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1.
A striking difference between two structurally related anti-estrogen
medicines is that tamoxifen is strongly hepatocarcinogenic in the rat,
whereas toremifene lacks such activity. To study the basis for this
difference, the initiating potential of tamoxifen and toremifene were
studied by measurement of rapid induction of hepatocellular altered foci
(HAF) that express placental-type glutathione S-transferase in the livers
of female Sprague-Dawley (S-D) rats and female Fischer 344 (F344) rats.
Both agents were administered by gavage at equimolar doses up to a dose
that produced marked weight gain suppression. In rats given the high dose
of 40 mg/kg per day tamoxifen continuously for 36 weeks, 75% of S-D rats
developed liver neoplasms, in contrast to only 10% of F344 rats. In the S-D
strain, tamoxifen produced a tendency to increased HAF at 2 weeks at the
dose of 40 mg/kg per day and by 12 weeks, a dose-related increase was
evident. In contrast, toremifene induced no HAF even at the equimolar high
dose of 42.4 mg/kg per day for 12 weeks. The induction of HAF by tamoxifen
was less in the F344 rats. Neither agent elicited increases in
hepatocellular proliferation in S-D or F344 rats. When phenobarbital was
administered for 24 weeks as a promoting agent after the anti-estrogens,
S-D rats given tamoxifen at 20 mg/kg per day for 12 weeks, developed liver
neoplasms, but not F344 rats or rats of either strain given even a higher
dose (42.4 mg/kg) of toremifene. Thus, tamoxifen has initiating activity in
these rat strains whereas toremifene does not.
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2.
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.
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3.
Dragan Y.P.; Fahey S.; Nuwaysir E.; Sattler C.; Babcock K.; Vaughan J.; McCague R.; Jordan V.C.; Pitot H.C. 《Carcinogenesis》1996,17(3):585-594
Long-term treatment of breast cancer patients with tamoxifenhas prompted concern over potential toxicity of this drug withchronic administration. Since tamoxifen has estrogenic actionin the rat liver and estrogenic agents can increase hepatomaincidence in rats, tamoxifen and two non-isomerizable, fixed-ringanalogs (FRT1 and FRT2) were evaluated as promoting agents ina two-stage model of hepatocarcinogenesis in female FischerF344 rats. The rats were subjected to 70% partial hepatectomyand half of the animals were administered the initiating agent,diethylnitrosamine (DEN; 10 mg/kg body wt), while the otherhalf were not initiated. Groups of initiated and uninitiatedanimals were allowed to recover for 2 weeks and were then administeredtamoxifen or one of the fixed-ring analogs admixed into AIN-76Adiet at 25, 100 or 250 mg/kg diet. After 6 months of anti-estrogenadministration the rats were sacrificed and uterine weights,blood levels of anti-estrogen, and liver histopathology wereassessed. Uterine weights were decreased 2- to 3-fold by eachof the agents, consistent with an anti-estrogenic action inthe rat. The serum levels in rats administered 250 mg anti-estrogen/kg diet for 6 months were 320 ± 20 ng/ml for tamoxifen,320 ± 10 for FRT1 and 350 ± 20 for FRT2. The liverlevels after a 6 month administration of 250 mg antiestrogen/kgdiet were 13 870 ± 860 ng/g for tamoxifen, 13 300 ±860 for FRT1 and 26 900 ± 1900 for FRT2. A dose-dependentincrease in serum and liver level of each compound was notedwhen measured at the 6 month time point. The number and percentageof the liver occupied by altered hepatic foci (AHF) were determinedby quantitative stereology. A dose-dependent increase aboveinitiated controls was observed in the initiated, tamoxifen-treatedrats. Both fixed-ring analogs also increased the number andsize of AHF compared with initiated controls, but were lesspotent than tamoxifen, suggesting that tamoxifen has an intrinsicpromoting action in the liver that is independent of its abilityto isomerize to more potent estrogenic compounds. In addition,the fixed-ring analogs have a weaker promoting activity in therat liver than does tamoxifen. This may be due to pharmacokineticdifferences at the lower two doses, but it is independent ofachieved serum level at the highest dose and hence may reflectdifferences in intrinsic activity of these compounds. Thus tamoxifenand the two fixed-ring analogs promote the development of rathepatocarcinogenesis. 相似文献
4.
