Radiation shielding analysis of a special linear accelerator for electron beam and X-ray.

The King AbdulAziz City for Science & Technology in the Kingdom of Saudi Arabia plans to build a 10 MeV, 15 kW linear accelerator (LINAC) for electron beam and X-ray. The accelerator will be supplied by EB Tech, Republic of Korea, and the design and construction of the accelerator building will be conducted in the cooperation with EB Tech. This report presents the shielding analysis of the accelerator building using the Monte Carlo N-Particle Transport Code (MCNP). In order to improve the accuracy in estimating deep radiation penetration and to reduce computation time, various variance reduction techniques, including the weight window (WW) method, the deterministic transport (DXTRAN) spheres were considered. Radiation levels were estimated at selected locations in the shielding facility running MCNP6 for particle histories up to 1.0×10+8. The final results indicated that the calculated doses at all selected detector locations met the dose requirement of 50 mSv/yr, which is the United State Nuclear Regulatory Commission (U.S. NRC) requirement.

[Relationship between ATP-binding cassette subfamily B member 1 and cytochrome P450 2C19 polymorphisms and the effect of clopidogrel post percutaneous coronary intervention in patients with acute coronary syndrome].

OBJECTIVE: To observe the relationship between ATP-binding cassette subfamily B member 1 (ABCB1) and cytochrome P450 (CYP)2C19 polymorphisms and the effect of clopidogrel post percutaneous coronary intervention in patients with coronary artery disease. METHODS: A total of 300 consecutive patients with acute coronary syndrome undergoing selected percutaneous coronary intervention in General Hospital of the People's Liberation Army from October 2010 to August 2012 and treated with clopidogrel were enrolled and retrospectively analyzed. Antiplatelet responsiveness of clopidogrel was estimated by thrombelastograph. The patients were divided into 3 groups: remarkable efficacy group (adenosine diphosphate pathway inhibition rate >80%, 105 cases), effective group (adenosine diphosphate pathway inhibition rate of 50%-80%, 100 cases), and poor responsiveness group (adenosine diphosphate pathway inhibition rate <50%, 95 cases). CYP2C19 and ABCB1 polymorphisms were detected by PCR combined with restrictive fragment length polymorphism (PCR-RELP) method in all patients. A total of 200 patients were performed by high performance liquid chromatography with electrospray tandem mass spectrum methods (HTLC-MS/MS), which was applied for determining the plasma concentration level of clopidogrel metabolites between remarkable efficacy group and poor responsiveness group. Major adverse cardiovascular events and bleeding events were observed through follow-up. RESULTS: (1) There were significantly differences in gender, smoking and alanine transaminase level among 3 groups(P<0.01 or 0.05). (2)There was no significant difference in the ratio of TT, CC and CT genotype of ABCB1 gene among 3 groups(P>0.05). There was significant difference in the ratio of poor, middle and strong metabolizer genotype of CYP2C19 gene (P<0.05). (3)Recurrent angina rates were 8.6%(9/105), 6.0%(6/100) and 18.9%(18/95) (P<0.05), and bleeding events rates were 1.0% (1/105), 1.0%(1/100) and 8.4%(8/95)respectively (P<0.01) in remarkable efficacy group, effective group and poor responsiveness group during the 1 year follow up. There were no significant difference in rates of myocardial infarction, heart failure, ischemic stroke and death among 3 groups (all P>0.05) during follow up. Rates of major adverse cardiovascular events and bleeding events were similar in patients with TT, CC and CT genotype of ABCB1 (14.6%(13/89), 12.8(19/148)and 11.6%(5/43), P>0.05). Rates of major adverse cardiovascular events and bleeding events were 9.5%(2/21), 17.8(27/152) and 7.5%(8/107) in poor, middle and strong metabolizer genotype of CYP2C19 gene patients (P<0.05). (4) Plasma concentration of clopidogrel was significantly lower and relative concentration of acid metabolites was significantly higher in poor responsiveness group than in remarkable efficacy group(P<0.01 or 0.05). There was no significantly different in plasma relative concentration of 2-oxo-clopidogrel between remarkable efficacy group and poor responsiveness group. CONCLUSION: ABCB1 gene polymorphism is not but CYP2C19 gene polymorphisms is related with antiplatelet responsiveness of clopidogrel and clinical cardiovascular disease events in patients with acute coronary syndrome undergoing selected percutaneous coronary intervention.

