Clastogenic and aneugenic effects of tamoxifen and some of its analogues in hepatocytes from dosed rats and in human lymphoblastoid cells transfected with human P450 cDNAs (MCL-5 cells)

Tamoxifen and its analogues 4-hydroxytamoxifen, toremifene, 4- hydroxytoremifene, clomifene and droloxifene were tested for clastogenic effects in a human lymphoblastoid cell line (MCL-5) expressing elevated native CYP1A1 and containing transfected CYP1A2, CYP2A6, CYP2E1 and CYP3A4 and epoxide hydrolase and in a cell line containing only the viral vector (Ho1). MCL-5 or Ho1 cells were incubated with 4-hydroxytamoxifen, 4-hydroxytoremifene, clomifene or droloxifene and the incidence of micronuclei estimated. With MCL-5 cells there was an increase in micronuclei with 4-hydroxytamoxifen, 4- hydroxytoremifene and clomifene but not with droloxifene. With Ho1 cells only 4-hydroxytamoxifen and 4-hydroxytoremifene caused an increase in micronuclei. MCL-5 cells were incubated with tamoxifen, 4- hydroxytamoxifen, toremifene, droloxifene, clomifene or diethylstilbestrol (0.25-10 microg/ml) for 48 h and subjected to 3 h treatment with vinblastine (0.25 microg/ml) to arrest cells in metaphase. The incidence of cells with chromosomal numerical aberrations (aneuploidy) was increased in cells treated with tamoxifen, 4-hydroxytamoxifen, toremifene, clomifene and diethylstilbestrol but not droloxifene. The frequency of cells with structural abnormalities (excluding gaps) was increased in cells treated with tamoxifen and toremifene but not 4-hydroxytamoxifen, clomifene, droloxifene or diethylstilbestrol. The clastogenic activities of tamoxifen (35 mg/kg), toremifene (36.3 mg/kg), droloxifene (35.2 mg/kg) and diethylstilbestrol (25 mg/kg) were compared in groups of four female Wistar rats. Each chemical was dissolved in glycerol formal, administered as a single dose by gavage and hepatocytes isolated by collagenase perfusion 24 h later. The cells were cultured in the presence of epidermal growth factor (40 ng/ml) for 48 h, colchicine (10 microg/ml) being added for the final 3 h of incubation. At least 100 chromosomal spreads were examined from each animal for the presence of numerical and structural abnormalities. The incidences of aneuploidy following treatment were: tamoxifen 81%, toremifene 46%, droloxifene 9.6%, diethylstilbestrol 45.7%, vehicle control 5.3%. The incidences of chromosomal structural abnormalities excluding gaps were: tamoxifen 4.3%, toremifene 0.8%, droloxifene 0.5%, diethylstilbestrol 0.8%, control 0.5%. The incidence of chromosomal structural aberrations excluding gaps in the treated animals was not statistically significantly different from controls except in the tamoxifen-treated group. Tamoxifen (35 mg/kg per os) and toremifene (36.3 mg/kg per os) were dosed to rats for 4 weeks and chromosomal spreads made from hepatocytes. The incidences of aneuploidy were: tamoxifen 94%, toremifene 57%, control 6.5%. The incidences of chromosomal aberrations excluding gaps were: tamoxifen 12%, toremifene 1%, control 0.5%. The incidence of tamoxifen-induced chromosomal structural abnormalities was significantly elevated compared with control levels. The results demonstrate that tamoxifen and toremifene are the only two drugs tested in the study that cause chromosomal structural and numerical aberrations in vitro and tamoxifen is the only drug that induces both these effects in rat liver cells stimulated to divide in culture following oral dosing. Since chromosomal mutations require cell division for their manifestation and tamoxifen is the only compound of those tested that causes hyperplasia in the rat liver, chromosomal aberrations and aneuploidy in the rat liver would only be expected to occur following treatment with tamoxifen alone, although aneuploidy could be induced by toremifene in conjunction with a promoter such as phenobarbitone.      

Cytogenetic and molecular genetic analysis of tumorigenic human bronchial epithelial cells induced by radon alpha particles

To establish a cell culture model for lung carcinogenesis, independent populations of the human papillomavirus 18-immortalized human bronchial epithelial cell line BEP2D were treated with high linear energy transfer radon-simulated alpha-particles, expanded and xenotransplanted into Nu/Nu mice. Six independent cell lines were established from tumors that developed from three separate radiation treatments as follows: treatment (Tx) 1 (30 cGy--two doses), H2BT, Tx 2 (30 cGy-- single dose), R30T1L, R30T2 and R30T3L, Tx 3 (30 cGy--single dose), H1ATN and H1ATBA1. Cytogenetic analysis revealed common changes in all tumor lines: loss of the Y chromosome (ch), one of three copies of ch8, one of three copies of ch14, and one of two copies of ch4p16-pter and ch11p15-pter. Analysis of polymerase chain reaction-amplified short tandem repeats of informative loci confirmed the loss of chY in all lines and loss of heterozygosity (LOH) at eight loci spanning the length of ch8 in all lines from Tx's 1 and 2. Our data support previous studies indicating the presence of tumor suppressor genes on ch8. LOH also was confirmed on ch14 at locus D14S306 in all cell lines from Tx 2 and in one of two lines from Tx 3. This region, 14q12-q13, may contain changes in one of the five known somatostatin receptor genes (SSTR1). No LOH was detected at any of the informative loci tested for on ch4 or ch11.      