Alterations of drug metabolizing and antioxidant enzyme activities during tamoxifen-induced hepatocarcinogenesis in the rat 总被引:3,自引:2,他引:1
The triphenylethylene drug tamoxifen is a hepatocarcinogen inrats, has genotoxic potential and may produce carcinoma of theendometrium in humans, while the structurally closely relatedtoremifene has no carcinogenic or genotoxic potential. We haveinvestigated the effects of long-term treatment with tamoxifenand toremifene on the activities of drug metabolizing and antioxidantenzymes in rat liver. Female Sprague-Dawley rats were dosedwith equimolar doses of tamoxifen (11.3 and 45 mg/kg) and toremifene(12 and 48 mg/kg) for 12 months and were killed after 2 days,5 weeks, 3, 6 and 12 months of treatment. After 12 months mostrats treated with the high dose of tamoxifen had hyperplasticnodules and hepatocellular carcinomas, while in rats given toremifeneor the low dose of tamoxifen, only foci were observed. A strikingobservation was strong inhibition of the hexose monophosphateshunt (HMS) by tamoxifen and toremifene, which, except in thegroup given the high dose of tamoxifen, lasted throughout thetreatment period. Both antiestrogens induced susceptibilityto oxidative stress, as indicated by decreased hepatic contentsof reduced glutathione and by increased peroxidation potentialof microsomal preparations. The activity of glutathione S-transferasewas permanently induced by the high dose of tamoxifen from 5weeks onwards and was greater in tamoxifen-induced liver tumorsthan in corresponding macroscopically normal tissue. Similarly,the activity of HMS was elevated by the high dose of tamoxifenat the latest time points, and a further elevation was seenin tamoxifen-induced liver tumors. No such alteration in glutathioneS-transferase or HMS activity was seen in animals treated withtoremifene or with the low dose of tamoxifen. In conclusion,tamoxifen and toremifene differ markedly with respect to productionof liver tumors, and this difference in hepatocarcinogenic potentialis reflected in differential effects on glutathione-S-transferaseand HMS activities in rat liver. 相似文献
5.
Genotoxic effects of the novel mixed antiestrogen FC-1271a in comparison to tamoxifen and toremifene
Hellmann-Blumberg U Taras TL Wurz GT DeGregorio MW 《Breast cancer research and treatment》2000,60(1):63-70
Tamoxifen has been used for the treatment of breast cancer since the 1970s, but is considered a carcinogen because it has been linked to liver cancer in rats and an increased risk of endometrial cancer in patients. In rats, DNA adducts appear to be responsible for carcinogenesis, but their contribution to carcinogenesis in humans is not clear. FC-1271a and toremifene are mixed antiestrogens similar to tamoxifen. In order to compare the genotoxicity of these different triphenylethylenes, we treated mice for 28 days with 50 mg/kg of either tamoxifen, toremifene, FC-1271a or vehicle control. DNA from liver and uterus was assayed by standard 32P-postlabeling and thin layer chromatography for the presence of DNA adducts. Two methods of drug administration (oral and subcutaneous) and two strains of mice were compared and the plasma and tissue concentrations of the drugs and three metabolites of tamoxifen and toremifene were determined. Regardless of the conditions, only tamoxifen-treated mice showed DNA adducts in the liver. Adduct levels did not correlate with drug or metabolite levels and adducts were present even when drug was not detectable. Mice were also treated orally with either 50, 100, or 200 mg/kg of drug for 7 days. Again, adducts were found only in liver tissue of mice treated with tamoxifen, and adduct levels were dose-dependent. In conclusion, the chlorinated triphenylethylene FC-1271a did not cause DNA adducts under various conditions in mice, suggesting a low carcinogenic potential. 相似文献
6.
