Abstract:
:The structure/activity relationships for inhibition of aromatase and cholesterol side-chain cleavage enzyme (CSCC) by aminoglutethimide and some of its analogues are reviewed. Although more effective against aromatase than CSCC, aminoglutethimide markedly inhibits both enzymes. Optimal competitive antagonism of aromatase is obtained with a free amino or basic group at the 4' position of the phenyl ring substituent. This is important because two major metabolites of aminoglutethimide where the amino group is conjugated have low or no inhibitory effect on aromatase. Relocation of the free amino group to the nitrogen atom of the piperidinedione ring enhances CSCC inhibition. The piperidinedione ring is not essential for inhibitory activity, several 4'-aminophenyl pyrrolidinediones being as potent as aminoglutethimide for aromatase but less effective against CSCC. In this series 3-(4'-aminophenyl)-pyrrolidine-2,5-dione is a selective aromatase inhibitor. Inactivity of 4'-aminophenyl derivatives of imidazolidinedione and pyrimidinetrione indicate that the 4'-aminophenyl moiety alone is insufficient for antagonist activity against aromatase. Replacement of the aminophenyl group by the stronger basic 4-pyridyl moiety in aminoglutethimide yields a selective aromatase inhibitor. The structure/activity data suggest that there is a critical distance between the basic centre and the dione moiety for effective aromatase inhibition. Aminoglutethimide and its analogues possessing a free basic centre elicit a Type II difference spectrum with various cytochrome P-450 isozymes. The spectrally-determined binding affinity correlates with inhibitory activity of these compounds and indicates binding of the amino group to the iron centre of this haem enzyme. In reviewing the postulated mechanisms for the enzyme-mediated aromatisation of substrates it is seen that the initial oxidative attack is at the C-19 position of the steroid. It is proposed that two binding or association sites on the protohaem moiety of this P-450 enzyme (iron and propionic acid residues respectively) are required for the orientation of the substrate. Crystallographic evidence indicates there is a distance of about 6.3 A between the C-17 oxygen and the C-19 methyl of the aromatase substrates (these points interacting with the association sites). There is a similar distance between the basic function and the C-6 keto group for aminoglutethimide (and the C-5 keto group for the pyrrolidinediones). It is proposed that aminoglutethimide and its active analogues interact with aromatase at these binding sites competitively inhibiting the aromatisation of androstenedione and testosterone.
journal_name
Breast Cancer Res Treatjournal_title
Breast cancer research and treatmentauthors
Nicholls PJ,Daly MJ,Smith HJsubject
Has Abstractpub_date
1986-01-01 00:00:00pages
S55-67eissn
0167-6806issn
1573-7217journal_volume
7 Supplpub_type
杂志文章abstract::We have evaluated tandem cycles of a tri-drug combination, termed CVP (cyclophosphamide, etoposide [VP-16], and cisplatin [Platinol]), at four levels in more than 300 patients with various types of tumors. Tandem CVP appears to be at least therapeutically equivalent to alternatives. A second potentially non-cross-resi...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章,评审
doi:10.1007/BF00668354
更新日期:1993-01-01 00:00:00
abstract::We concluded a randomized crossover trial comparing tamoxifen 40 mg daily with ovarian ablation for treatment of metastatic breast cancer in premenopausal women. Objective responses (complete response (CR) plus partial response (PR)) were observed in 5/20 patients treated initially with tamoxifen and in 3/19 patients ...
journal_title:Breast cancer research and treatment
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1023/a:1005895813401
更新日期:1997-07-01 00:00:00
abstract:BACKGROUND:The Z0011 trial initiated a paradigm shift in the axillary treatment of breast cancer patients with a positive sentinel lymph node biopsy (SLNB), disregarding patients with a positive ultrasound-guided lymph node biopsy (UGLNB). We examined whether relevant differences exist between these patients to determi...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-017-4342-1
更新日期:2017-10-01 00:00:00
abstract:PURPOSE:The safety of immediate breast reconstruction (IBR) in older women is largely unknown. This study aimed to determine the 30-day postoperative complication rates following IBR (implant-based or autologous) in older women (≥ 70 years) with breast cancer and to compare them to younger women (18-69 years). METHODS...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-019-05273-1
更新日期:2019-08-01 00:00:00
abstract::A review of the current literature on immunohistologic and histochemical methods for the detection of steroid hormone binding sites in breast cancer, reveals that many, but not all of the criteria for establishing hormone-receptor binding interactions have been met. These include tissue specificity, binding between la...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/BF01806746
更新日期:1981-01-01 00:00:00
abstract::Although the psychosocial concomitants of early-stage breast cancer have been well-documented, the relationship between cancer recurrence and quality of life remains less clear. We conducted a prospective, longitudinal study in order to clarify the relationship between recurrent cancer and quality of life, and to dete...
