most commonly used tumor model NCI-H295R. In an attempt to broaden the current preclinical armamentarium, we aimed at the development of patient-individual tumor models. During these studies, one xenograft (MUC-1) displayed marked engraftment and sustained tumor growth. MUC-1 tumor analysis revealed highly vascularized, proliferating and SF-1 positive xenografts. In a next step, we characterized all currently available human tumor models for ACC for Ki67, SF-1 and EGF-receptor status in comparison with MUC-1-xenografts. In addition, we established a primary culture, which is now viable over 31 passages with sustained nuclear SF-1 and cytoplasmic 3ßHSD immuno-positivity. Subsequent investigation of therapeutic responsiveness upon treatment with the current systemic gold standard EDP-M (etoposide, doxorubicin, cisplatin and mitotane) demonstrated maintenance of the clinically observed drug resistance for MUC-1 exclusively. In summary, we provide evidence for a novel patient-derived tumor model with the potential to improve clinical prediction of novel therapeutic strategies for patients with ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Biomarcadores Tumorais/metabolismo , Modelos Animais de Doenças , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/metabolismo , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Receptores ErbB/metabolismo , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Feminino , Humanos , Antígeno Ki-67/metabolismo , Masculino , Mitotano/administração & dosagem , Mitotano/uso terapêutico , Mucina-1/metabolismo , Transplante de Neoplasias , Fatores de Processamento de RNA/metabolismo , Células Tumorais Cultivadas , Adulto Jovem
13.
Arch Iran Med ; 19(9): 671-3, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27631184

RESUMO

Adrenal cell carcinoma is a rare tumor and more than 70% of patients present with advanced stages. Adrenal cell carcinoma is an aggressive tumor with a poor prognosis. Surgical intervention is the gold standard treatment and mitotane is the only drug approved for the treatment of adrenal cell carcinoma. Until recently in 2012, the etoposide, doxorubicin, cisplatin plus mitotane are approved as first-line therapy based on response rate and progression-free survival. This case illustrates a case of advanced adrenal cell carcinoma in a young girl who presented with huge adrenal mass with inferior vena cava thrombosis and pulmonary embolism. Multi-approach of therapy was used to control the tumor size and metastasis. Therefore, it may prolong her survival rate for up to 5 years and 4 months.


Assuntos
Neoplasias do Córtex Suprarrenal/diagnóstico por imagem , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/diagnóstico por imagem , Carcinoma Adrenocortical/patologia , Neoplasias Hepáticas/secundário , Adolescente , Neoplasias do Córtex Suprarrenal/terapia , Adrenalectomia/métodos , Carcinoma Adrenocortical/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Evolução Fatal , Feminino , Humanos , Laparotomia/métodos , Mitotano/administração & dosagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
14.
Endocr Relat Cancer ; 23(10): 825-37, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27550961

RESUMO

Systemic therapy of adrenocortical carcinoma (ACC) is limited by heterogeneous tumor response and adverse effects. Recently, we demonstrated anti-tumor activity of LEDP-M (etoposide, liposomal doxorubicin, liposomal cisplatin, mitotane), a liposomal variant of EDP-M (etoposide, doxorubicin, cisplatin, mitotane). To improve the therapeutic efficacy and off-target profiles of the clinical gold standard EDP-M, we investigated liposomal EDP-M regimens in different preclinical settings and in a small number of ACC patients with very advanced disease. Short- and long-term experiments were performed on two ACC models (SW-13 and SJ-ACC3) in vivo We evaluated the anti-tumoral effects and off-target profiles of EDP-M, LEDP-M and a novel regimen L(l)EDP-M including liposomal etoposide. Furthermore, the role of plasma microRNA-210 as a therapeutic biomarker and first clinical data were assessed. Classical and liposomal protocols revealed anti-proliferative efficacy against SW-13 (EDP-M P < 0.01; LEDP-M: P < 0.001; L(l)EDP-M: P < 0.001 vs controls), whereas in SJ-ACC3, only EDP-M (P < 0.05 vs controls) was slightly effective. Long-term experiments in SW-13 demonstrated anti-tumor efficacy for all treatment schemes (EDP-M: P < 0.01, LEDP-M: P < 0.05, L(l)EDP-M P < 0.001 vs controls). The analysis of pre-defined criteria leading to study termination revealed significant differences for control (P < 0.0001) and EDP-M (P = 0.003) compared to L(l)EDP-M treatment. Raising its potential for therapy monitoring, we detected elevated levels of circulating microRNA-210 in SW-13 after LEDP-M treatment (P < 0.05). In contrast, no comparable effects were detectable for SJ-ACC3. However, overall histological evaluation demonstrated improved off-target profiles following liposomal regimens. The first clinical data indicate improved tolerability of liposomal EDP-M, thus confirming our results. In summary, liposomal EDP-M regimens represent promising treatment options to improve clinical treatment of ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ensaios de Seleção de Medicamentos Antitumorais , Lipossomos/uso terapêutico , Pesquisa Médica Translacional , Adulto , Idoso , Animais , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Ensaios de Seleção de Medicamentos Antitumorais/tendências , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Mitotano/administração & dosagem , Polietilenoglicóis/administração & dosagem , Pesquisa Médica Translacional/métodos , Pesquisa Médica Translacional/tendências , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Endocr Relat Cancer ; 23(1): R43-69, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26475053