Studies of tamoxifen as a promoter of hepatocarcinogenesis in female Fischer F344 rats 总被引:3,自引:0,他引:3
Yvonne P. Dragan Susan Fahey Kellee Street Jennifer Vaughan V. Craig Jordan Henry C. Pitot 《Breast cancer research and treatment》1994,31(1):11-25
Tamoxifen, an antiestrogen used in the treatment of breast cancer, was assessed for carcinogenic potential in the two-stage model of experimental hepatocarcinogenesis. Groups of female Fischer F344 rats were initiated with a non-necrogenic, subcarcinogenic dose of diethylnitrosamine (DEN; 10 mg/kg, po) and fed tamoxifen at a concentration of 250 mg per kg of AIN-76A diet for 6 or 15 months. The livers of these animals exhibited an increase in size and number of altered hepatic foci compared with those animals which were initiated with DEN but not exposed to tamoxifen. This finding indicates that tamoxifen may have a carcinogenic potential in the rat liver. After 6 months of treatment, neoplastic nodules were observed in 3/8 rats in the DEN-initiated, tamoxifen-treated group. In the initiated group provided with tamoxifen for 15 months, neoplastic nodules were observed in 7/8 rats and hepatocellular carcinomas in 3/8 rats. The serum level of tamoxifen in these rats was 200–300 ng/ml. The ratio of tamoxifen, 4-hydroxy tamoxifen, and N-desmethyl tamoxifen was 1:0.1:0.5-1 in the serum. When adjusted for age-related weight increases, the serum and liver levels of tamoxifen and its N-desmethyl metabolite did not change over the 15 months. In the rat liver, the level of tamoxifen and its N-desmethyl metabolite was 10-29 µg/g liver after 6 or 15 months of chronic dietary administration. The ratio of tamoxifen:4-hydroxy tamoxifen:N-desmethyl tamoxifen was 1:0.1:1.3-2.3 in the liver. Therefore, the liver had 20- to 30-fold more tamoxifen and 4-hydroxy tamoxifen and at least 100-fold more N-desmethyl tamoxifen than the serum (assuming 1 gram of tissue is equivalent to 1 ml of serum). These results indicate that tamoxifen is a promoting agent for the rat liver at serum levels found in patients given the usual therapeutic course of tamoxifen. The high concentrations of tamoxifen attained in the rat liver indicate that actions other than its known estrogenicity for liver could contribute to its promoting action. In addition, these results indicate that the pharmacodynamic differences in tamoxifen metabolism in rats and humans and at low versus high doses should be determined. Thus, the therapeutic indications for tamoxifen should be balanced by the potential risk it may present as a promoting agent in mammalian liver. 相似文献
7.
Genotoxic potential of tamoxifen and analogues in female Fischer F344/n rats, DBA/2 and C57BL/6 mice and in human MCL-5 cells. 总被引:10,自引:0,他引:10
I N White F de Matteis A Davies L L Smith C Crofton-Sleigh S Venitt A Hewer D H Phillips 《Carcinogenesis》1992,13(12):2197-2203
Chronic administration of tamoxifen to female rats causes hepatocellular carcinomas. We have investigated damage to liver DNA caused by the administration of tamoxifen to female Fischer F344/N rats or C57B1/6 or DBA/2 mice using 32P-postlabelling. Following the administration of tamoxifen for 7 days (45 mg/kg/day) and extraction of hepatic DNA, up to 7 radiolabelled adduct spots could be detected after PEI-cellulose chromatography of the 32P-labelled DNA digests. Tamoxifen caused a time-dependent increase in the level of adduct detected up to a value of at least 1 adduct/10(6) nucleotides after 7 days dosing. A dose response relationship was demonstrated over the range of 5-45 mg/kg/day (0.013-0.12 mmol/kg/day). On cessation of dosing there was a loss of adducts from the liver DNA. These adducts were not detected in DNA from vehicle-dosed controls or in DNA from kidney, lung, spleen, uterus or peripheral lymphocytes. Pyrrolidinotamoxifen caused a similar level of adduct formation as tamoxifen. In contrast, no significant adduct formation could be detected in liver DNA from rats given droloxifene or toremifene. Mice given tamoxifen (45 mg/kg/day for 4 days) showed levels of adducts in the liver which were 30-40% of those present in rats. Exposure of rat hepatocytes to tamoxifen in vitro, resulted in induction of unscheduled DNA synthesis, when preparations from rats which had been pretreated with tamoxifen in vivo were used. No such increase could be detected in hepatocytes from control rats, suggesting tamoxifen may induce enzymes responsible for its own activation. Tamoxifen induced a significant increase in micronucleus formation in a dose dependent manner in cultures of MCL-5 cells, a human cell line that expresses 5 different human cytochrome P450 isoenzymes, as well as epoxide hydrolase. 相似文献
8.