journal_title:Breast cancer research and treatment
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1023/a:1006172024218
更新日期:1999-03-01 00:00:00
abstract::Identifying risk factors for lymphedema in patients treated for breast cancer has become increasingly important, given the current lack of standardization surrounding diagnosis and treatment. Reports on the association of body mass index (BMI) and weight change with lymphedema risk are conflicting. We sought to examin...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-013-2715-7
更新日期:2013-11-01 00:00:00
abstract:PURPOSE:Compared to breast cancer risk genes such as BRCA2, ATM, PALB2, and NBN, no defined phenotype is currently associated with biallelic pathogenic variants (PVs) in CHEK2. This study compared the prevalence of breast and other cancers in women with monoallelic and biallelic CHEK2 PVs. METHODS:CHEK2 PV carriers we...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-020-05543-3
更新日期:2020-04-01 00:00:00
abstract::Although high mammographic density is a risk factor for postmenopausal breast cancer, its etiology remains unclear. We examined whether serum and dietary cholesterol, which increase breast cancer risk and are involved in endogenous estrogen formation, were associated with increased mammographic density. We conducted a...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1007/s10549-010-0927-7
更新日期:2011-01-01 00:00:00
abstract::Molecular profiles of asynchronous breast cancer metastases are of clinical relevance to individual patients' treatment, whereas the role of profiles in synchronous lymph node metastases is not defined. The present study aimed to assess individual biomarkers and molecular subtypes according to the St Gallen classifica...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-013-2617-8
更新日期:2013-07-01 00:00:00
abstract::Invasion factors uPA/PAI-1 are guideline-recommended (ASCO, AGO) biomarkers for decision support regarding adjuvant chemotherapy (CTX) in women with primary breast cancer. They define a high-risk group with strong benefit from adjuvant CTX and a low-risk group with uncertain benefit and excellent survival without CTX....
journal_title:Breast cancer research and treatment
pub_type: 杂志文章,随机对照试验
doi:10.1007/s10549-013-2496-z
更新日期:2013-04-01 00:00:00
abstract::Weight gain is a common problem amongst women receiving adjuvant chemotherapy for early breast cancer. We undertook a study to determine the causes of this weight gain. Prospective measurements of body mass and composition (skinfolds, bioelectrical impedance, total body potassium), energy balance (resting energy expen...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1023/B:BREA.0000014037.48744.fa
更新日期:2004-02-01 00:00:00
abstract::We characterized the structure and the function of insulin receptors isolated from 10 human breast cancer specimens. We observed that the insulin receptor content, as determined by a specific radioimmunoassay, was four fold increased in human breast cancer tissue when compared to normal breast tissues. In both cancer ...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/BF00662403
更新日期:1993-01-01 00:00:00
abstract:PURPOSE:To determine if response to endocrine therapy of breast cancer can be predicted by either a metabolic "flare reaction" detected by positron emission tomography (PET) with 2-[(18)F]-fluoro-2-deoxyglucose (FDG), induced by an estradiol challenge, or by estrogen-receptor (ER) status, determined by PET with the est...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-008-9953-0
更新日期:2009-02-01 00:00:00
abstract::Triple-negative breast cancers lack estrogen receptor α (ERα), progesterone receptor, and do not overexpress human epidermal growth factor receptor 2 (Her-2). They are neither susceptible to endocrine therapy nor to a therapy using the anti-Her-2 antibody, trastuzumab. Therefore, an efficient targeted therapy is warra...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-012-1968-x
更新日期:2012-07-01 00:00:00
abstract::Aromatase inhibitors (AIs) are used for treatment of estrogen receptor α (ER)-positive breast cancer; however, resistance is a major obstacle for optimal outcome. This preclinical study aimed at identifying potential new treatment targets in AI-resistant breast cancer cells. Parental MCF-7 breast cancer cells and four...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-015-3284-8
更新日期:2015-02-01 00:00:00
abstract::Sustained breast cancer growth and metastasis requires paracrine signals between the tumor cells and the normal surrounding host tissue. One crucial function of these signals is to recruit endothelial cells and thus new blood vessels for the nourishment of the expanding tumor mass. This proliferation and migration of ...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章,评审
doi:10.1007/BF00666148
更新日期:1994-01-01 00:00:00
abstract::This study compared the efficacy and safety of a 3-monthly 10.8-mg depot goserelin (Zoladex(TM)) injection with the current 3.6 mg monthly dose in pre-menopausal Japanese women with estrogen receptor-positive (ER+) early breast cancer. This was a multicenter, open-label, randomized study. Primary endpoint was a non-in...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1007/s10549-010-1332-y
