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1.
The effect of dietary beta-carotene on colon carcinogenesis induced by 1,2-dimethylhydrazine [(DMH) CAS: 540-73-8] was studied in female inbred Swiss Webster (ICR) mice. At age 10 weeks and continuing throughout the experiment, mice received diets consisting mainly of natural foods (laboratory chow) and containing 2 or 22 mg beta-carotene/kg. At age 15 weeks they received 7 weekly sc injections of DMH (total dose: 196 mg DMH X diHCI/kg body wt). When autopsied 31 weeks after the first DMH injection, the incidence (percent of mice with tumors) and multiplicity (number of tumors/tumor-bearing mouse) of colon tumors were reduced by half in the mice supplemented with beta-carotene. There was a much greater decrease in adenocarcinomas than in adenomas. Mice observed for 13 additional weeks revealed that the mortality rate, due largely or wholly to colon cancer, was only about half in supplemented mice. Mice sacrificed 12 weeks after the first dose of DMH (i.e., well before tumors appeared) showed mild colon mucosal hyperplasia. beta-Carotene supplementation, however, did not alter this, indicating that the protective effect against colon cancer may have occurred at a late stage of carcinogenesis. 相似文献
2.
In order to evaluate the role of beta-carotene as an inhibitor of skin carcinogenesis, hairless female HRA/Skh mice were treated with the initiator 7,12-dimethylbenz[a]anthracene (DMBA) and with the promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), and were fed a balanced diet free from vitamin A either with or without gavage-administered beta-carotene. There was no evidence of avitaminosis A or differences in body weight in mice deprived of beta-carotene and vitamin A, compared with those given 290 or 1430 IU beta-carotene/kg per day. Mice fed with normal animal feed pellets displayed a significantly higher body weight (28.5 +/- 1.95 g) compared with mice on the special diet (25.7 +/- 1.9 g), and also displayed a higher papilloma yield. However animals on the special diet, fed with beta-carotene from weaning, displayed significantly lower numbers of papillomas per mouse. This lower papilloma yield was evident particularly between 12-24 weeks after commencement of the study, which coincided with the period of maximum tumor yield in DMBA/TPA-treated mice. The characteristic regression of papillomas after that time points to the reversibility of many earlier papillomas, and their dependence on continued TPA administration. Evaluation of carcinomas in mice on the various dietary regimes showed there was no significant difference between any group, including those fed with beta-carotene continuously from weaning. The present results demonstrate that a sustained dietary intake of beta-carotene from 3 weeks of age partially suppressed the growth of papillomas, but did not affect the course of malignant progression in DMBA/TPA-treated HRA/Skh mice. It is evident that beta-carotene predominantly affects TPA-dependent papillomas, which possess reversible properties and have a low probability of progression to form carcinomas. 相似文献
3.
β—胡萝卜素对TAⅡ小鼠移植性乳腺癌MA737影响的研究 总被引:4,自引:0,他引:4
观察β-胡萝卜素对移植性乳腺癌生长,荷瘤小鼠生存期及对CMF化疗毒副作用的影响。方法采用TAⅡ小鼠移植性乳腺癌模型,荷瘤小鼠给予BC和CMF不同处理。结果(1)BC组、BC+CMF组平均每只小鼠生存时间较对照组显著延长,CMF组小鼠因化疗毒性其生存时间较对照组明显缩短。(2)CMF小鼠在实验7天内全部死亡外,BC组、BC+CMF组在实验不同时期肿瘤体积均明显小于对照组。(3)长期单独灌喂BC小鼠均 相似文献
4.
Lung carcinogenesis and formation of 8-hydroxy-deoxyguanosine in mice by diesel exhaust particles 总被引:17,自引:5,他引:17
Ichinose T; Yajima Y; Nagashima M; Takenoshita S; Nagamachi Y; Sagai M 《Carcinogenesis》1997,18(1):185-192
In order to clarify the involvement of oxygen radicals in lung
carcinogenesis induced by diesel exhaust particles (DEP), the relationship
between lung tumour response and formation of 8- hydroxydeoxyguanosine
(8-OHdG) in lung DNA was examined. The role of high dietary fat and
beta-carotene on these responses was also studied. Mice were
intratracheally injected with 0.05, 0.1 and 0.2 mg of DEP per animal once
weekly for 10 weeks. After 12 months, the lung tumour incidence in mice
treated with 0.05 mg and 0.1 mg showed similar increases (30% and 31%), but
was decreased to 24% at 0.2 mg. High dietary fat enhanced the incidence of
both benign and malignant tumours. beta-carotene partially prevented the
tumour development. After the 10 weekly treatments of DEP, inflammatory
reaction was observed in the respiratory tract and alveoli. The formation
of 8-OHdG in lung DNA from mice treated with DEP showed a dose dependent
increase. 8-OHdG formation was enhanced by high dietary fat and partially
reduced by beta-carotene. Formation of 8-OHdG was significantly correlated
with the lung tumour incidence except at 0.2 mg. These results suggest that
the induction of oxidative DNA damage may be an important factor in the
initiation of DEP-induced lung carcinogenesis, and that beta-carotene and
high dietary fat may play a role in the regulation of tumour development
via modulation of the formation of 8-OHdG.