T Shirai K Imaida M Ohshima S Fukushima M S Lee C M King N Ito 《Japanese journal of cancer research》1985,76(1):16-19
The promoting activities of phenobarbital (PB) on the development of gamma-glutamyl-transpeptidase-positive (gamma-GT+) foci in rat liver with three different initiating agents were compared in a short-term system (8 weeks). Male F344 rats were initiated by a single application of 200 mg/kg of diethylnitrosamine (DEN), 30 mg/kg of N-hydroxy-2-acetylaminofluorene (N-OH-AAF), 1.0 or 0.5 mg/kg of aflatoxin B1 (AFB1) or the vehicles alone. Two weeks after the initiation, animals were placed on a 0.05% PB diet for 6 weeks. Partial hepatectomy was performed at the end of the third week of the experiment. As a positive control, some animals were fed diet containing 0.06% 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) after the initiation. The number and area of gamma-GT+ foci in the liver were quantified. All three initiators showed a summation effect with 3'-Me-DAB on the appearance of gamma-GT+ foci. Promotion by PB, however, was observed only in DEN-initiated rats and not in N-OH-AAF- or AFB1-initiated rats. It is apparent from the present experimental data that the promoting potential of PB on liver carcinogenesis depends on the initiating agent. 相似文献
9.
Characterization of the promotion of altered hepatic foci by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the female rat. 总被引:1,自引:0,他引:1
Y P Dragan X H Xu T L Goldsworthy H A Campbell R R Maronpot H C Pitot 《Carcinogenesis》1992,13(8):1389-1395
Previous studies have suggested that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) acts as a promoting agent in various organ systems including the rat liver. Since a major characteristic of the stage of tumor promotion is its operational reversibility, we have assessed whether TCDD-induced promotion is reversible in a two-stage model of hepatocarcinogenesis. In this model, female Fischer F344 rats were administered a single, intragastric dose of the initiating agent, diethylnitrosamine (DEN, 10 mg/kg), at the peak of proliferation induced by a partial hepatectomy. TCDD was then administered biweekly (0.14 micrograms/kg, s.c.) for 1, 3 or 5 months. One group of animals was killed at each of these time points, while a second group was maintained for each time point for an additional 6 months in the absence of further TCDD. Four serial frozen sections of liver were each stained with a different enzyme marker of altered hepatic foci (AHF). The AHF were identified and the number and volume fraction determined by quantitative stereology. Exposure to TCDD resulted in an increase in the number and size of AHF in the initiated relative to the uninitiated rats. Increasing the duration of promotion with TCDD led to an increase in the number of AHF per liver, the volume fraction of the liver occupied by AHF and the number of markers expressed aberrantly by a single AHF. Discontinuation of TCDD administration for 6 months before killing the animals resulted in a decrease in the total number of AHF observed, but those AHF that remained increased in size with an overall increase in volume fraction of AHF. Analysis of the size class distribution for AHF for each of the periods of TCDD promotion revealed an increase in the larger AHF but a decrease in the smaller, thereby resulting in an overall decrease in number of AHF with an increase in the volume fraction of AHF. Increasing the duration of the TCDD exposure prior to its withdrawal led to an increased AHF size, phenotypic complexity and number of AHF remaining after cessation of TCDD administration. Although the levels of TCDD in livers of rats 6 months after cessation of TCDD administration were still greater than background, they were markedly reduced compared to immediately after administration. Thus, cessation of exposure to TCDD after a brief duration led to a reversal of its promotional effects on the majority of AHF, while prolonged exposure led to maintained promotion of a minority of AHF. 相似文献
10.
The effect of the dose of diethylnitrosamine on the initiation of altered hepatic foci in neonatal female rats 总被引:1,自引:0,他引:1
The doseresponse characteristics of initiation of hepatocarcinogenesisby diethylnitrosamine (DEN) was investigated in the neonatalfemale rat by means of the quantitative stereologic estimationof altered hepatic foci (AHF) expressing multiple markers. At5 days of age, female SpragueDawley rats were given asingle i.p. dose of DEN (0.130 mg/kg body wt) or thevehicle (trioctanoin). The semisynthetic AIN-76A diet was providedto half of the rats in each treatment group, while the remainderreceived this diet containing 500 mg phenobarbital (PB)/kg for8 months from weaning until the animals were killed. To ascertainmore exactly the doseresponse relationship for initiationby DEN, the number, volume percentage and phenotypes of theresulting AHF were determined by quantitative stereologicalanalysis on serial sections of frozen tissue, each stained forone of four markers of preneoplasia. A linear relationship wasobserved between the dose of DEN (030 mg/kg) and thenumber and volume percentage of AHF detected, with each singlemarker or the total number of AHF detected when the placentalisozyme of glutathione S transferase, 相似文献
11.