Overexpression of cyclin D1 correlates with early recurrence in superficial bladder cancers.

Cyclin D1 is a cell cycle regulator essential for G1 phase progression and is frequently overexpressed in several human tumour types as a consequence of gene amplification or chromosomal rearrangements. We analysed the expression of cyclin D1 in 75 patients with transitional cell carcinoma (TCC) to investigate the possible relationship between its expression and clinical outcome as well as histopathological findings using the immunohistochemical method. We observed strong staining (++, > 50% positive cells) for cyclin D1 in 19 cases (25.3%) and weak staining (+, 5-50% positive cells) in 19 cases (25.3%). Overexpression of cyclin D1 was not associated with tumour invasion. No significant association was found between overexpression of cyclin D1 and tumour grade (P > 0.05). We assessed the differences of disease-free interval in superficial tumours and actuarial survival probability in invasive tumours according to the status of cyclin D1 expression. Tumours with (++) staining for cyclin D1 recurred much more rapidly than (-) and/or (+) staining tumours (P < 0.01 for - vs ++; P < 0.05 for + vs ++). However, overexpression of cyclin D1 was not associated with a shortened overall survival of patients with invasive tumours (P < 0.1). These results suggest that genetic alteration of cyclin D1 appears to be an early event in the tumorigenesis of bladder TCC and is associated with early recurrence in superficial tumours.     

4种少见脑膜瘤的临床病理观察

报告４种少见的脑膜瘤亚型：分泌型、微囊型、脂肪瘤和黄色瘤型。临床表现主要有头痛、恶心、轻度呕吐、眼底水肿和肢体功能障碍。形态学：分泌型脑膜瘤以散在多个嗜酸性近圆形包含体为特征，包含体对ＣＥＡ、ＥＭＡ呈特异性表达；微囊性脑膜瘤含微小囊腔状如海绵，囊内含粉染浆液，囊壁由疏松和涡漩状排列之瘤细胞组成；脂肪瘤和黄色瘤型脑膜瘤分别在其瘤组织中含有大量脂肪细胞或泡沫细胞为特征。文中讨论了肿瘤形成机制及鉴别要点。     

卡铂、5－Fu序贯腔内用药治疗癌性腹水

作者对５０例癌性腹水病人应用卡铂．５－Ｆｕ序贯腔内给药治疗，其中完全缓解（ＣＲ）２２例，占４４％，部分缓解（ＰＲ）２４例，占４８％，总有效率（ＣＲ＋ＰＲ）为９２％，毒副作用主要表现为恶心、厌食，偶见低热、腹痛和一过性白细胞下降，表明本疗法对癌性腹水近期疗效高，毒性低、缓解期长，值得在基层医院推广。     

维生素C对阿司匹林的血药浓度及药物动力学的影响

 采用一阶导数光谱法测定水杨酸的血药浓度，研究了口服维生素Ｃ对阿司匹林在兔体内血药浓度及药物动力学的影响。结果表明：水杨酸血药浓度在１０～１４０ｕｇ·ｍｌ－１范围内呈良好的线性关系（ｒ＝０．９９７４），维生素Ｃ对水杨酸血药浓度测定无影响。阿司匹林加维生素Ｃ组的药动学平均参数与单独使用阿司匹林组比较：Ｔ＿（ｍａｘ）值减少（Ｐ＜０．０５），Ｋａ值增大（Ｐ＜０．０１）。维生素Ｃ能加快阿司匹林的吸收，两者联合使用能提早达到治疗浓度，加快了阿司匹林发挥作用。     

血余炭炮制工艺研究

研究结果表明，温度直接影响血余炭的质量，血余炭最佳炮制工艺为３００℃扣锅煅制２０ｍｉｎ，该炮制品的浸出物、钙元素含量高，并具有明显的止血作用。     

Diagnostic value of C-reactive protein in children with perforated appendicitis

The diagnostic value of serum C-reactive protein (CRP) levels in children with perforated appendicitis was prospectively studied in 78 consecutive patients with histologically confirmed appendicitis. The patients were divided into two groups: group A included 56 patients with perforated appendicitis and group B consisted of 22 patients with simple appendicitis. Serum CRP level and leucocyte count were assayed in all and abdominal ultrasonography was performed in 75. The mean age of group A patients was significantly lower than that of group B patients (7.5 vs. 10.4 years,P<0.001). Group A patients had a significantly higher mean serum CRP levels than group B patients (92 vs. 31 mg/l,P<0.001), while the mean leucocyte count was comparable in the two groups. Of 75 examined patients, 73 (97%) had a pre-operative sonographic diagnosis of appendicitis.     

Potential adverse endocrine effects of inhaled corticosteroids

Abstract: Evidence exists for a potential role for inhaled corticosteroids, particularly when used in high dose to cause growth impairment, delayed maturation and adrenal suppression in children and adolescents with asthma. The functional significance of biochemical adrenal suppression remains uncertain. Similarly, there is as yet insufficient evidence to determine whether inhaled corticosteroids may adversely affect bone mineral density in children and adolescents with asthma.