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1.
J Immunotoxicol ; 12(1): 24-32, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24350727

RESUMO

Primary aromatic amine drugs are structural alerts in drug development because of their association with a high incidence of idiosyncratic drug reactions (IDRs). If biomarkers could be found that predict IDR risk, it would have a major impact on drug development. Previous attempts to do this through screening of hepatic gene expression profiles in rodents treated with aromatic amine drugs found limited changes. Of the drugs studied, aminoglutethimide (AMG) induced the most changes, and this led to a more comprehensive study of its effects on the liver. Brown Norway rats treated with AMG for up to 14 days showed only a transient elevation of glutamate dehydrogenase. Pathway-specific PCR arrays found few AMG-induced gene changes associated with an immune response and, of these changes, the majority were involved with innate immunity such as Tlr2, Ticam2, CD14, and C3. AMG treatment also led to significant changes in the apoptosis and mitochondrial panel of genes. It was recently found that AMG does induce significant changes in the bone marrow of rats, and agranulocytosis is a common IDR caused by AMG. In contrast, liver injury is not a common IDR associated with AMG. Therefore, the liver may be able to effectively deal with AMG reactive metabolites, and changes observed in this study may be involved in adaptation. Myeloperoxidase is also known to be able to oxidize aromatic amines to reactive metabolites, and these observations suggest that metabolism outside of the liver may be important for the mechanism of aromatic amine-induced IDRs.


Assuntos
Agranulocitose/imunologia , Aminoglutetimida/efeitos adversos , Glutamato Desidrogenase/metabolismo , Fígado/efeitos dos fármacos , Mitocôndrias/metabolismo , 3,3'-Diaminobenzidina/química , Agranulocitose/induzido quimicamente , Aminoglutetimida/administração & dosagem , Aminoglutetimida/química , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Complemento C3/genética , Complemento C3/metabolismo , Humanos , Imunidade Inata/efeitos dos fármacos , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/metabolismo , Fígado/imunologia , Masculino , Mitocôndrias/genética , Peroxidase/metabolismo , Ratos Endogâmicos , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo
2.
Br J Cancer ; 108(7): 1408-14, 2013 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-23511562

RESUMO

BACKGROUND: There exists evidence that body mass index (BMI) impacts on the efficacy of aromatase inhibitors in patients with breast cancer. The relationship between BMI and the efficacy of tamoxifen is conflicting. We investigated the impact of BMI on the efficacy of single tamoxifen and tamoxifen plus an aromatase inhibitor in the well-defined prospective study population of the ABCSG-06 trial. METHODS: ABCSG-06 investigated the efficacy of tamoxifen vs tamoxifen plus aminoglutethimide in postmenopausal women with hormone receptor-positive breast cancer. Taking BMI at baseline, patients were classified as normal weight (BMI=18.5-24.9 kg m(-)(2)), overweight (BMI=25-29.9 kg m(-)(2)), and obese (30 kg m(-)(2)) according to WHO criteria. RESULTS: Overweight+obese patients had an increased risk for distant recurrences (hazard ratio (HR): 1.51; Cox P=0·018) and a worse overall survival (OS; HR: 1·49; Cox P=0·052) compared with normal weight patients. Analysing patients treated with single tamoxifen only, no difference between overweight+obese patients and normal weight patients regarding distant recurrence-free survival (HR: 1.35; Cox P=0·24) and OS (HR: 0.99; Cox P=0·97) could be observed. In contrast, in the group of patients treated with the combination of tamoxifen plus aminoglutethimide, overweight+obese patients had an increased risk for distant recurrences (1.67; Cox P=0·03) and a worse OS (1.47; Cox P=0·11) compared with normal weight patients. CONCLUSION: BMI impacts on the efficacy of aromatase inhibitor-based treatment but not single tamoxifen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Sobrepeso/fisiopatologia , Tamoxifeno/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Aminoglutetimida/administração & dosagem , Aminoglutetimida/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversos , Índice de Massa Corporal , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Estudos Prospectivos , Receptores de Superfície Celular/biossíntese , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Resultado do Tratamento
3.
Pathologe ; 27(1): 61-4, 2006 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-16320017