Intracellular annexin A2 regulates NF-κB signaling by binding to the p50 subunit: implications for gemcitabine resistance in pancreatic cancer.

Annexin A2 (ANXA2) expression is highly upregulated in many types of cancer. Although cell surface localization of ANXA2 has been reported to have a critical role in the progression and metastasis of a variety of tumors, including pancreatic cancer, the biological role of intracellular ANXA2 is not fully understood. Herein the role of intracellular ANXA2 was investigated in a pancreatic cancer cell line. We first determined whether ANXA2 is involved in NF-κB signaling pathways. ANXA2 bound to the p50 subunit of NF-κB in a calcium-independent manner, and the ANXA2-p50 complex translocated into the nucleus. Furthermore, ANXA2 increased the transcriptional activity of NF-κB in both the resting and activated states and upregulated the transcription of several target genes downstream of NF-κB, including that encoding interleukin (IL)-6, which contributes to anti-apoptotic signaling. In Mia-Paca2 cells, we determined the effects of wild-type ANXA2 and an ANXA2 mutant, Y23A, which suppresses the cell surface localization, on upregulation of NF-κB transcriptional activity and secretion of IL-6. Both wild-type and Y23A ANXA2 induced anti-apoptotic effects in response to treatment with tumor necrosis factor-α or gemcitabine. Based on these results, we suggest that ANXA2 mediates resistance to gemcitabine by directly increasing the activity of NF-κB. Collectively, these data may provide additional information about the biological role of ANXA2 in pancreatic cancer and suggest that ANXA2 is a potential biomarker for the drug resistance phenotype and a candidate therapeutic target for the treatment of pancreatic cancer.

Performance of electron beam irradiation for treatment of groundwater contaminated with acetone.

The purposes of this study were to evaluate the efficiency of acetone removal by electron beam irradiation in groundwater and the effect of various conditions. According to the results, the removal kinetics of acetone were pseudo first-order, and the removal efficiencies were expressed to the (%) removal and G-values. By adding sulfite, it was confirmed that acetone was mainly degraded by the reaction with the hydrated electrons. The presence of nitrate caused the removal of acetone to decrease. But there was no significant effect of alkalinity on the removal of acetone. The effect of the initial pH values (pH 5 to 9) on the acetone removal efficiency was negligible, but the pH value decreases due to the formation of acidic compounds after irradiation. Consequently, the radiation-induced removal reactions of acetone followed the pseudo-first-order kinetic model; in addition to the initial concentration of acetone, nitrate and the absorbed dose were important factors in removing acetone from an aqueous solution using electron beam irradiation. The effects of general pH and alkalinity on the degrading acetone were negligible.

Diffusion tensor imaging in patients with essential tremor.

BACKGROUND AND PURPOSE: The traditional paradigm has regarded essential tremor (ET) as a benign disorder. However, recent clinical, neuroimaging, and neuropathologic studies suggest that ET may be a progressive neurologic disorder. Based on clinicopathologic findings that cerebellum and its outflow are the key structures in ET and degeneration of gray matter in cerebellum is followed by consequent wallerian degeneration of white matter (WM) fibers, the aim of the present study was to investigate changes in anisotropy in patients with ET. MATERIALS AND METHODS: Fractional anisotropy (FA) images were generated from DTI data acquired at 1.5T in 10 patients with ET compared with 8 control subjects by using statistical parametric mapping to make voxel-by-voxel comparisons. RESULTS: Compared with the control subjects, the patients with ET exhibited significantly reduced FA (P(uncorrected) < .005) in the anterolateral portion of the right pons and decreased FA in the bilateral cerebellum, left retrorubral area of the midbrain, and bilateral deep WM, including the orbitofrontal, lateral frontal, parietal, and temporal WM. CONCLUSION: This study demonstrates that structural changes in the WM are extensive in patients with ET, supporting the findings of previous functional neuroimaging and pathologic studies.

Novel synthesis of nanorod ZnO and Fe-doped ZnO by the hydrolysis of metal powders.

