Epidermal growth factor receptor levels increase but epidermal growth factor receptor ligand levels decrease in mouse mammary tumors during progression from hormone dependence to hormone independence

Summary Twenty-six serially transplanted Grunder (GR) strain mouse mammary tumors were analyzed for epidermal growth factor receptor (EGFR) and EGFR-ligand levels, in addition to steroid hormone receptors (estrogen receptor, ER, progesterone receptor, PgR). In concordance with earlier studies, hormone dependent (HD) and hormone responsive (HR) tumors were found to be positive for both ER and PgR, whereas hormone independent (HI) tumors contained only 30% of the ER concentration that was found in the HD tumors. PgR was undetectable in HI tumors. HI tumors contained 2.5 to 3-fold higher EGFR levels than HD/HR tumors, an observation which shows remarkable concordance with studies on EGFR in human breast cancer. On the other hand, the level of EGFR-ligand(s) was positively associated with ER levels and was three-fold higher in HD/HR tumors than in HI tumors. The low EGFR in HD/HR tumors relative to HI tumors may be the result of downregulation by EGFR ligands produced under ER control. During progression to hormone independence this downregulation of EGFR is then abolished in absence of ER. The increase in EGFR may therefore be a secondary effect rather than a key event in the progression to hormone independence in this mouse mammary tumor model.Abbreviations EGF Epidermal Growth Factor - EGFR Epidermal Growth Factor Receptor - ER Estrogen Receptor - PgR Progesterone Receptor - HD Hormone Dependent - HR Hormone Responsive - HI Hormone Independent - HAP Hydroxylapatite - DCC Dextran Coated Charcoal - GR Grunder - TGF- Transforming Growth Factor-     

Pharmacokinetics of the antitumor antibiotic n-pentyl-sparsomycin in beagle dogs

Summary N-pentyl-sparsomycin (PSm) is a lipophilic analogue of sparsomycin (Sm), which is a well known inhibitor of protein synthesis. This compound was selected for preclinical pharmacokinetic studies because of its high in vitro and in vivo antitumor activity. In this study in which the drug was evaluated in beagle dogs under anaesthesia, the drug concentrations in plasma, urine and bile samples were determined using high performance liquid chromatography (HPLC). Plasma protein binding was approximately 54%. The mean t1/2 was 0.2 hours (12 minutes) and t1/2 was 0.75 ± 0.1 hours (45 ± 6 minutes). During continuous infusions up to 5.25 hours, the steady state was reached in 3 out of 6 experiments, suggesting that in some cases the real t1/2 was longer than measured. PSm was actively reabsorbed from the renal tubuli. This process was saturable at the higher doses. Tubular reabsorption played only a minor role in pharmacokinetics as most of the drug (67%) was eliminated by the non-renal clearance. The non-renal clearance was saturable at higher doses of PSm and was the reason for non-linearity of pharmacokinetics.     

Photorefractive keratectomy with the erbium: YAG laser

BACKGROUND: Ablation experiments and preclinical studies have shown increased thermal damage and surface roughness after photorefractive keratectomy (PRK) with the erbium: YAG laser. MATERIALS AND METHODS: In this study, the thermal damage was investigated on enucleated pig corneas for various laser pulse durations (80 ns to 1 ms) and radiant exposures (0.2-5 J/cm2). The "scanning-spot" method and the fundamental mode photo-ablation were used for spherical corrections. SEM pictures and surface roughness measurements enabled comparison with the morphology after ArF-excimer laser treatment. The surface roughness is one order of magnitude higher compared to the ArF-excimer laser ablation. The surface of the tissue after ablation looks melted. RESULTS: The thermal damage reduces with increased intensity, and at high intensities the thermal damage results in a constant thickness of > 5 microns. CONCLUSIONS: Laser-induced melting processes might be the main reason for the high thermal damage and the increased surface roughness after erbium: YAG laser treatment. This leads to the conclusion that the erbium: YAG laser is not a real alternative to the ArF-excimer laser in PRK.     

Quality control of estrogen receptor assays in the Netherlands

Summary Lyophilized receptor-positive tissue powders and cytosols, prepared from calf uterus and human breast tumor tissue, are used to assess the validity of routine dextran-coated charcoal estrogen receptor assays. Since 1978 lyophilized reference preparations have been analyzed twice yearly by 18 laboratories in the Netherlands. During 8 consecutive trials 20 different lyophilized samples were studied. The inter-laboratory variability of estrogen receptor results decreased with time. Most laboratories found receptor values around the median value of all groups together, though some participants consistently reported estrogen receptor values that were higher or lower than the median. The variability of estrogen receptor results between labs seemed to be associated with cytosol dilution, determination of non-specific binding, concentration and volume of dextrancoated charcoal, and the use of single dose assays or Scatchard analysis. The agreement on the presence or absence of estrogen receptors was more than 98% for lyophilized reference samples with high receptor content. For samples with low receptor content 85% agreement was observed, while 12% of the assays performed on receptor-negative material were reported to be estrogen receptor-positive. The use of the same protein determination (Coomassie Brilliant Blue) and human serum albumin standard has decreased the interlaboratory variation coefficient of the protein results to 7.5%. Address for reprnts: A. Koenders, Dept. of Experimental and Chemical Endocrinology, St. Radboud Hospital, Geert Grooteplein Z 8, 6500 HB Nijmegen, the Netherlands List of participating laboratories and institutions: Hospital de Lichtenberg, Amersfoort; Antoni van Leeuwenhoek Hospital, Amsterdam; Foundation Medical Laboratories, Breda; Foundation of Cooperative Hospitals Delft (SSDZ), Delft; Catharina Hospital, Eindhoven; Hospital de Stadsmaten and Ziekenzorg, Enschede; Academic Hospital, Groningen; The Wever Hospital, Heerlen; Laboratory of Public Health, Leeuwarden; Department of Pathological Chemistry, Academic Hospital, Leiden; Department of Experimental and Chemical Endocrinology, Sint Radboud Hospital, Nijmegen; Scientific Development Group Organon International B.V., Oss; Department of Biochemistry II, Erasmus University Rotterdam, Rotterdam; Rotterdam Radio-Therapeutic Institute/ Dr Daniel den Hoed Clinic, Rotterdam; Institute of Oncology Dr Bernard Verbeeten, Tilburg; Department of Endocrinology, Academic Hospital, Utrecht; Laboratory for Nuclear Medicine Voorburg, Vught; Sophia Hospital, Zwolle.     