RESUMO

The structure of the normal adrenal cortex is changed by stimulating hormones (ACTH) and inhibiting hormonal drugs (especially glucocorticoids). ACTH induces hyperplasia and lipid depletion in the fascicular and reticular zones, whereas glucocorticoids lead to atrophy and lipid accumulation in both zones. In animal experiments, the adrenostatic drug mitotane causes shrinkage of the cells of the fascicular and reticular zones, whereas metyrapone induces a decrease in the steroid producing organelle system and aminoglutethimide leads to an increase in lipids. In the therapy of patients with adrenocortical cancer, mitotane can cause an increase in of necrosis and fibrosis, but also in intracellular lipid. The ultrastructure shows increased liposomes, more pigment-rich lysosomes and laminated bodies.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Córtex Suprarrenal/patologia , Antineoplásicos/uso terapêutico , Córtex Suprarrenal/efeitos dos fármacos , Neoplasias do Córtex Suprarrenal/patologia , Hormônio Adrenocorticotrópico/fisiologia , Aminoglutetimida/efeitos adversos , Aminoglutetimida/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Humanos , Organelas/efeitos dos fármacos , Organelas/patologia
4.
J Clin Oncol ; 21(6): 984-90, 2003 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-12637461

RESUMO

PURPOSE: To determine whether the addition of aminoglutethimide to tamoxifen is able to improve the outcome in postmenopausal patients with hormone receptor-positive, early-stage breast cancer. PATIENTS AND METHODS: A total of 2,021 postmenopausal women were randomly assigned to receive either tamoxifen for 5 years alone or tamoxifen in combination with aminoglutethimide (500 mg/d) for the first 2 years of treatment. Tamoxifen was administered at 40 mg/d for the first 2 years and at 20 mg/d for 3 years. RESULTS: All randomized and eligible patients were included in the analysis according to the intention-to-treat principle. After a median follow-up of 5.3 years, the 5-year disease-free survival in the aminoglutethimide plus tamoxifen group was 83.6% versus 83.7% in the monotherapy group (P =.89). The corresponding data for overall survival at 5 years were 91.4% and 91.2%, respectively (P =.74). More patients failed to complete combination treatment (13.7%) because of side effects as compared to tamoxifen alone (5.2%; P =.0001). CONCLUSION: Aminoglutethimide given for 2 years in addition to tamoxifen for 5 years does not improve the prognosis of postmenopausal patients with receptor-positive, lymph node-negative or lymph node-positive breast cancer.


Assuntos
Aminoglutetimida/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Moduladores de Receptor Estrogênico/uso terapêutico , Pós-Menopausa , Tamoxifeno/uso terapêutico , Idoso , Aminoglutetimida/administração & dosagem , Aminoglutetimida/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Áustria , Neoplasias da Mama/química , Quimioterapia Adjuvante , Progressão da Doença , Esquema de Medicação , Moduladores de Receptor Estrogênico/administração & dosagem , Moduladores de Receptor Estrogênico/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Segunda Neoplasia Primária/etiologia , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Análise de Sobrevida , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Resultado do Tratamento
5.
J Small Anim Pract ; 43(3): 104-8, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11924551

RESUMO

The aim of this study was to evaluate the efficacy and safety of aminoglutethimide in the treatment of dogs with pituitary-dependent hyperadrenocorticism (PDH). Ten dogs were diagnosed with PDH based on clinical and laboratory data, adrenal function tests (adrenocorticotropic hormone [ACTH] stimulation test and urinary cortisol/creatinine ratio [UCCR] combined with a high dose oral dexamethasone suppression test) and ultrasonographic evaluation of the adrenal glands. Aminoglutethimide was administered daily at a dose of 15 mg/kg bodyweight for one month. Median basal cortisol concentration and post-ACTH cortisol concentration one month after treatment were significantly lower than pretreatment values. Complete response was achieved in one dog, and partial response was obtained in three dogs. Severe side effects of anorexia, vomiting and weakness occurred in one dog and medication was withdrawn. Two further dogs developed decompensations of concurrent diseases and medication was stopped in these animals as well. Mild toxicity occurred in four dogs. Moderate to severe elevations in liver enzymes occurred in all dogs. The efficacy of this drug is lower than that observed using mitotane and ketoconazole, and adverse effects limit its use. Aminoglutethimide, using the protocol described, cannot be recommended for long-term management of PDH in the dog.