Fe-doped ZnO nanorods have been synthesized by a novel process employing a hydrolysis of metal powders. Zn and Fe nano-powders were used as starting materials and incorporated into distilled water. The solution was refluxed at 60 degrees C for 24 h to obtain the precipitates from the hydrolysis of Zn and Fe. X-ray diffraction patterns for all the samples showed a pure wurtzite single phase, without any segregation of the Fe into the particulates within the instrumental resolution limit. The TEM results for ZnO with and without an Fe-doping showed that the produced powders had a rod-like shape. The rod shape was attributable to the zinc oxide from the hydrolysis of Zn. With an increasing Fe content, the UV-vis spectra were shifted to a long wave length and this result indicates that the band gap was changed by an Fe-doping.

Nanoscale periodic morphologies on the fracture surface of brittle metallic glasses.

Out-of-plane, nanoscale periodic corrugations are observed in the dynamic fracture surface of brittle bulk metallic glasses with fracture toughness approaching that of silica glasses. A model based on the meniscus instability and plastic zone theory is used to explain such dynamic crack instability. The results indicate that the local softening mechanism in the fracture is an essential ingredient for controlling the formation of the unique corrugations, and might provide a new insight into the origin of fracture surface roughening in brittle materials.

Primary small-bowel non-Hodgkin's lymphoma: a study of clinical features, pathology, management and prognosis.

The records of 34 patients diagnosed with primary small bowel non-Hodgkin's lymphoma during a 10-year period between January 1996 and December 2005, including 27 cases for which complete follow-up records were available, were studied. Abdominal pain (70.6% of patients) was the main presenting symptom, followed by intestinal obstruction (38.2%). The most common primary site was the ileum (58.8%), followed by the jejunum (26.5%) and duodenum (17.6%); one case had tumours at two sites in the small bowel. Twenty-seven patients had small bowel B-cell lymphoma (24 diffuse large B-cell lymphoma; three mucosa-associated lymphoid tissue B-cell lymphoma) and seven patients had small bowel T-cell lymphoma. Cumulative survival in patients with small bowel B-cell lymphoma was higher than that in patients with small bowel T-cell lymphoma. Data on 16 male and eight female patients with diffuse large B-cell lymphoma showed that 62.5% of these patients presented with disease stages I or II and 37.5% with stages III or IV. Cumulative survival in patients at stages IE or IIE was significantly higher than that of patients at stages IIIE or IVE. Four of five patients who died from diffuse large B-cell lymphoma had abnormal levels of lactate dehydrogenase and serum albumin.

Temporospatial sequence of cellular events associated with etoposide-induced neuronal cell death: role of antiapoptotic protein Bcl-X(L).

Etoposide-induced death comprises such nuclear events as the formation of topoisomerase II-DNA cleavable complex and cytosolic events including caspase activation. By first establishing the temporospatial death sequence triggered by etoposide in a neuronal cell line, MN9D overexpressing Bcl-X(L) (MN9D/Bcl-X(L)) or control vector (MN9D/Neo), we examined whether formation of this complex is primarily responsible for cell death and at which strategic points and how Bcl-X(L) blocks etoposide-induced neuronal death. Etoposide induced death that was dependent on caspase, cycloheximide, and calpain in MN9D/Neo cells. Etoposide also induced death in enucleated MN9D/Neo cells, although this was less severe. The level of topoisomerase II-DNA cleavable complex reached at a maximum of 2 hr after etoposide treatment was identical in MN9D/Neo and MN9D/Bcl-X(L) cells. In MN9D/Neo cells, cytochrome c release into the cytosol and caspase activation occurred as early as 2 hr and 3-6 hr after etoposide treatment, respectively. Etoposide-induced DNA laddering potentially via caspase appeared as early as 12 hr after drug treatment, followed by nuclear swelling in MN9D/Neo cells (>18-20 hr). Subsequently, nuclear condensation started by 24-28 hr and became apparent thereafter. All of these events except for nuclear swelling were substantially blocked in MN9D/Bcl-X(L). At the later stage of cell death (<32-36 hr), a specific cleavage of Bax and fodrin appeared that was completely blocked by calpain inhibitor or by Bcl-X(L). Taken together, our data suggest that Bcl-X(L) prevents etoposide-induced neuronal death by exerting its anticaspase and anticalpain effect on cellular events after the formation of topoisomerase II-DNA cleavable complex that may not be a major contributor to cell death.

