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41.
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.
相似文献
42.
Ki-ras mutations are an early event and correlate with tumor stage in transplacentally-induced murine lung tumors 总被引:2,自引:2,他引:2
Leone-Kabler S; Wessner LL; McEntee MF; D'Agostino RB Jr; Miller MS 《Carcinogenesis》1997,18(6):1163-1168
A previous study from this laboratory demonstrated that treatment of
pregnant mice with 3-methylcholanthrene (MC) caused lung tumors in the
offspring at 1 year after birth, the incidence of which correlated with
fetal inducibility of Cyp1a1. Analysis by PCR amplification and allele-
specific hybridization (ASO) of paraffin-embedded tumors generated from
that study revealed the presence of point mutations in exon 1 of the Ki-
ras gene. This work has now been expanded by PCR amplification and ASO
analysis of 31 additional lesions. Point mutations were found in 37 of the
47 (79%) lesions analyzed in this and the previous study, the majority of
which were G-->T transversions in the first or second base of codon 12.
The mutational spectrum appeared to be dependent on the relative stage of
differentiation of the lesion, as both the incidence of mutation and type
of mutation produced correlated with malignant progression. Mutations
occurred in 60% of the hyperplasias, 80% of the adenomas and 100% of the
adenocarcinomas. In the lesions with mutations, GLY12-->CYS12
transversions occurred in 100% of the hyperplasias, 42% of the adenomas and
14% of the adenocarcinomas. The GLY12-->VAL12 transversions occurred in
none of the hyperplasias, 42% of the adenomas and 57% of the
adenocarcinomas. The remaining mutations, which consisted of ASP12
transitions and ARG13 transversions, occurred only in adenomas (17%) and
adenocarcinomas (29%). Between this study and our previous analyses, the
identity of the mutations obtained by ASO were confirmed by sequence
analysis of eight of the 37 lesions that harbored mutations at the Ki-ras
gene locus. There were no differences in the type or incidence of mutations
relative to the metabolic phenotype or sex of the mice. These data suggest
that mutational activation of the Ki-ras gene locus is an early event in
transplacental lung tumorigenesis, and that the type of mutations produced
by exposure to chemical carcinogens can influence the carcinogenic
potential of the tumor. This may have prognostic significance in
determining the malignant progression of the neoplasm.
相似文献
43.
ABSTRACT An unusual presentation of acute lymphoblastic leukaemia (ALL) in a 6-year-old girl is reported. She presented with unilateral cervical lymphadenopathy, a mixed obstructive/cholestatic jaundice and a progressive pancytopenia. Ultrasound examination revealed an obstructed common bile duct with gross thickening of the wall of the duct and intrahepatic bile duct dilatation. The jaundice resolved with high dose intravenous (i.v.) methylprednisolone. It is postulated that this was due to infiltration of the common bile duct, given the failure to demonstrate any other cause for the bile duct pathology. 相似文献
44.
45.
46.
THE GAUZE-HAMMOCK OPERATION 总被引:1,自引:0,他引:1
47.
Absence of microdeletions in the Y chromosome in patients with a history of cryptorchidism and azoospermia or oligospermia 总被引:6,自引:0,他引:6
OBJECTIVE: To determine if cryptorchidism is associated with microdeletions of interval 6 of the Y chromosome, we evaluated this locus in men with a history of cryptorchidism with and without azoospermia or oligospermia and in a control group. DESIGN: Clinical study. SETTING: Academic research environment. PATIENT(S): Men in whom surgical treatment of cryptorchidism had been performed in childhood and healthy control male subjects. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genotyping of interval 6 of the Y chromosome. RESULT(S): Analysis of semen obtained from men treated for cryptorchidism in childhood showed azoospermia or oligospermia in 14 of 38 (37%) men. No microdeletions were identified with polymerase chain reaction amplification of 17 distinct sequence tagged sites located on the long arm of the Y chromosome and the sex determining region on Y (SRY) gene. CONCLUSION(S): Microdeletions of interval 6 of the Y chromosome were not detected in either the formerly cryptorchid or in the healthy subjects. Although we cannot exclude the possibility of point mutations, we conclude that cryptorchidism or cryptorchidism associated with azoospermia or oligospermia is not due to microdeletions involving interval 6 of the Y chromosome. 相似文献
48.
宁国贝母生物碱的分离和结构鉴定 总被引:2,自引:0,他引:2
从贝母新种——宁国贝母(Fritillaria ningguoensis S. C. Chen et S. F. Yin)鳞茎中分离出五个生物碱,其中碱V是一种新的生物碱,命名为宁贝新(ningpeisine),根据理化常数和光谱解析以及衍生物制备,测定其结构为N-methyl-3β-hydroxy-5α-veratranine-6-one。其余四种生物碱鉴定为浙贝甲素(peimine,verticine,Ⅰ),浙贝乙素(peiminine,verticinone,Ⅱ),异浙贝甲素(isoverticine,Ⅲ)和贝母辛(peimisine,Ⅳ)。 相似文献
49.
J. KRØLL 《Scandinavian journal of immunology》1993,37(3):381-383
Insulin monomers and polymers were analysed by quantitative immunoelectrophoretic procedures. The Zn-insulin hexamer dissociated reversibly by dialysis against the Zn-free electrophoresis buffer. The Zn-insulin polymers showed precipitin reactions of partial identity. Monomeric salt-free insulin migrated as soluble immune complexes in the antiserum gel. The insulin monomer did not absorb the precipitating antibodies against the Zn-insulin polymers. Thus the polymer structure creates antigenic epitopes absent from the insulin monomer. As insulin is probably released from the β cells in the relatively stable form of Zn-insulin hexamers, selective monomer assays might underestimate the total content of immunoreactive insulin in the biological fluids. Electroimmunoassay of Zn-insulin immunoreactive antigens in human urine defines a normal reference range of 10–25 ng/ml. 相似文献
50.
ABSTRACT. Longitudinal bone growth in rabbits during treatment with hydrocortisone was measured by means of Roentgen Stereophotogrammetric Analysis, RSA. This method allows accurate measurement of the distance between metallic markers inserted into long bones. Hydrocortisone was given in i.m. injections as single doses and as repeated doses, daily or every other day. Single injections of hydrocortisone resulted in three types of growth effect, depending on dosage. Low dosage (less than 4 mg/kg b.w.) produced no blunting of growth. Intermediate dosage (4–32 mg/kg b.w.) retarded growth during the first but not the second day after the injection. The effect of high dosage (64–128 mg/kg b.w.) lasted for two days. During daily treatment (4 and 16 mg/kg b.w.), growth decreased to a constant level. During alternate-day steroid injections with a double dose every other day, growth almost normalized during the steroid-free days. Average growth was significantly greater during alternate-day injections than during daily injections. It is concluded that alternate-day treatment has no unfavorable effect on growth so long as the interval between injections exceeds the duration of the growth effect of each single dose. 相似文献