Assuntos
Adrenérgicos/uso terapêutico , Hiperfunção Adrenocortical/veterinária , Aminoglutetimida/uso terapêutico , Doenças do Cão/tratamento farmacológico , Glândulas Suprarrenais/diagnóstico por imagem , Adrenérgicos/efeitos adversos , Hiperfunção Adrenocortical/diagnóstico , Hiperfunção Adrenocortical/tratamento farmacológico , Aminoglutetimida/efeitos adversos , Animais , Doenças do Cão/diagnóstico , Cães , Feminino , Masculino , Ultrassonografia
6.
Eur J Med Res ; 7(11): 487-90, 2002 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-12568977

RESUMO

BACKGROUND: Tumor necrosis factor alpha (TNF) and its cellular and soluble (s) receptors (TNF-R) are important mediators in acute myeloid leukemia (AML) and infectious complications during cytoreductive therapy. We investigated the serum concentrations of sTNF-RII in previously untreated patients with AML at the onset of cytoreductive therapy and in non-febrile chemotherapy-associated neutropenia. PATIENTS AND METHODS: Of 54 eligible patients with AML, serum concentrations of sTNF-RII could be evaluated in 25 non-neutropenic, non-febrile and in 11 neutropenic, non-febrile patients. RESULTS: At baseline, non-neutropenic, non-febrile AML patients showed high median serum sTNF-RII concentrations of 3,804 pg/mL. In neutropenia, there was a non-significant trend (p = 0.18) to lower median sTNF-RII levels of 3,246 pg/mL. CONCLUSIONS: Serum sTNF-RII concentrations in non-febrile AML patients before chemotherapy are in the range of levels reached in uncomplicated febrile episodes in otherwise healthy individuals. This must be taken into account when evaluating the cytokine profile for sepsis in patients with therapy-associated neutropenia. Concentrations are still elevated in neutropenia, suggesting that a normal number of leukocytes is not necessarily required for the activation of the TNF ligand/TNF receptor system in AML.


Assuntos
Imunoglobulina G/sangue , Leucemia Mieloide Aguda/sangue , Receptores do Fator de Necrose Tumoral/sangue , Adulto , Idoso , Aminoglutetimida/administração & dosagem , Aminoglutetimida/efeitos adversos , Antígenos CD/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Danazol/administração & dosagem , Danazol/efeitos adversos , Etanercepte , Feminino , Febre , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neutropenia/sangue , Neutropenia/induzido quimicamente , Estudos Prospectivos , Receptores Tipo II do Fator de Necrose Tumoral , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos
7.
Breast Cancer Res Treat ; 61(2): 103-10, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10942095

RESUMO

The efficacy of combined endocrine therapy with tamoxifen (TAM), aminoglutethimide (AG), and hydrocortisone (H) or tamoxifen and fluoxymesterone (FLU) was evaluated against treatment with tamoxifen alone in 311 patients above 65 years of age with a first recurrence of a metastatic breast cancer. A total of 279 patients were eligible. The response rates were assessed for 258 fully evaluable patients and were the following for the TAM (N = 94), the TAM+AG+H (N = 83), and the TAM+FLU (N = 81) groups, respectively, PR: 14, 18, and 21%, and CR: 20, 11, and 23%. The overall response rates are not statistically different (p = 0.30). The 95% CL of difference in response rates for TAM vs. TAM+AG+H are -9-19% and for TAM vs. TAM+FLU -4-25%. Time to treatment failure was comparable with median values of 9.2, 7.7, and 9.2 months in the TAM, TAM+AG+H, and TAM + FLU group, respectively (p = 0.17). The corresponding figures for survival are median times of 22.0, 24.1, and 21.1 months with a p-value of 0.62. Toxicity was more pronounced in both the combined treatment groups, and could in most instances be attributed to treatment with either AG+H or FLU. Currently, new specific aromatase inhibitors with lesser toxicity than AG are being evaluated in combination with TAM for treatment of primary and metastatic breast cancer. In conclusion, the simultaneous use of TAM and AG +H or FLU does not seem to improve the therapeutic efficacy in elderly postmenopausal patients with metastatic disease. So far, combined endocrine therapy in this group of patients should only be used in the context of clinical trials.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Aminoglutetimida/administração & dosagem , Aminoglutetimida/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Progressão da Doença , Sinergismo Farmacológico , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Fluoximesterona/administração & dosagem , Fluoximesterona/efeitos adversos , Humanos , Hidrocortisona/administração & dosagem , Tábuas de Vida , Metástase Neoplásica , Proteínas de Neoplasias/antagonistas & inibidores , Terapia de Salvação , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Análise de Sobrevida , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Resultado do Tratamento
10.
Endocr Relat Cancer ; 6(1): 75-92, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10732791