Combined functional magnetic resonance imaging and transcranial magnetic stimulation evidence of ipsilateral motor pathway with congenital brain disorder: a case report.

We present the case of 28-year-old man with schizencephaly who had mild left hemiparesis with mirror movement. Brain mapping using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) for both hand muscles was done to evaluate his neurologic state. Motor evoked potential (MEP) from both abductor pollicis brevis (APB) muscles was obtained simultaneously. fMRI showed that the left primary sensorimotor cortex became active when the right fingers performed the flexion-extension exercise. The left primary sensorimotor cortex, left prefrontal area, and both supplementary motor areas were activated with flexion-extension exercise of the left hand. Brain mapping for both APB muscles using TMS showed that no MEP was evoked in the right hemisphere, but a APB total of 5 sites were evoked in the left hemisphere simultaneously. The optimal scalp site for both APB muscles was present at the same site. The MEPs of both muscles which were evoked by stimulation of the optimal scalp site, showed similar latencies, amplitudes, and figures of potential. The similarities in both MEPs and the same optimal scalp site support the assumption that MEPs of both APB muscles are produced by the corticospinal tract originating from the same motor cortex. Our results showed that the ipsilateral motor pathway extended from the unaffected left hemisphere to both hand muscles. This finding may reflect functional reorganization of motor area in a patient with congenital brain disorder.

Organotropic chemopreventive effects of n-3 unsaturated fatty acids in a rat multi-organ carcinogenesis model.

Organotropic chemopreventive effects of n-3 unsaturated fatty acids were studied using a multi-organ carcinogenesis model in male rats. Rats were treated with diethylnitrosamine (DEN), N-methyl-N-nitrosourea (MNU), N-butyl-N-4-hydroxybutylnitrosamine (BBN), 1,2-dimethylhydrazine (DMH) and dihydroxy-di-n-propylnitrosamine (DHPN) during the first 7 weeks, and then given unsaturated fatty acid (UFAs), docosahexaenoic acid (n-3, C(22:6)) (DHA), eicosapentaenoic acid (n-3, C(20:5)) (EPA), linoleic acid (n-6, C(18:2)) (LA) or oleic acid (n-9, C(18:1)) (OA) at a dose of 1.0 ml/rat, 3 times a week by gavage for the consecutive 30 weeks. All rats were fed a low LA basal diet throughout the experiment and a calorie-restricted basal diet during the period of UFAs feeding administration. DHA significantly reduced tumor size and numbers in the large intestine as compared to OA treatment. Furthermore, DHA showed a tendency to inhibit carcinogenesis in the small intestine and lung. EPA also showed a tendency to inhibit intestinal carcinogenesis. On the other hand, LA showed a tendency to inhibit lung carcinogenesis, but to promote large intestinal carcinogenesis. However these UFAs did not influence preneoplastic and neoplastic lesion development in the liver, kidney, and urinary bladder. Levels of the administered fatty acids were clearly increased in the serum and organs. In contrast, arachidonic acid (AA) levels in the large and small intestines and liver were markedly decreased by treatment with DHA and EPA. Decreased levels of AA in the large intestine correlated well with tumor incidence, although the number of glutathione S-transferase-positive (GST-P(+)) foci showed an inverse correlation with AA levels. The data thus provide evidence that an organotropism exists with regard to the influence of UFAs on carcinogenesis, which correlates with reduction of tissue AA levels in the target organs.

A ferulic acid derivative, ethyl 3-(4'-geranyloxy-3-methoxyphenyl)-2-propenoate, as a new candidate chemopreventive agent for colon carcinogenesis in the rat.