相似文献
5.
D M Freedman J A Tangrea J Virtamo D Albanes 《Cancer epidemiology, biomarkers & prevention》1999,8(12):1115-1116
In the alpha-Tocopherol, beta-Carotene Cancer Prevention (ATBC) study, a large randomized placebo-controlled trial designed to test the cancer prevention effects of alpha-tocopherol (50 mg/day) and beta-carotene (20 mg/day), participants receiving supplemental beta-carotene had significantly higher rates of lung cancer than those not receiving beta-carotene. It has been hypothesized that the supplemental beta-carotene may have interfered with the synthesis of vitamin D and that the resulting lower concentrations of vitamin D contributed to the elevated cancer incidence. We evaluated whether supplementation with beta-carotene altered the serum concentrations of either 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D in the ATBC Study, by comparing on-study changes between baseline and follow-up serum samples among 20 randomly selected matched pairs of subjects from the beta-carotene and placebo groups. In a matched-pair analysis, the difference between the changes in both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in the beta-carotene supplement and placebo groups were small and statistically nonsignificant. These results provide no evidence that beta-carotene supplementation interferes with the endogenous production of 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D and suggest that it is unlikely that an interaction between supplemental beta-carotene and vitamin D metabolites contributed to the modest increase in lung cancer incidence observed in the ATBC Study. 相似文献
6.
This study examined the effects of palm carotene feeding on DNA damage of
bone marrow, recovery of peripheral leukocyte counts, and the survival of
mice that received whole-body X-ray irradiation. The palm carotene was
composed of alpha- and beta-carotene in a ratio of 1:3. Mice were fed
either a basal diet or a carotene diet (50 mg carotene/100 g diet) for 2
weeks, then irradiated. The carotene diet was prepared by the dietary
protocol that markedly enhanced the accumulation of carotene in tissues (J.
Nutr. 125, 3081, 1995). DNA damage in bone marrow was evaluated by
micronucleus assay using peripheral blood. When mice received X-ray (1.5
Gy), marked DNA damage in bone marrow and reduction of peripheral leukocyte
count were observed. These changes were significantly attenuated in mice
fed the carotene diet. In addition, X-ray (6.5 Gy)-induced survival of mice
fed the carotene diet was higher than those fed the basal diet. In mice fed
the carotene diet, alpha- and beta-carotene were detected in bone marrow
and liver, and concentration of vitamin A in liver was about four times
higher compared with that in mice fed the basal diet. These findings
suggest that feeding mice palm carotene prevents radiation- induced damages
by way of its antioxidant activity and/or vitamin A activity.
相似文献
7.
Skin tumor promotion after a short-term exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA) was studied in female SENCAR mice. Mice were dosed once by the topical application of 20 micrograms of dimethylbenz[a]anthracene (DMBA) in 0.2 ml acetone. A week later, they received topical applications of TPA (2 or 4 micrograms per 0.2 ml acetone) once or twice a week for periods of 1-10 weeks and were killed at 30 weeks. Skin tumors were counted and measured for size weekly. When TPA was applied once a week for 10 weeks or only twice a week for 2 weeks, there was significant promotion of papilloma formation in a large proportion of mice initiated with DMBA. Mice that received one or two applications had a few skin tumors. The total number of papillomas decreased considerably and the majority appeared to regress after 20 weeks in mice that received TPA treatment for 10 weeks. In mice that received only 4 TPA treatments, however, the majority of the papillomas grew progressively in size and did not regress during the entire experimental period. A greater proportion of these tumors progressed to carcinoma than did those in mice receiving TPA for 10 weeks. Thus, a short-term exposure was effective in causing certain changes in skin of SENCAR mice that led to tumor development and progression. 相似文献
8.