Female F344/N rats were given 70% partial hepatectomies and intubated with diethyl-nitrosamine (DEN, 10 mg/kg) 24 hours later. They were fed a cereal-based diet, NIH-07 (NIH) + 0.05% phenobarbital (PB) for 6 months, at which time NIH + PB was withdrawn and the rats were ovariectomized (OV) or sham-operated (SH). Groups of 7-10 rats were fed a semipurified diet (AIN-76) for 1 or 2 months after withdrawal of NIH + PB, or NIH + PB for 2 months, or AIN-76 diet for 1 month and subsequently NIH + PB for 1 month. Placental glutathione S-transferase (PGST)- and gamma-glutamyltransferase (GGT)-positive (+) altered hepatic foci (AHF) were analysed by quantitative stereology. Ovariectomy stimulated growth of AHF after withdrawal and reintroduction of NIH + PB. AHF, especially PGST+ AHF, continued to regress throughout the PB withdrawal period in rats fed AIN-76 diet. In most studies of chemical hepatocarcinogenesis, females have been shown to develop a greater volume of AHF than males. In our study, however, ovariectomy stimulated the growth of AHF after withdrawal and reintroduction of PB. Because AHF occurring spontaneously in male rats develop more rapidly than in female rats, the greater rate of growth of AHF in OV female rats may reflect a similar mechanism. 相似文献
12.
H P Glauert D Beer M S Rao M Schwarz Y D Xu T L Goldsworthy J Coloma H C Pitot 《Cancer research》1986,46(9):4601-4606
The effect of feeding hypolipidemic peroxisome proliferators on the induction of altered hepatic foci (AHF) in Fischer rats was studied in order to determine whether such agents can induce or promote the development of AHF. In the first study, rats were fed ciprofibrate (10 mg/kg/day) for 1 yr. AHF, neoplastic nodules, and hepatocellular carcinomas were induced. The presence of putative gamma-glutamyltranspeptidase (GGT) activity was numerically the most common marker, although it was absent in larger foci and nodules. A deficiency in canalicular ATPase and glucose-6-phosphatase provided the best markers for the larger foci and nodules. In the second study, rats were subjected to partial hepatectomy, and half of the animals were then intubated with diethylnitrosamine (10 mg/kg). One wk later, rats were fed Wy-14,643 at concentrations of 0, 0.05, and 0.1% in the diet for 6 mo. At 6 mo, the number and volume of foci were increased by the feeding of Wy-14,643 after partial hepatectomy alone and were greatly increased when Wy-14,643 was fed after partial hepatectomy/diethylnitrosamine administration. Canalicular adenosine triphosphatase and glucose-6-phosphatase deficiencies were the most common markers of AHF, and AHF of these phenotypes occupied practically all of the focal volume. The larger AHF did not express GGT, and those foci exhibiting GGT were much less common and occupied very little volume. The absence of the GGT protein itself, as opposed to an inhibition of GGT activity, was verified by immunohistochemical staining using an antibody to GGT. These studies show that hypolipidemic peroxisome proliferators can stimulate an increase in AHF following a single dose of diethylnitrosamine and a mitotic stimulus, and they thus can act as promoters in two-stage liver carcinogenesis. GGT is a poor marker for identifying AHF induced by peroxisome proliferators during the early, premalignant phase of hepatocarcinogenesis. 相似文献
13.
R C Moon G J Kelloff C J Detrisac V E Steele C F Thomas C C Sigman 《Anticancer research》1992,12(4):1147-1153
The chemopreventive efficacies of the retinoid all-trans-N-(4-hydroxyphenyl)-retinamide (4-HPR) and the anti-estrogen tamoxifen citrate were evaluated against N-methyl-N'-nitrosourea (MNU) induced mammary cancer in 120-day old female Sprague-Dawley rats. The agents were tested alone and in combination. They were administered in a modified AIN-76A diet, beginning 60 days prior to a single i.v. dose of 50 mg MNU/kg-bw and continuing until the end of the study, 180 days post-carcinogen treatment. At 782 mg/kg diet, 4-HPR alone significantly inhibited the induction of mammary adenocarcinomas compared with carcinogen controls. At 0.250 mg/kg diet, tamoxifen alone reduced tumor incidence compared with carcinogen controls. At 0.125 mg/kg diet, tamoxifen was ineffective. Combinations of 782 mg 4-HPR/kg diet with either 0.250 or 0.125 mg tamoxifen/kg diet were effective in inhibiting MNU-induced adenocarcinomas. The reductions in tumor incidence were greater for these combinations than for either agent alone. 4-HPR and 0.250 mg tamoxifen/kg diet decreased tumor incidence 81% (p less than 0.005), whereas 4-HPR and 0.125 mg tamoxifen/kg diet decreased tumor incidence 72% (p less than 0.005) compared with carcinogen controls. The combination of 391 mg 4-HPR/kg diet and 0.500 mg tamoxifen/kg diet was also tested and was effective in reducing tumor incidence. 相似文献
14.