The inhibitory influence of ferulic acid (FA), a rice germ component, and its geranylated derivative 3-(4'-geranyloxy-3-methoxyphenyl)-2-propenoate (EGMP) on the post-initiation stage of azoxymethane (AOM)-induced colon carcinogenesis was studied in male F344 rats given two s.c. injections of AOM (15 mg / kg body weight) during week 1. Diets containing EGMP or FA at doses of 0.1 or 0.2% were then fed for 3 weeks from week 2 to 5, when the animals were sacrificed. The numbers of aberrant crypt foci (ACF) and aberrant crypts (AC) per rat in the group given 0.2% FA were significantly decreased (P < 0.001) as compared to the AOM alone group. Furthermore, the numbers of ACF and AC per rat fed the 0.2% and 0.1% EGMP were significantly reduced (P < 0.001 and P < 0.01, respectively). Colonic epithelial cells in S-phase, as measured by bromodeoxyuridine (BrdU) labeling, in rats fed EGMP were significantly decreased in the 0.2 and 0.1% EGMP groups as compared to the AOM alone group (P < 0.05). BrdU labeling indices in rats fed FA and EGMP assessed by a test using a coefficient for linear contrast were also significantly decreased as compared to the AOM alone value (P < 0.05, P < 0.01, respectively). The results indicate that FA and EGMP have inhibitory effects on ACF and AC development, EGMP being more potent, possibly due to stronger suppressive effects on cell proliferation. No toxic effects were observed in rats given either compound in terms of body and organ weights, and liver or kidney histology. The findings thus suggest that EGMP and FA, especially the former, might have potential as chemopreventive agents against colon tumor development.

Milk and dairy products in cancer prevention: focus on bovine lactoferrin.

Milk and dairy products constitute an important part of the western style diet. A large number of epidemiological studies have been conducted to determine effects of consumption on cancer development but the data are largely equivocal, presumably reflecting the different included components. It has been proposed that whereas fats in general could promote tumor development, individual milk fats like conjugated linoleic acid could exert inhibitory effects. There is also considerable evidence that calcium in milk products protects against colon cancer, while promoting in the prostate through suppression of circulating levels of 1,25-dihydroxyvitamin D3. Whey protein may also be beneficial, as shown by both animal and human studies, and experimental data have demonstrated that the major component bovine lactoferrin (bLF), inhibits colon carcinogenesis in the post-initiation stage in male F344 rats treated with azoxymethane (AOM) without any overt toxicity. The incidence of adenocarcinomas in the groups receiving 2% and 0.2% bLF were thus 15% and 25%, respectively, in contrast to the 57.5% control value (P<0.01 and P<0.05, respectively). Results in other animal models have provided further indications that bLF might find application as a natural ingredient of milk with potential for chemoprevention of colon and other cancers.

Immunohistochemical localization of inducible nitric oxide synthase and 3-nitrotyrosine in rat liver tumors induced by N-nitrosodiethylamine.

Human liver cancers have been associated mainly with chronic inflammations such as viral hepatitis B or C. This suggests that prolonged cell damage by chronic inflammation is critical in cancer development. Overproduction of nitric oxide (NO.) and its derivative (NOx, peroxynitrite) has been implicated as a cause of tissue damage by inflammation, thus contributing to tumor promotion. We have demonstrated the expression of the inducible isoform of nitric oxide synthase (iNOS) and 3-nitrotyrosine, a marker of peroxynitrite formation, by immunohistochemistry in preneoplastic and neoplastic rat liver tissues induced by continuous infusion of N-nitrosodiethylamine with mini-pumps. The preneoplastic lesions were characterized by proliferation of phenotypically altered hepatic foci (PAHF), dysplastic hepatocytes and oval cells. Histologically, the tumors were hepatocellular carcinomas (HCCs) of trabecular, (pseudo)glandular and solid types with or without cholangiocellular involvement. iNOS was located mainly in oval cells, capillary endothelial and muscular cells, epithelia of cholangiomas and glandular HCCs. 3-Nitrotyrosine was observed in the cytoplasms of PAHF and dysplastic hepatocytes in preneoplasias and in the cytoplasms of some living or apoptotic HCC cells, connective tissues, proteinaceous fluids, sinusoidal endothelia of tumorous hepatocytes and cholangiomas in tumors. From these observations, we suggest that: (i) chronic tissue damage by chemical carcinogens may act to induce iNOS and peroxynitrite formation; (ii) oval cells play a key role in development and/or growth of tumor tissues by producing NO. via iNOS, which may also cause tissue damage by peroxynitrite; (iii) iNOS can be considered as a phenotypic marker in cells of oval cell lineage and neovascularized capillaries in tumor tissues.