RESUMO

Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens to estrogens, is the major mechanism of estrogen synthesis in the post-menopausal woman. We review some of the recent scientific advances which shed light on the biologic significance, physiology, expression and regulation of aromatase in breast tissue. Inhibition of aromatase, the terminal step in estrogen biosynthesis, provides a way of treating hormone-dependent breast cancer in older patients. Aminoglutethimide was the first widely used aromatase inhibitor but had several clinical drawbacks. Newer agents are considerably more selective, more potent, less toxic and easier to use in the clinical setting. This article reviews the clinical data supporting the use of the potent, oral competitive aromatase inhibitors anastrozole, letrozole and vorozole and the irreversible inhibitors 4-OH androstenedione and exemestane. The more potent compounds inhibit both peripheral and intra-tumoral aromatase. We discuss the evidence supporting the notion that aromatase inhibitors lack cross-resistance with antiestrogens and suggest that the newer, more potent compounds may have a particular application in breast cancer treatment in a setting of adaptive hypersensitivity to estrogens. Currently available aromatase inhibitors are safe and effective in the management of hormone-dependent breast cancer in post-menopausal women failing antiestrogen therapy and should now be used before progestational agents. There is abundant evidence to support testing these compounds as first-line hormonal therapy for metastatic breast cancer as well as part of adjuvant regimens in older patients and quite possibly in chemoprevention trials of breast cancer.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase , Neoplasias da Mama/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Estrogênios , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Adulto , Aminoglutetimida/efeitos adversos , Aminoglutetimida/farmacologia , Aminoglutetimida/uso terapêutico , Anastrozol , Androstadienos/efeitos adversos , Androstadienos/farmacologia , Androstadienos/uso terapêutico , Androstenodiona/efeitos adversos , Androstenodiona/análogos & derivados , Androstenodiona/farmacologia , Androstenodiona/uso terapêutico , Antineoplásicos Hormonais/farmacologia , Aromatase/fisiologia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/prevenção & controle , Desenho de Fármacos , Interações Medicamentosas , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/classificação , Inibidores Enzimáticos/farmacologia , Estrogênios/biossíntese , Feminino , Humanos , Letrozol , Pessoa de Meia-Idade , Proteínas de Neoplasias/fisiologia , Neoplasias Hormônio-Dependentes/enzimologia , Neoplasias Hormônio-Dependentes/prevenção & controle , Nitrilas/efeitos adversos , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Pós-Menopausa , Pré-Menopausa , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Triazóis/efeitos adversos , Triazóis/farmacologia , Triazóis/uso terapêutico
12.
South Med J ; 91(11): 1014-8, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9824181

RESUMO

BACKGROUND: The morbidity of hypercortisolemia due to ectopic production of ACTH by various tumors may be greater than the morbidity of the tumor itself. METHODS: We report three cases of long-term treatment of ectopic ACTH syndrome due to metastatic bronchial carcinoid, islet cell carcinoma, and malignant thymoma tumors. Clinical and biochemical eucortisolemia was achieved in each case and was sustained from 24 to 55 months. We review the therapeutic options and their reported efficacy. RESULTS: Cessation of therapy resulted in recurrence of hypercortisolemia in each case, showing the effectiveness of therapy. CONCLUSION: Long-term treatment of ectopic ACTH-induced hypercortisolemia by blocking adrenal steroidogenesis is clinically effective and well tolerated.