Sargent L.M.; Dragan Y.P.; Sattler C.; Bahnub N.; Sattler G.; Martin P.; Cisneros A.; Mann J.; Thorgeirsson S.; Jordan V.C.; Pitot H.C. 《Carcinogenesis》1996,17(5):1051-1056
Since tamoxifen is efficacious for the prevention of secondprimary breast neoplasms in humans and has a low reported incidenceof acute side effects, several structurally related compoundshave been developed for the treatment of breast cancer includingtoremifene and idoxifene. We have compared the karyotypic alterationsthat occur after a single per os administration of 35 mg/kgof tamoxifen, toremifene or idoxifene to female Sprague-Dawleyrats. One day following treatment, the rats were sacrificedand the hepatocytes isolated and cultured. After 47 h in culture,colcemid was added for 3 h prior to harvest of the hepatocytesfor karyotypic evaluation. At least 100 metaphase spreads wereexamined for each of five rats per treatment. Toremifene resultedin aneuploidy in 50±7% of the cells examined and idoxifeneinduced a 57±4% aneuploidy compared with the 85±7%level induced by tamoxifen. Since the level of aneuploidy insolvent-treated rats was 3±3%, the induction of aneuploidyin at least 50% of the cells from rats treated with tamoxifen,toremifene or idoxifene was highly significant Analysis of electronmicrographs of cultures treated with these antiestrogens demonstrateda range of phenotypes including multipolar spindles in toremifene-treatedrats and condensed chromosomes in the presence of an intactnuclear envelope in occasional idoxifene-treated rat hepatocytes.The exclusion of chromosomes from the spindle apparatus andthe lagging of some chromosomes on the metaphase plate correlatewith the high rate of induction of aneuploidy in the rat liveras determined by karyotypic analysis of hepatocytes from ratstreated with these triphenylethylenes. 相似文献
15.
Tamura K; Nakae D; Horiguchi K; Akai H; Kobayashi Y; Andoh N; Satoh H; Denda A; Tsujiuchi T; Yoshiji H; Konishi Y 《Carcinogenesis》1997,18(11):2133-2141
The effects of N-(4-hydroxyphenyl)retinamide (4-HPR) and all-trans-
retinoic acid (tRA) on the exogenous and endogenous models of rat liver
carcinogenesis respectively using diethylnitrosamine (DEN) and a
choline-deficient, L-amino acid-defined (CDAA) diet were studied. For the
exogenous study, male Fischer 344 rats, 6 weeks old, were given a single
i.p. dose of 200 mg/kg body wt of DEN, partially hepatectomized at week 3,
administered 4-HPR at doses of 0, 0.04, 0.08 and 0.16% or tRA at 0, 0.004,
0.008 and 0.015% in diet from week 2 for 6 weeks, and killed at the end of
week 8. For the endogenous study, rats were fed the CDAA diet containing
4-HPR or tRA for 12 weeks and killed at the end of week 12. 4-HPR decreased
the numbers and sizes of the glutathione S-transferase placental
form-positive foci, assayed as putative preneoplastic lesions, the levels
of 8-hydroxyguanine (8-OHG), a parameter of oxidative DNA damage, and the
bromodeoxyuridine labeling indices (BrdU L.I.) by all three doses in the
DEN-initiated case and, more prominently, in the CDAA diet-associated case.
In contrast, while tRA failed to exert inhibitory effects apparently on
foci development, 8-OHG formation or BrdU labeling in the DEN-initiated
case, it reduced the numbers and sizes of the foci, the 8-OHG levels and
the BrdU L.I. by all three doses in the CDAA diet-associated case.