David Finkle Zhi Ricky Quan Vida Asghari Jessica Kloss Nazli Ghaboosi Elaine Mai Wai Lee Wong Philip Hollingshead Ralph Schwall Hartmut Koeppen Sharon Erickson 《Clinical cancer research》2004,10(7):2499-2511
PURPOSE: This study examined the effectiveness of early and prolonged mu4D5 (the murine form of trastuzumab/Herceptin) treatment in transgenic mice that overexpress human HER2 (huHER2), under the murine mammary tumor virus promoter, as a model of huHER2-overexpressing breast cancer. EXPERIMENTAL DESIGN: Mice were randomly assigned to one of three treatment groups and received i.p. injections from 17 weeks of age until either 52 weeks of age or morbidity. Fourteen mice received 100 mg/kg mu4D5, 14 mice received 100 mg/kg antiherpes simplex virus glycoprotein D control antibody, and 11 mice received a diluent control. RESULTS: High levels of huHER2 expression were detectable in mammary glands of young virgin founder mice. Mammary adenocarcinomas were frequently found in female founders and progeny at an average age of 28 weeks, with some progressing to metastatic disease. The incidence of mammary tumors was significantly reduced, and tumor growth inhibition was observed in mice receiving mu4D5 compared with control mice. In addition, Harderian gland neoplasms, highly associated with overexpression of huHER2 in this transgenic line, were entirely absent in the mu4D5 treatment group, indicating down-regulation of huHER2 in vivo activity. CONCLUSIONS: Early intervention with mu4D5 was of benefit in our transgenic mice at high risk for developing huHER2-overexpressing breast cancer. This study suggests a potential benefit of early treatment with Herceptin in HER2-positive primary breast cancer. 相似文献
9.
Hiroyuki Konno Tatsuo Tanaka Iwao Matsuda Toshikazu Kanai Yuji Maruo Nobuhiko Nishino Satoshi Nakamura Shozo Baba 《International journal of cancer. Journal international du cancer》1995,61(2):268-271
Angiogenesis inhibitors have attracted considerable interest. The anti-tumor and anti-metastatic effects of TNP-470, an angiogenesis inhibitor, and mitomycin C (MMC), a representative anti-neoplastic agent, were investigated using a xenotrans-planted human colon cancer, TK-4. Suturing of small pieces of TK-4 tumors to the cecal wall in nude mice (orthotopic transplantation) induced liver metastasis. Mice were randomly divided into 3 groups; a control group given saline solution, a group receiving TNP-470 and a group receiving MMC. TNP-470 was given s.c. on alternate days for 5 weeks from day 10 after cecal transplantation and MMC was administered intraperitoneally (i.p.) once a week from day 10 after cecal transplantation. MMC significantly inhibited cecal tumor growth. In the control group, liver metastases developed in 9 out of 10 mice, including 3 with more than 20 metastatic foci. Liver metastasis also developed in 8 out of 10 mice receiving MMC, 2 of which had many metastases. In contrast, liver metastasis developed in only 2 out of 8 mice in the TNP-470 group and neither of these animals had numerous metastases. © 1995 Wiley-Liss, Inc. 相似文献
10.
M J Xu P M Plezia D S Alberts S S Emerson Y M Peng S M Sayers Y Liu C Ritenbaugh H L Gensler 《Journal of the National Cancer Institute》1992,84(20):1559-1565
BACKGROUND: Beta-carotene is one of the most commonly used compounds in clinical trials of chemopreventive agents in various neoplastic diseases. Animal studies, including our own, have documented that dietary beta-carotene can reduce plasma alpha-tocopherol (vitamin E) levels, but few published studies have examined the clinical or pharmacokinetic ramifications of long-term, high-dose beta-carotene regimens on other fat-soluble vitamins such as alpha-tocopherol. PURPOSE: This study was designed to determine the effects of long-term beta-carotene supplementation on plasma concentrations of alpha-tocopherol in normal human subjects and in an experimental C3H/HeN mouse model. METHODS: In a double-blind study, 45 normal subjects were randomly assigned to receive 0 (placebo), 15, 30, 45, or 60 mg of oral beta-carotene daily for approximately 9 months. Monthly plasma samples were collected. Thirty-five C3H/HeN mice were fed a basal diet with or without beta-carotene and treated topically with or without alpha-tocopherol, except for the control mice, which received UV radiation for 27 weeks from week 3 to week 30. Plasma and dorsal skin samples were taken after 40 weeks and were analyzed for alpha-tocopherol and/or beta-carotene by high-performance liquid chromatography. RESULTS: Long-term dietary beta-carotene administration resulted in statistically significant reductions in levels of alpha-tocopherol in the skin and plasma of UV-irradiated mice. In the human study, the decrease in plasma alpha-tocopherol levels was progressive and significant between 6 and 9 months of beta-carotene dosing in all dosage groups. The greatest decrease was observed during the 9th (last) month of dosing, with a decrease of 40% from baseline. All oral beta-carotene doses (15-60 mg/d), however, resulted in similar decreases in steady-state plasma levels of alpha-tocopherol and in only small differences in beta-carotene plasma levels. CONCLUSION: Long-term oral administration of beta-carotene decreased steady-state plasma concentrations of alpha-tocopherol. The lack of a significant dose-response effect between doses of beta-carotene and alpha-tocopherol plasma levels is not unexpected, given the small differences in steady-state beta-carotene plasma levels in the four beta-carotene dose groups. IMPLICATIONS: Studies are needed to determine how long-term beta-carotene dosing influences tissue distribution of dietary alpha-tocopherol. Careful surveillance for this and other potentially harmful nutrient interactions should become part of all long-term intervention studies. 相似文献
11.
