Chlorocarbamate-mustard-linked 1,1,2-triphenylbut-1-enes with a selective antitumor activity on mammary tumors containing estrogen receptors

Summary A 1,1,2-triphenylbut-1-ene with a 4-OH group at one C-1 phenyl ring and a chlorocarbamate mustard moiety at the second C-1 ring (compound 3) was synthesized in order to obtain a cytotoxic estrogen with a specific antitumor effect on estrogen-receptor-containing tumors. This compound was tested in comparison to the carrier (compound 1) and a compound (2) having a carbamate mustard group on both C-1 phenyl rings. The estrogen receptor affinity of compound 3 was only about one-quarter lower than that of compound 1, but much higher than that of compound 2. Compounds 2 and 3 showed only partially irreversible binding to the receptor owing to their relatively low alkylating properties. The growth inhibition of the receptor-positive MCF-7 breast cancer cell line by compound 3, but not by compound 1 or 2, was more pronounced than the inhibition of the receptor-negative line MDA. In vivo the hormone-dependent, transplantable mammary tumor MXT M3.2 of the mouse was much better inhibited by compound 3 than its hormone-resistent line MXT OVEX. Compounds 1–3 had no antiestrogenic properties in the mouse, but estrogenic activity was in the order 1>3>2. From these results and because the antitumor activity of compound 3 was superior to that of compounds 1 and 2 in the hormone-dependent tumor models, a selective, receptor-mediated cytotoxic effect of compound 3 on estrogen-receptor-positive tumors in obvious.Supported by the Deutsche Forschungsgemeinschaft, SFB 234 and the Matthias Lackas StiftungDedicated to Prof. Dr. M. F. El Etreby on the occasion of his 50th birthday     

γ-Enolase and glial fibrillary acidic protein in nervous system tumors

Summary A large series of central and peripheral nervous system tumors was studied for the presence of glial fibrillary acidic protein (GFAP) and -enolase (neuron-specific enolase, NSE), using specific monoclonal antibodies (mAbs). Occurrence in and specificity of GFAP to glial and mixed tumors was confirmed and depended on the malignancy grade and features such as meningeal invasion. Using a well-characterized mAb, -enolase was demonstrated in neuronal, as well as in a whole range of non-neuronal tumors. This lack of specificity of -enolase prohibits its use as an exclusive neuronal marker. Nevertheless quantization or comparison with other types of enolases could still prove to be useful in well-defined situations. The advantages inherent to mAbs and a highly sensitive detection system turn GFAP stainings into a specific and readily reproducible technique.Supported in part by FGWO (grant no. 3.0019.86) and by the Geconcerteerde Actie (grant no. 84/89-68, Brain specific proteins)     

Ultrastructure of capillary walls in human brain tumors

Summary Changes in capillary walls between human glial, non-glial and metastatic brain tumors were studied with conventional ultrathin section and freeze-fracture replica techniques. The following results were obtained. (1) In glial tumors, ultrathin section studies showed cell junctions of the capillaries were either short or elongate. Moreover, endothelial hyperplasia, surface infolding of endothelial cells, irregularity of the basal lamina and a large extravascular space were observed. Freeze-fracture replicas of capillary endothelium showed tight junctions as two to seven strands. In addition, pinocytotic vesicles had increased markedly and were an average of 25 per m². Both ultrathin and freeze fracture studies showed that, in contrast to malignant gliomas, there were only slight changes in benign astrocytomas. (2) In non-glial tumors, ultrathin sections showed surface infoldings, increased vesicles, many fenestrations of endothelial cells, irregularity of basal lamina and enlarged perivascular space. Freeze-fracture replicas of vascular endothelium, showed that the average number of pinocytotic vesicles and fenestrations were 25 and 22 per m², respectively. Moreover, the tight junction was composed of one or two strands which appeared to be a discontinuous array of particles. (3) In metastatic brain tumors, ultrathin studies showed capillary endothelia were proliferated, had marked infolding, and showed an increased number of pinocytotic vesicles and many fenestrations. Moreover, short and elongate intercellular junctions were presented but no open junction was detected. Finally the basal lamina lost its three-layered appearance and was irregular in width. Freeze-fracture replicas showed pinocytotic vesicles had increased and were 24 per m² on average in four cases, but fenestrations and tight junctions could not be detected. The most fundamental feature of vessels in these three different kinds of tumors was whether they were fenestrated or not. Glial tumors were non-fenestrated, whereas non-glial and metastatic tumors were fenestrated.     