Assuntos
Síndrome de ACTH Ectópico/tratamento farmacológico , Hiperfunção Adrenocortical/tratamento farmacológico , Aminoglutetimida/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Metirapona/administração & dosagem , Síndrome de ACTH Ectópico/sangue , Síndrome de ACTH Ectópico/etiologia , Adolescente , Hiperfunção Adrenocortical/sangue , Hiperfunção Adrenocortical/etiologia , Aminoglutetimida/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Metirapona/efeitos adversos , Pessoa de Meia-Idade , Recidiva
13.
Ann Oncol ; 9(6): 639-45, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9681078

RESUMO

BACKGROUND: The study compares letrozole and aminoglutethimide (AG), a standard therapy for postmenopausal women with advanced breast cancer, previously treated with antioestrogens. PATIENTS AND METHODS: 555 women were randomly assigned letrozole 2.5 mg once daily (n = 185), letrozole 0.5 mg once daily (n = 192) or aminoglutethimide 250 mg twice daily with corticosteroid support (n = 178) in an open-label, multicentre trial. The primary endpoint was objective response rate (ORR), with time events as secondary. ORR was analysed nine months after enrollment of the last patient, while survival was analysed 15 months after the last patient was enrolled. We report the results of these analyses plus an extended period of observation (covering a total duration of approximately 45 months) to determine the duration of response and clinical benefit. RESULTS: Overall objective response rates (complete + partial) of 19.5%, 16.7% and 12.4% were seen for letrozole 2.5 mg, 0.5 mg and AG respectively. Median duration of response and stable disease was longest for letrozole 2.5 mg (21 months) compared with letrozole 0.5 mg (18 months) and AG (14 months). Letrozole 2.5 mg was superior to AG in time to progression, time to treatment failure and overall survival. Treatment-related adverse events occurred in fewer patients on letrozole (33%) than on AG (46%). Transient nausea was the most frequent event with letrozole (7% on 0.5 mg, 10% on 2.5 mg, 10% on AG), rash with AG (11%, 1% on 0.5 mg, 3% on 2.5 mg letrozole). CONCLUSIONS: Letrozole 2.5 mg offers longer disease control than aminoglutethimide and letrozole 0.5 mg in the treatment of postmenopausal women with advanced breast cancer, previously treated with anti-oestrogens.


Assuntos
Aminoglutetimida/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Nitrilas/administração & dosagem , Triazóis/administração & dosagem , Administração Oral , Idoso , Aminoglutetimida/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalos de Confiança , Progressão da Doença , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Letrozol , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nitrilas/efeitos adversos , Razão de Chances , Pós-Menopausa , Prognóstico , Taxa de Sobrevida , Falha de Tratamento , Triazóis/efeitos adversos
14.
Praxis (Bern 1994) ; 87(17): 584-8, 1998 Apr 22.
Artigo em Alemão | MEDLINE | ID: mdl-9623325

RESUMO

Aromatase inhibition is now an acknowledged second line treatment modality for advanced breast cancer in postmenopausal women. Aminoglutethimide is an inhibitor of adrenal steroid biosynthesis and blocks the conversion of cholesterol to pregnenolone, and therefore reduces levels of adrenal androgens, which are a source of estrogens in both premenopausal and postmenopausal women. Aminoglutethimide has produced antitumor response rates of 35% in unselected patients, most of whom have undergone prior therapy with either chemotherapy or hormonal manipulation. As is true of other hormonal responses, high response rates of up to 70% are observed in patients who are ER and/or PR positive. The reason why these drugs are currently used after tamoxifen is mainly due to the side effects of aminoglutethimide, which impairs the mineralocorticoid and glucocorticoid synthesis. New, less toxic compounds appear, which block the conversion of androstenedione to estrone and efficiently suppress plasma estrogen levels., e.g. formestane, anastrozole and letrozole. Aromatase inhibitors are now being compared to tamoxifen as first-line endocrine treatment in relapsing patients. If these trials confirm a similar or better response rate to new aromatase inhibitors compared to tamoxifen, the time will come to study them as the first line adjuvant treatment in non-metastatic disease.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase , Neoplasias da Mama/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Aminoglutetimida/efeitos adversos , Aminoglutetimida/uso terapêutico , Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Neoplasias Hormônio-Dependentes/mortalidade , Neoplasias Hormônio-Dependentes/patologia , Tamoxifeno/efeitos adversos , Tamoxifeno/uso terapêutico
15.
Clin Cancer Res ; 4(1): 37-44, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9516950