Furthermore, both 4-HPR and tRA inhibited the CDAA diet-associated
induction of hepatocyte necrosis and connective tissue increase but not
intrahepatocellular fat accumulation. These results indicate that 4-HPR
exerts chemopreventive effects against the exogenous and endogenous rat
liver carcinogenesis, while tRA can inhibit only the latter.
相似文献
16.
Prospective study on gynaecological effects of two antioestrogens tamoxifen and toremifene in postmenopausal women 总被引:4,自引:0,他引:4
Marttunen MB Cacciatore B Hietanen P Pyrhönen S Tiitinen A Wahlström T Ylikorkala O 《British journal of cancer》2001,84(7):897-902
To assess and compare the gynaecological consequences of the use of 2 antioestrogens we examined 167 postmenopausal breast cancer patients before and during the use of either tamoxifen (20 mg/day, n = 84) or toremifene (40 mg/day, n = 83) as an adjuvant treatment of stage II-III breast cancer. Detailed interview concerning menopausal symptoms, pelvic examination including transvaginal sonography (TVS) and collection of endometrial sample were performed at baseline and at 6, 12, 24 and 36 months of treatment. In a subgroup of 30 women (15 using tamoxifen and 15 toremifene) pulsatility index (PI) in an uterine artery was measured before and at 6 and 12 months of treatment. The mean (+/-SD) follow-up time was 2.3 +/- 0.8 years. 35% of the patients complained of vasomotor symptoms before the start of the trial. This rate increased to 60.0% during the first year of the trial, being similar among patients using tamoxifen (57.1%) and toremifene (62.7%). Vaginal dryness, which was present in 6.0% at baseline, increased during the use of tamoxifen (26.2%) and toremifene (24.1%). Endometrial thickness increased from baseline (3.9 +/- 2.7 mm) to 6.8 +/- 4.2 mm at 6 months (P< 0.001), and no difference emerged between the 2 regimens in this regard. Before the start of the antioestrogen regimen, the endometrium was atrophic in 71 (75.5%) and proliferative in 19 of 94 (20.2%) samples; 4 patients had benign endometrial polyps. During the use of antioestrogen altogether 339 endometrial samples were taken (159 in tamoxifen group, 180 in toremifene group). The endometrium was proliferative more often in the tamoxifen group (47.8%) than in the toremifene group (32.2%) (P< 0.0001). 20 patients had a total of 24 polyps (17 in tamoxifen and 9 in toremifene group, P< 0.05) during the use of antioestrogens. One patient in the toremifene group developed endometrial adenocarcinoma at 12 months, and one patient had breast cancer metastasis on the endometrium. Tamoxifen failed to affect the PI in the uterine artery, but toremifene reduced it by 15.0% (P< 0.05) by 12 months. In conclusion, tamoxifen and toremifene cause similarly vasomotor and vaginal symptoms. Neither regimen led to the development of premalignant endometrial changes. Our data suggest that so close endometrial surveillance as used in our study may not be mandatory during the first 3 years of use of antioestrogen treatment. 相似文献
17.
Saito Y Amano S Kashio M Abe H Kuboi Y Sakurai K Aoki N Hata S Negishi N 《Gan to kagaku ryoho. Cancer & chemotherapy》2004,31(6):911-914
We report a 64-year-old woman who underwent mastectomy for stage II (T2N1M0) advanced breast cancer, in whom multiple spine metastases developed 18 months postoperatively. She received 6 cycles of CA (cyclophosphamide 500 mg/m2, ADM 50 mg/m2 3 wq) therapy and oral tamoxifen (20 mg/body) administration for adjuvant therapy. The multiple bone metastases of the spine were revealed by technetium bone scan. The level of serum tumor marker CA15-3 increased two times over the normal range 18 months after surgery. She also developed osteoporosis a few years later, so we selected high-dose toremifene administration (120 mg/body) as a second-line therapy. No adverse effects have occurred and bone metastases disappeared. Moreover, the tumor marker was also normalized 6 months after toremifene therapy started. It was shown that high-dose treatment of toremifene was useful for recurrent breast cancer with bone metastasis. 相似文献
18.