Endocrinology: Substrate dependency of C19 conjugates in hirsute hyperandrogenic women and the influence of adrenal androgen

Serum C₁₉ conjugates, specifically 3-androstanediol glucuronide(3G), reflect peripheral androgen action through the actionof 5-reductase activity. The origin of 5-reduced C₁₉ conjugateshas been controversial and it has been suggested that they arederived primarily from adrenal androgens. We examined concentrationsof 3G, 3-androstanediol sulphate (3S), androsterone glucuronide(AoG) and androsterone sulphate (AoS) in 40 hirsute hyperandrogenicwomen. These patients were divided into four groups based uponindividual, combined or normal concentrations of the adrenalandrogens dehydroepiandrosterone (DHEAS) and 11-hydroxy-androstenedione.Testosterone, unbound testosterone and androstenedione weresimilar in these groups. Serum 3G was equally high in all groupsand was correlated significantly with hirsutism, while the otherconjugates were not. Androsterone glucuronide was raised inall groups but was higher in patients with raised DHEAS. Serum3S was raised in all groups and was higher where both adrenalandrogens were raised. Serum AoS was highly correlated withDHEAS. Serum 3G was correlated with unbound testosterone andandrostenedione but not with the adrenal androgens. The glucuronideconjugates were correlated with one another as were the sulphateconjugates but glucuronides and sulphates were not correlated.These data confirm ovarian and adrenal dependency of C₁₉ conjugates.Serum 3G appears to reflect hirsutism most accurately and isleast dependent on adrenal androgens in patients with mixedhyperandrogenism.     

Classification of Breast Masses Using Selected Shape,Edge-sharpness,and Texture Features with Linear and Kernel-based Classifiers

Breast masses due to benign disease and malignant tumors related to breast cancer differ in terms of shape, edge-sharpness, and texture characteristics. In this study, we evaluate a set of 22 features including 5 shape factors, 3 edge-sharpness measures, and 14 texture features computed from 111 regions in mammograms, with 46 regions related to malignant tumors and 65 to benign masses. Feature selection is performed by a genetic algorithm based on several criteria, such as alignment of the kernel with the target function, class separability, and normalized distance. Fisher's linear discriminant analysis, the support vector machine (SVM), and our strict two-surface proximal (S2SP) classifier, as well as their corresponding kernel-based nonlinear versions, are used in the classification task with the selected features. The nonlinear classification performance of kernel Fisher's discriminant analysis, SVM, and S2SP, with the Gaussian kernel, reached 0.95 in terms of the area under the receiver operating characteristics curve. The results indicate that improvement in classification accuracy may be gained by using selected combinations of shape, edge-sharpness, and texture features.     

Changes in anti-Müllerian hormone serum concentrations over time suggest delayed ovarian ageing in normogonadotrophic anovulatory infertility

BACKGROUND: Anti-Müllerian hormone (AMH), produced by growing pre-antral and early antral ovarian follicles, has been shown to be a useful marker for ovarian ageing. Serum AMH concentrations are elevated during reproductive life in anovulatory women, especially in those patients exhibiting polycystic ovaries (PCO). The current study was designed to investigate whether the decrease in AMH serum concentrations over time is different comparing women with normogonadotrophic anovulation [World Health Organization (WHO) group 2 (including polycystic ovary syndrome (PCOS)] and normo-ovulatory controls. METHODS AND RESULTS: AMH serum levels were assessed on two occasions in 98 patients suffering from WHO 2 anovulatory infertility as well as in 41 normo-ovulatory premenopausal women. Median time interval between both visits was 2.6 years (range 0.3-9.0) for WHO 2 patients compared with 1.6 years (range 1.0-7.3) in controls. Serum AMH concentrations were significantly (P < 0.0001) elevated on both occasions in WHO 2 patients (AMH1, median = 7.5 microg/l, range 0.1-35.8; and AMH2, median = 6.7 microg/l, range 0.0-30.6) compared with controls (AMH1, median = 2.1 microg/l, range 0.1-7.4; and AMH2, median = 1.3 microg/l, range 0.0-5.0). Regression analysis, corrected for age, indicated a significant relative decrease in serum AMH concentrations over time for both groups (P < 0.001). However, the decline in serum AMH in WHO 2 patients was significantly less compared with controls (P = 0.03). CONCLUSION: The present longitudinal study shows that serum AMH concentrations decrease over time both in women presenting with WHO 2 anovulatory infertility and in normo-ovulatory controls. The decrease in WHO 2 patients is less pronounced despite distinctly elevated concentrations. This observation may suggest retarded ovarian ageing and hence a sustained reproductive life span in these patients.     

Serous papillary carcinoma of the endometrium arising from endometrial polyps: a clinical, histological, and immunohistochemical study of 13 cases

Serous papillary carcinoma is an aggressive tumor. Point mutations in the p53 suppressor gene might explain in part the rapid growth of this malignant tumor and its unfavorable outcome. The aims of this study were to evaluate the behavior of serous papillary carcinoma developing in endometrial polyps and to assess the p53 protein overexpression. Patients included in this study were treated in our institution between 1982 and 2003. All clinical and pathological materials were examined. A p53 protein immunohistochemical analysis was performed on paraffin-embedded tissues. Thirteen serous papillary carcinomas arising from benign polyps of the endometrium were identified. The patients' age averaged 73 years. All patients were treated surgically. After an average follow-up of 22 months, 54% of the patients were dead or alive with disease. Of 10 serous papillary carcinomas, 8 (80%) for which paraffin blocks were available overexpressed the p53 protein. A serous papillary carcinoma arising from benign polyps of the endometrium remains a malignant neoplasia with an unfavorable outcome even if the primary tumor is limited to the polyp. The high rate of protein p53 overexpression suggests that a p53 gene mutation occurs early in the disease and might explain the rapid growth of the tumor.