RESUMO

Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. Discrimination between ACCs and adrenocortical adenomas (ACAs) remains challenging, with the current gold standard being the Weiss score, consisting of several histopathological characteristics. However, new markers like Ki67, a marker for proliferation, and the staining of reticulins are promising not only as it comes to identifying malignancy but also as prognostic markers in patients with ACC. Currently, surgery is still the only curative treatment for ACC. Mitotane, an adrenolytic drug, is used in the adjuvant setting and in case of metastatic or advanced disease. Patients with progressive disease are frequently treated with mitotane, alone or in combination with etoposide, doxorubicine and cisplatin. Radiotherapy is indicated in selected cases. The low response rates and high toxicity of the systemic therapies emphasize the need for markers that enable the identification of responders and non-responders. Consequently, research is focusing on predictive factors varying from the expression of DNA repair genes to clinical patient characteristics. Subgroups of ACC with different prognosis have been identified based on transcriptome characteristics. As a conclusion from large molecular studies, ACCs appear to harbor many abnormalities compared to ACAs. Altered pathways driving ACC pathogenesis include the IGF, TP53 and the Wnt signaling pathway, allowing these as new potential targets for medical therapy. However, despite efforts in preclinical and clinical studies investigating efficacy of targeting these pathways, most novel therapies appear to be effective in only a subset of patients with ACC. New treatment concepts are therefore urgently needed.


Assuntos
Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/terapia , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/terapia , Neoplasias do Córtex Suprarrenal/epidemiologia , Adrenalectomia/métodos , Carcinoma Adrenocortical/epidemiologia , Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Quimioterapia Adjuvante , Técnicas de Diagnóstico Endócrino/tendências , Humanos , Mitotano/administração & dosagem , Radioterapia Adjuvante
19.
Eur J Endocrinol ; 172(6): R263-80, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25637072

RESUMO

Steroidogenesis enzyme inhibitors are the mainstay of medical therapy in Cushing's syndrome (CS). Ketoconazole (KTZ) and metyrapone are the most commonly used agents. Although there is considerable experience of their use in individual specialist centres, these drugs have not been rigorously tested in prospective clinical trials. Clinicians face uncertainties and concerns with respect to the safety profile of these agents, and best means to monitor effect. We review steroidogenesis inhibitors in the management of CS, including older agents (KTZ, metyrapone, etomidate and mitotane) and those currently under development (LCI699, non-racemic KTZ), and offer a practical approach for their use in clinical practice.


Assuntos
Síndrome de Cushing/tratamento farmacológico , Etomidato , Imidazóis , Cetoconazol , Metirapona , Mitotano , Piridinas , Inibidores da Síntese de Esteroides , Etomidato/administração & dosagem , Etomidato/efeitos adversos , Etomidato/farmacologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Imidazóis/farmacologia , Cetoconazol/administração & dosagem , Cetoconazol/efeitos adversos , Cetoconazol/farmacologia , Metirapona/administração & dosagem , Metirapona/efeitos adversos , Metirapona/farmacologia , Mitotano/administração & dosagem , Mitotano/efeitos adversos , Mitotano/farmacologia , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/farmacologia , Inibidores da Síntese de Esteroides/administração & dosagem , Inibidores da Síntese de Esteroides/efeitos adversos , Inibidores da Síntese de Esteroides/farmacologia
20.
Ther Drug Monit ; 37(1): 58-65, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24887633

RESUMO

BACKGROUND: Mitotane is the drug of choice in medical treatment of adrenocortical carcinoma. The antineoplastic effect seems to be correlated with a minimum plasma level of 14 mg/L, but plasma concentration build-up is in general slow due to the long elimination half-life. Consequently, the therapeutic effect sets in after weeks or even months. The objective of this study was to develop a pharmacokinetic model that enables clinicians to adjust dosing based on a target drug exposure, which facilitates personalized therapy. METHODS: Data on dosing and plasma level measurements performed throughout mitotane therapy were retrospectively collected in a population of 29 patients from 2 hospitals. A population pharmacokinetic model was constructed based on data from 20 patients using iterative 2-stage Bayesian fitting (MWPharm). The model was validated in an independent sample of 9 patients. RESULTS: The concentration-time data were best described by a 3-compartment model. The model estimated mitotane clearance at 0.94 ± 0.37 L/h and a volume of distribution in the steady state at 161 ± 68 L/kg of lean body mass. The mean prediction error was 14% ± 13%. CONCLUSIONS: A pharmacokinetic model was developed, which characterized mitotane by slow clearance and large volume of distribution. The model seems to be able to predict mitotane levels in individual patients with an error margin of 14%. The model enables one to adapt dosing based on individual plasma level measurements in prospective setting, which improves the accuracy of the prediction. We expect that individualization of mitotane dosing leads to anticipated and more rapid attainment of the therapeutic levels and potentially to improved clinical management of mitotane treatment.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/metabolismo , Antineoplásicos Hormonais/farmacocinética , Antineoplásicos Hormonais/uso terapêutico , Mitotano/farmacocinética , Mitotano/uso terapêutico , Adulto , Idoso , Antineoplásicos Hormonais/administração & dosagem , Área Sob a Curva , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitotano/administração & dosagem , Modelos Estatísticos , Medicina de Precisão , Estudos Retrospectivos , Adulto Jovem
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