The effects of the short-term withdrawal of phenobarbital (PB)and of the feeding of purified diets during the long-term withdrawalof dietary PB on the stability of altered hepatic foci (AHF)were studied. In both experiments female CD rats initially receivedan intragastric dose of diethylnitrosamine (10 mg/kg) 20 h afterbeing subjected to partial hepatectomy. In the short-term studyrats were fed 0.05% PB in a cerealbased diet for 6 months; atthis time half of the rats were killed, whereas the other halfwere withdrawn from PB for 10 days before sacrifice. WithdrawingPB for 10 days resulted in a decrease in the number and volumeof AHF, particularly those which stained positively for gamma-glutamyltranspeptidase(GGT). In the long-term experiment rats were fed 0.05% phenobarbitalin a cereal-based diet for 3 months; they were then withdrawnfrom the cereal-based diet containing PB and fed either a low-fator a high-fat purified diet without PB for 8 months. At thistime the number and volume of AHF were much less than that seenat the time of PB withdrawal. In addition, the distributionof phenotypes was altered: the percentage of foci containingGGT as a marker decreased dramatically. These results indicatethat certain phenotypic characteristics of AHF, specificallytheir observable number and total volume, rapidly decrease afterthe withdrawal of PB from rats fed a cereal-based diet and thatthe feeding of purified diets after such PB withdrawal doesnot result in the reappearance of AHF. These studies suggestthat the phenotype, volume and observable number of AHF maychange in the absence of PB as compared with its presence inthe diet and that some cereal-based diets may contain unspecifiedagents which stabilize or enhance the phenotypicappearance of AHF. 相似文献
19.
目的 探讨托瑞米芬 (TOR)在乳腺癌术后辅助治疗中对血脂的影响程度。方法 10 3例乳腺癌患者分为治疗组和对照组。治疗组包括TOR组和TAM组 ,TOR组口服TOR 60mg/天 ,TAM组口服TAM 2 0mg/天。在内分泌治疗前 ,治疗 3、6、9和 12个月后 ,分别晨取患者空腹静脉血进行血脂检测。结果 TOR治疗组血总胆固醇平均水平下降 11.0 % ,S LDL平均水平下降 11.1% ,血甘油三酯平均水平下降 10 .7% ;TAM治疗组血总胆固醇平均水平下降 9.0 % ,S LDL平均水平下降 17.4% ,而血甘油三酯水平无明显变化 (P =0 .491)。结论 TOR对血脂的影响程度与TAM相近 ,2组血总胆固醇和S LDL平均水平均较治疗前下降。不同的是 ,TOR治疗组血甘油三酯水平下降 ,而TAM治疗组无明显变化。提示TOR可影响与冠心病发病相关的血脂水平。 相似文献
20.
Incorporation of bromodeoxyuridine in glutathione S-transferase-positive hepatocytes during rat multistage hepatocarcinogenesis 总被引:1,自引:0,他引:1
Cell proliferation is pivotal to all stages of the carcinogenesisprocess and is one of the primary characteristics of the promotionstage of cancer development. Both a two-stage model of initiationand promotion for analysis of early preneoplasia and a three-stageinitiation-promotion-progression model of hepatocarcinogenesiswere used to address the effect of the liver tumor-promotingagent phenobarbital (PB) on hepatic cellular proliferation.Male rats were subjected to a 70% partial hepatectomy and 10mg diethyInitrosamine (DEN)/kg or the solvent alone and wereadministered PB for 48 months. Analysis of bromodeoxyuridine(BrdU) incorporation (1 h pulse) in liver within (focal) andnot with in (non-focal) altered hepatic foci (AHF) demonstrateda labeling index in AHF of 2% in DEN-initiated rats; the non-focallabeling index of placental glutathione S-transferase expressinghepatocytes was 0.30.6%. The focal labeling index wasconstant over the 8 month period of promotion. Inasmuch as onecharacteristic of promotion is the reversibility of the inducedeffects on clonal expansion of initiated cells, groups of ratsinitially promoted with PB were maintained in the absence ofcontinued promotion for 4 or 8 months prior to being killed.Assessment of the focal labeling index after cessation of PBtreatment indicated a drop in the index from 2.3% to 0.7%. Whena progressor agent, ethylnitrosourea, was given at the timePB was discontinued for 4 or 8 months, a significant changein focal labeling index was not observed relative to the indexin AHF when the animals were killed immediately after 8 monthsof PB promotion. Thus, cell proliferation plays an integralrole in both the promotion and progression stages of multistagerat hepatocarcinogenesis and is influenced by administrationof promoting and progressor agents. 相似文献