更新日期:2011-04-01 00:00:00
abstract:PURPOSE:Being at hereditary risk of breast cancer (BC) may lead to elevated levels of distress because of the impact of the BC-process in relatives. OBJECTIVE:Determine the association between psychological distress and BC in relatives. We studied: kind of kinship with the affected relative(s), degree of involvement w...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-004-2623-y
更新日期:2005-01-01 00:00:00
abstract::Recent studies in patients with breast cancer suggest the immune microenvironment influences response to therapy. We aimed to evaluate the relationship between growth rates of tumors in common spontaneous mammary tumor models and immune biomarkers evaluated in the tumor and blood. TgMMTV-neu and C3(1)-Tag transgenic m...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-014-3199-9
更新日期:2014-12-01 00:00:00
abstract:PURPOSE:Breast cancer is the most common cancer among females worldwide. Axillary lymph node involvement is an important prognostic factor in pre-operative evaluation. The aim of this study was to evaluate the sensitivity and accuracy of AUS during the initial breast cancer diagnosis and the contribution of ultrasound ...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-020-05830-z
更新日期:2020-10-01 00:00:00
abstract::The population-based Ontario Breast Screening Program (OBSP) provides two-yearly screening by both nurse examiner clinical breast examination (CBE) and two-view mammography to women aged 50 to 69. CBE alone accounts for about 5% of cancer detection. The purpose of this study was to determine whether CBE information af...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1023/a:1005990806919
更新日期:1998-03-01 00:00:00
abstract::Transforming growth factor-beta (TGFB) is a potent inhibitor of normal epithelial cell proliferation, and may be one of the regulatory factors that are perturbed during tumor development. While many tumor cell lines no longer respond to the inhibitory effects of TGFB due to a reduction or absence of the type II recept...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1023/a:1023918026437
更新日期:2003-05-01 00:00:00
abstract:PURPOSE:To evaluate the patterns of failure, relapse-free survival and overall survival among African American breast cancer patients younger than 40 years. PATIENTS AND METHODS:We retrospectively reviewed the records of 124 African American breast cancer patients younger than 40 years who were registered with the How...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1023/a:1022161629156
更新日期:2003-03-01 00:00:00
abstract::Triple-negative breast cancer is a particularly aggressive and lethal breast cancer subtype that is more likely to be interval-detected rather than screen-detected. The purpose of this study is to discover and initially validate novel early detection biomarkers for triple-negative breast cancer using preclinical sampl...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-012-2204-4
更新日期:2012-09-01 00:00:00
abstract::Our aim was to develop an accurate diagnostic system using gene expression analysis by means of DNA microarray for prognosis of node-negative and estrogen receptor (ER)-positive breast cancer patients in order to identify a subset of patients who can be safely spared adjuvant chemotherapy. A diagnostic system comprisi...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-010-1145-z
更新日期:2011-08-01 00:00:00
abstract:BACKGROUND:Gemcitabine (G) and vinorelbine (V) have favorable safety profile and antitumor activity in metastatic breast cancer. To exploit their different mechanism of action and lack of overlapping toxicity, we performed a phase I and II study of G and V in combination. PATIENTS AND METHODS:Fifty-three patients with...
journal_title:Breast cancer research and treatment
pub_type: 临床试验,杂志文章
doi:10.1023/a:1013034311284
更新日期:2001-12-01 00:00:00
abstract:PURPOSE:Contralateral prophylactic mastectomy is increasing, despite unclear evidence of improving survival. To investigate the age-related risk factors for contralateral breast cancer (CBC). METHODS:This study included 8716 patients diagnosed with non-metastatic unilateral invasive breast cancer between 1989 and 2008...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-018-5031-4
更新日期:2019-02-01 00:00:00
abstract::A detailed analysis of the immune system response has been performed during the development and progression of dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors. For this aim, a number of immune parameters (thymocyte and splenocyte proliferative response to T-dependent mitogens, antibody production, lymphocy...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/BF00665692
更新日期:1993-09-01 00:00:00
abstract:PURPOSE:It has been suggested that type 2 diabetes may affect breast cancer prognosis, possibly due to increased diabetes-related comorbidity, or direct effects of insulin resistance and/or hyperinsulinemia. The purpose of this study was to examine the impact of diabetes on survival following breast cancer. METHODS:Us...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-007-9654-0
更新日期:2008-05-01 00:00:00