RESUMO

Management of prostate cancer progression after failure of initial hormonal therapy is controversial. Recently, the activity of the simple discontinuation of antiandrogen therapy has been established by several groups, as well as the enhanced activity when combined with adrenal suppression (i.e., aminoglutethimide and hydrocortisone). Furthermore, suramin has generated considerable interest following reports of response rates ranging from 17 to 70%. More recently, suramin response rates of 18 and 22% have been reported when the potential confounding variables of flutamide withdrawal and hydrocortisone were prospectively controlled. On the basis of the activity of combining aminoglutethimide with flutamide withdrawal, we designed a protocol in which suramin was combined with aminoglutethimide in two cohorts of patients (those with simultaneous antiandrogen withdrawal compared to those who had previously discontinued antiandrogen therapy). Eighty-one evaluable patients were enrolled in this study between June 1992 and November 1994. Patients were a priori divided into two cohorts, those receiving prior antiandrogen withdrawal (n = 56) and those receiving simultaneous antiandrogen withdrawal (n = 25) at the time the patients were enrolled into the trial. For the group that discontinued antiandrogen prior to enrolling in therapy, the partial response rate (> 50% decline in PSA for > 4 weeks) was 14.2%, whereas the partial response was 44% for those patients who discontinued their antiandrogen at the time of starting suramin and aminoglutethimide. The median time to progression was 3.9 months in patients failing prior antiandrogen withdrawal and 5.5 months in those patients having concomitant antiandrogen withdrawal (P = 0.36 for the overall difference). The progression-free survival estimate at 1 year for patients having prior antiandrogen withdrawal was 19.8% [95% confidence interval (CI), 11-32.9%]. For those patients who experienced antiandrogen withdrawal simultaneous with the treatment, the progression-free survival estimates at 1 and 2 years were 27.1 (95% CI, 13.2-47.6%) and 4.5% (95% CI, 0.8-21.6%). The median survival time for those patients having prior antiandrogen withdrawal was 14.2 months, whereas the median survival was 21.9 months for those having concomitant antiandrogen withdrawal (P = 0.029 for the overall difference). In conclusion, the partial response rate of 44% for those who had concomitant flutamide withdrawal with adrenal suppression was consistent with that of other reports using a similar maneuver. Although this study was not randomized and thus we should not over-interpret the results, flutamide withdrawal plus adrenal suppression appears to have greater activity than flutamide withdrawal alone. Furthermore, these data suggest that suramin adds little to the response rate observed for other adrenal suppressive agents in the presence of antiandrogen withdrawal. This interpretation is in agreement with those studies controlling for adrenal suppression and flutamide withdrawal prior to suramin administration, which noted modest activity of short duration. Given that antiandrogen withdrawal is now accepted as an active maneuver for a subset of patients progressing after maximum androgen blockade, we propose that future trials attempting to maximize response rates incorporate this maneuver whenever possible into prospectively designed regimens.


Assuntos
Aminoglutetimida/administração & dosagem , Antagonistas de Androgênios/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Suramina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminoglutetimida/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/mortalidade , Suramina/efeitos adversos , Taxa de Sobrevida
16.
Eur J Cancer ; 33(11): 1767-73, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9470830