Stage migration in breast cancer: surgical decisions concerning isolated tumour cells and micro-metastases in the sentinel lymph node.

AIMS: Sentinel lymph node biopsy has replaced the axillary lymph node dissection (ALND) in primary surgery for breast cancer in many hospitals and is expected to become the standard of care in due time. Since the sentinel lymph node is subjected to more extensive pathologic examination than the lymph nodes in the axillary dissection specimen, more patients are found to be node positive (N+); however many of them contain micro-metastases (相似文献   

Responsiveness of the generic EQ-5D summary measure compared to the disease-specific EORTC QLQ C-30

Introduction: We investigated whether the sensitivity of the generic health-related quality of life (HRQoL) EQ-5D summary measure (or index) to detect changes over time in a clinical setting is comparable with that of a disease-specific HRQoL questionnaire. Methods: Patients with liver metastases (n = 75) filled out the five domains of the EQ-5D self-classifier, the EQ VAS, and the EORTC QLQ C-30 (a disease-specific (cancer) HRQoL questionnaire). The HRQoL instruments were completed before intervention, and 1/2 month and 3 and 6 months after intervention. Three analyses were performed. First, the EQ-5D index (based on self-classification) was compared to the EQ VAS. Second, the EQ-5D domains were compared to corresponding EORTC QLQ C-30 scales. Third, EQ-5D index and EQ VAS were compared with the EORTC QLQ C-30 global health-status scale. Effect size was chosen as the metric of responsiveness. Results: The EQ-5D index was slightly less responsive than the EQ VAS. Overall, the responsiveness of the EQ-5D index and EQ VAS was equal to the EORTC QLQ C-30 global health-status scale. Conclusion: Despite its generic principle and the apparent crudeness of its framework, the responsiveness of the EQ-5D proved to be comparable to that of a disease-specific HRQoL questionnaire in this specific clinical setting.     

CYP1A2 and NAT2 genotype/phenotype relations and urinary excretion of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in a human dietary intervention study.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mutagenic and carcinogenic heterocyclic amine formed during ordinary cooking, and is subsequently metabolically activated by cytochrome P4501A2 (CYP1A2) and N-acetyltransferase 2 (NAT2). Respective genes encoding for these enzymes, display polymorphic distribution in the human population and are thus believed to cause interindividual differences in cancer risk susceptibility. The present study investigated the influence of dietary exposure and CYP1A2 and NAT2 genotypes and phenotypes on differential urinary PhIP excretion levels in 71 human volunteers after consumption of either a high (7.4 ng/g) or low (1.7 ng/g) dose of PhIP. Urinary PhIP excretion levels were found to reflect recent dietary exposure levels, with average levels of 174% (high dose group) and 127% (low dose group), as compared to pre-feed levels. Urinary caffeine metabolite ratios were significantly different between the two NAT2 genotypes, whereas for CYP1A2, the apparent difference in metabolic ratios between the genotypes was statistically non-significant. Significant correlations were firstly found between the CYP1A2-164A-->C (CYP1A2*1F) polymorphism and differential urinary PhIP excretion levels. Although the found correlations are driven primarily by a small number of subjects possessing the homozygous variant constellation, the strong influence of this genotype indicates that the CYP1A2*1F polymorphism could play an important role in human cancer risk susceptibility.     

Contribution of growth phases to adult size

Based on the data of the First Zurich Longitudinal Growth Study we investigate how interindividual differences in adult size arise in the variables leg height, sitting height and standing height, arm length, biiliac width and bihumeral width. Specifically, we are also interested in the question of whether across sexes and variables the same growth phases and the same parameters are predictive for achieving a certain adult size. A rather complex pattern emerges, demonstrating that regulation of growth is not the same for boys and girls and moreover is not the same for the six anthropometric variables studied. Prepubertal growth is characterized by its intensity (average velocity) and by its duration. Whereas duration has by itself no appreciable influence on adult size, prepubertal intensity determines adult size to a high degree across all variables and both sexes. The intensity of prepubertal growth determines adult size to a larger degree for boys than for girls. For a given size at the end of the prepubertal period, a small duration enhances the chance of obtaining a large adult size. Compared with prepubertal growth, the amount of variance of adult size explained is small for pubertal parameters, and - with respect to linear measures - significant for girls only. A small duration of prepubertal growth is in the following mainly compensated by a stronger pubertal spurt (PS), to a varying degree across variables. The overall picture which emerges indicates that sitting height - and to a lesser extent bihumeral width - develop in a more irregular fashion than the variables biiliac width and leg height.