Farnesylcysteine methyltransferase activity and Ras protein expression in human stomach tumor tissue.

The processing pathway of G-proteins and Ras family proteins includes the isoprenylation of the cysteine residue, followed by proteolysis of three terminal residues and alpha-carboxyl methyl esterification of the cysteine residue. Farnesylcysteine methyltransferase (FCMT) activity is responsible for the methylation reaction which play a role in the membrane attachment of a variety of cellular proteins. Four kinds of Ras protein (c-Ha-ras, c-N-Ras, c-Ki-Ras, pan-Ras) expression were detected in adenocarcinoma of human tissue by immunohistochemical method, and hematoxylin and eosin staining. The level of Ras protein in human stomach tumor tissues was much higher than in normal and peritumoral regions of the same biopsy samples. The FCMT activities of each cellular fractions were high in mitochondrial fraction followed by microsomal fraction, whole homogenate and cytosolic fraction. The inhibitory effect on FCMT activity on stomach tumor tissue was determined after treatment with 0.25 microM of S-adenosyl-L-homocysteine. S-adenosyl-L-homocysteine inhibited FCMT activity from 11.2% to 30.5%. These results suggested that FCMT might be involved in Ras proteins activity.

Enhancement by indole-3-carbinol of liver and thyroid gland neoplastic development in a rat medium-term multiorgan carcinogenesis model.

The modification potential of indole-3-carbinol (I3C), a naturally occurring compound found in cruciferous vegetables, on neoplastic development was assessed using a rat medium-term multiorgan carcinogenesis model. One-hundred male Sprague-Dawley (SD) rats were randomly divided into three groups and sequentially treated with diethylnitrosamine (DEN; 100 mg/kg b.w., a single i.p.), N-methyl-N-nitrosourea (MNU; 20 mg/kg b.w., four times i.p., at days 5, 8, 11 and 14), and dihydroxy-di-N-propyl-nitrosamine (DHPN; 0.1% in the drinking water during weeks 1 and 3) (DMD treatment; groups 1 and 2) or the vehicles alone (group 3) in the first 3-week initiation period. Animals of groups 1 and 3 were then given diet containing 0.25% I3C from week 4 until week 24, followed by a return to basal diet for 28 weeks, and subgroups were killed at weeks 24 and 52. I3C caused significant increases in both number (no./cm2) and area (mm2/cm2) of glutathione S-transferase placental form (GST-P)-positive liver cell foci assessed at week 24 of the experiment (P<0.01, 0.001). The incidence of hepatocellular adenomas in the DMD and I3C group at week 52 showed a tendency for elevation as compared to the DMD alone group, but this was not statistically significant. The thyroid gland tumour incidences in the DMD and I3C groups were significantly increased compared with the DMD alone group values at week 52 (P<0.01). In conclusion, I3C enhanced liver and thyroid gland neoplastic development when given during the promotion stage in the present rat medium-term multiorgan carcinogenesis model.

Potential preventive effects of Chelidonium majis L. (Papaveraceae) herb extract on glandular stomach tumor development in rats treated with N-methyl-N'-nitro-N nitrosoguanidine (MNNG) and hypertonic sodium chloride.

The modifying effects of Chelidonium majis L. (Papaveraceae) herb extract (CH), an analgesic traditionally prescribed for gastric and duodenal ulcer patients, on gastric tumor development were studied in rats given N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Sixty-four male 6-week-old Wistar rats were used. Group 1 rats were initially given MNNG (200 mg/kg b.w.) by gavage at days 0 and 14 as well as saturated sodium chloride solution (S-NaCl, 1 ml per rat) every 3 days during weeks 0-3 (six times), and then placed on basal diet containing 0.1 or 0.2% CH for 16 weeks from week 4. Rats of Group 2 and 3 were treated with MNNG together with S-NaCl or saline (0.9% NaCl, 1 ml per rat), respectively, timed as in Group 1 but without further treatment. All surviving animals were killed at week 20 and histopathologically investigated. In the glandular stomach, the number of preneoplastic pepsinogen 1 altered pyloric glands (PAPGs) in the MNNG + S-NaCl-->CH (0.1%) group (Group 1) was significantly smaller than in the MNNG + S-NaCl group (Group 2) (P < 0.02). The incidences of forestomach neoplastic lesions (papillomas and squamous cell carcinomas) also showed a tendency to decrease with the CH treatment. The results thus indicate that CH exerts inhibitory effects on glandular stomach carcinogenesis in the rat, so that it may have potential as a chemopreventive agent for stomach cancer in man.