RESUMO

In a European multicentre phase II study, 80 postmenopausal patients (pts) with advanced breast cancer progressing on aminoglutethimide (AG) at daily doses of > or = 500 mg were enrolled. Seventy-eight received exemestane (200 mg daily orally), including 33 pts resistant to prior AG, 39 pts who had progressed after an initial response to AG, and 6 pts whose response to AG was either unavailable or not evaluable. Three pts were pretreated with AG only, 69 with tamoxifen and AG, and 6 with tamoxifen, AG and other hormone therapies; 55% had also previously received chemotherapy. The predominant site of disease was visceral in 34 cases, bone in 27 and soft tissue in 17. Based on Peer Review assessment, the overall objective response rate (CRs plus PRs) was 26% (12% in pts resistant to AG and 33% in AG-responsive pts). Disease stabilisation > or = 24 weeks was achieved in an additional 13% of patients (15% of those resistant to AG and 13% of those AG-responsive), resulting in an overall success rate of 39% (28-50, 95% confidence interval). The median duration of objective response, overall success and median TTP were 59, 48 and 21 weeks, respectively. Toxicities were usually mild to moderate in severity, with hot flushes (21%), nausea (19%), dizziness (12%), weakness (12%), increased sweating (12%), androgenic symptoms (10%) and peripheral oedema (9%) as the most common side-effects. Only 2 pts (3%) discontinued treatment due to adverse events. These results are very promising considering that exemestane was administered as third- or fourth-line hormonal treatment in most cases and confirm previous observations about the lack of cross-resistance when steroidal aromatase inhibitors are sequenced with the non-steroidal aromatase inhibitor AG.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Aminoglutetimida/administração & dosagem , Aminoglutetimida/efeitos adversos , Androstadienos/administração & dosagem , Androstadienos/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Resultado do Tratamento
17.
Biol Psychiatry ; 37(6): 369-75, 1995 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-7772645

RESUMO

Twenty patients, diagnosed as suffering from treatment-resistant major depression, were treated with one or more drugs that decrease corticosteroid biosynthesis. Nine were psychotic, 11 nonpsychotic. Seventeen completed the treatment (8 psychotic, 9 nonpsychotic); 13 responded (5 psychotic, 8 nonpsychotic; 11 responded completely (i.e., a drop in the Hamilton Depression Scale of at least 50%, to < or = 15), and 2 responded partially. The mean age of the responders (45.2 +/- 12.6 years) did not differ significantly from that of the nonresponders (48.7 +/- 12/3). Data were analyzed in the following categories; (1) the presence or absence of psychosis, (2) response or nonresponse to treatment, and (3) the drug(s) used (aminoglutethimide, ketoconazole, or a combination of either of these with metyrapone). The patients improved over time on the Hamilton Depression Scale independent of the medication used. Responders demonstrated improvement in mood, insomnia, anxiety, diurnal variation, paranoia and obsessive compulsiveness. Nonpsychotics responded better than psychotics.


Assuntos
Corticosteroides/antagonistas & inibidores , Aminoglutetimida/administração & dosagem , Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Cetoconazol/administração & dosagem , Metirapona/administração & dosagem , Transtornos Psicóticos/tratamento farmacológico , Corticosteroides/sangue , Adulto , Aminoglutetimida/efeitos adversos , Transtorno Bipolar/sangue , Transtorno Bipolar/psicologia , Transtorno Depressivo/sangue , Transtorno Depressivo/psicologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Cetoconazol/efeitos adversos , Masculino , Metirapona/efeitos adversos , Pessoa de Meia-Idade , Inventário de Personalidade , Transtornos Psicóticos/sangue , Transtornos Psicóticos/psicologia
20.
Oncology ; 51(5): 411-5, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-8052481

RESUMO

Eighty-five postmenopausal women with metastatic breast cancer were randomized to receive aminoglutethimide (AG), medroxyprogesterone acetate (MPA), or AG+MPA. Patients with aggressive visceral disease were excluded. Response was observed in 36% of the patients in the AG treatment group, 31% in the MPA treatment group, and 47% in the combination treatment group. Statistical analysis showed that the percentage of responders was not different among the three treatment groups. Similarly, the duration of response did not differ. Toxicity of all three regimens was moderate, not necessitating discontinuation of treatment. In conclusion, AG, MPA and the combination of AG+MPA were found to be equally effective therapies for metastatic breast cancer in postmenopausal women with nonaggressive visceral disease. The lack of statistically significant superiority of the combination of AG+MPA suggests that sequential endocrine monotherapies may be more beneficial than combined hormonotherapies for this patient population.


Assuntos
Aminoglutetimida/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Acetato de Medroxiprogesterona/uso terapêutico , Idoso , Aminoglutetimida/efeitos adversos , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Feminino , Humanos , Acetato de Medroxiprogesterona/efeitos adversos , Pessoa de Meia-Idade , Pós-Menopausa , Estudos Prospectivos
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