Promotion potential of tamoxifen on hepatocarcinogenesis in female SD or F344 rats initiated with diethylnitrosamine.

The liver promotion potential of tamoxifen (TAM), which has been widely used in the treatment of hormone-dependent breast cancers, was investigated using female SD or F344 rat initiated with diethylnitrosamine (DEN). In Experiment 1, 45 newborn female SD rats were administered DEN (100 mg/kg, i.p.) (Groups 1 and 2) or saline (Group 3) 24 h after birth. After weaning at week 3, Groups 1 and 3 were subcutaneously injected with TAM citrate (1 mg/rat per day), suspended in corn oil, in the subscapular region, while Group 2 was given the vehicle alone (s.c.) daily for 9 weeks, and killed at week 12. In Experiment 2, 70 female F344 rats at 7 weeks of age were divided into five groups. All animals were initially given DEN (200 mg/kg i.p.) for initiation. Two weeks later Groups 1-4 were given diets containing 100, 250, 500 ppm TAM, or 500 ppm PB for 6 weeks, respectively, while Group 5 was administered basal diet as a control for the same period. The rats were subjected to two-thirds partial hepatectomy (PH) at week 3 and were killed at week 8. The enhanced development of glutathione S-transferase-placental form (GST-P)-positive liver cell foci after DEN exposure in both newborn SD and adult F344 rat medium-term liver bioassay models (Experiments 1 and 2). This suggests that TAM exerts promotion potential for hepatocarcinogenesis in female rats.

Biphasic modifying effect of indole-3-carbinol on diethylnitrosamine-induced preneoplastic glutathione S-transferase placental form-positive liver cell foci in Sprague-Dawley rats.

The biphasic modifying effects of indole-3-carbinol (I3C), a naturally occurring constituent of edible cruciferous vegetables, on the development of glutathione S-transferase placental form (GST-P)-positive liver cell foci were investigated by using a medium-term liver bioassay system and a newborn rat hepatocarcinogenesis system. In Experiment 1, a total of 65 male Sprague-Dawley (SD) rats were divided into 5 groups. Animals were given a single intraperitoneal (i.p.) injection of 200 mg/kg diethylnitrosamine (DEN) dissolved in saline for groups 1, 2, and 3 or a single i.p. injection of saline for groups 4 and 5. Group 1 was given the diet containing 0.25% I3C for 2 weeks prior to DEN initiation and then basal diet for 8 weeks. Group 2 was given basal diet for 4 weeks prior to and after DEN initiation and then the diet containing 0.25% I3C for 6 weeks. The rats of group 3 were placed on basal diet during the experiment. Animals of groups 4 and 5 were treated in the same manner as those of groups 1 and 2 except for injection with saline instead of DEN solution. All rats were subjected to two-thirds partial hepatectomy at week 3 and were killed at week 8 after DEN or saline injection. In Experiment 2, a total of 45 female SD rats were dosed with DEN (100 mg/kg, i.p.) or saline at 24 h after birth. After weaning at week 3, the rats were fed diet containing 0.25% I3C for 9 weeks and then were killed at week 12. In Experiment 1, preinitiation exposure to 0.25% I3C caused a significant decrease in numbers of GST-P-positive liver cell foci (P < 0.05), while postinitiation exposure to 0.25% I3C caused significant increases in both number (No./cm2) and area (mm2/cm2) of GST-P-positive liver cell foci (P < 0.05 or 0.01). In Experiment 2, the relative liver weight in the DEN + I3C group was significantly increased (P < 0.001). The numbers and areas of GST-P-positive liver cell foci in the DEN + I3C group were significantly increased as compared to the values of the DEN-alone group (P < 0.001). These results clearly demonstrated that I3C exerts a promoting effect on the postinitiation stage as well as an inhibitory effect on the preinitiation stage in the medium-term liver bioassay.