Beta-carotene levels of exfoliated oral mucosa cells can be increased severalfold by the oral administration of this provitamin. Beta-carotene was estimated by HPLC analysis in pronase-treated exfoliated cells obtained by brushing the entire oral mucosa with a toothbrush. A small percentage of individuals did not respond with an increase of beta-carotene in their mucosa cell in spite of a relatively large intake of the provitamin (360 mg in 4 days, or 2880 mg in 16 weeks, respectively). Levels of beta-carotene in the mucosa cells are affected by the concurrent administration of vitamin A: 0.27 ng beta-carotene per 10(6) cells in the placebo group, 1.79 ng following the intake of beta-carotene (180 mg/week for 16 weeks), and 4.29 ng after beta-carotene (180 mg/week for 16 weeks) plus vitamin A (100,000 IU/week for 16 weeks) consumption. The considerable variations in tissue levels of beta-carotene following its oral administration must be taken into account when cancer intervention trials using this agent are designed and evaluated. 相似文献
12.
目的 建立一个小鼠急性髓系白血病(AML)净化后骨髓移植的模型并探讨益康唑(Econazole, Ec)药物净化的效果。方法 利用小鼠P815 AML细胞转染新霉素抗性基因,即NeoR基因后与小鼠骨髓细胞混合,体外短期培养净化;通过移植后血液系统恢复,白血病微小残留病变和小鼠的存活进行评估。结果 接受放射治疗后经尾静脉注射P815/NeoR细胞而未经净化的小鼠100 %可检测到白血病细胞;Ec体外净化后骨髓移植小鼠造血恢复没有延迟,而残留白血病细胞阳性率明显降低且小鼠的总生存明显改善。结论 实验所设计的P815/NeoR小鼠AML净化后骨髓移植模型简单易行、重复性好;Ec可用于AML的净化后骨髓移植。 相似文献
13.
N Potischman T Byers L Houghton M Root T Nemoto T C Campbell 《Cancer epidemiology, biomarkers & prevention》1992,1(7):555-559
The interpretation of case-control studies in which blood nutrient levels are examined as etiological factors in cancer is complicated by the possibility that either the disease or its treatment may alter these levels. Circulating levels of selected nutrients were examined prior to diagnostic biopsy and compared with levels 3 to 4 months after diagnosis among 71 women with breast cancer and 95 women with benign breast disease. Among women with benign breast disease or women with breast cancer who were not given postsurgical adjuvant drug therapy, levels of alpha-carotene, lycopene, alpha-tocopherol, cholesterol, and triglycerides did not change over time. In contrast, women who received chemotherapy had increased levels of cholesterol, retinol, and alpha- and gamma-tocopherol, and women on antiestrogen therapy showed increased levels of triglycerides and alpha-tocopherol. Overall, the concentrations of carotenoids (lycopene, alpha-carotene, and beta-carotene) did not change in breast cancer cases, although subgroup analyses showed increased levels of beta-carotene among cases not receiving drug treatment and decreased levels among those receiving antiestrogens. In summary, blood levels of some nutrients did not appear to be affected by breast cancer or its treatments, but changes were noted for levels of plasma lipids, tocopherols, retinol, and beta-carotene. Those investigating the etiological relationship between breast cancer and circulating nutrients need to consider these effects in designing and interpreting epidemiological studies. 相似文献
14.
BACKGROUND AND OBJECTIVES: Bone metastases are typically treated with bisphosphonates as adjuncts to radiation therapy. The goal of this study was to determine whether radiotherapy combined with a bisphosphonate could restore bone density, microarchitecture, and biomechanical strength of a tumor-burdened bone to normal. MATERIALS AND METHODS: Breast cancer cells were injected into the right femur of 30 female nude mice. Mice were divided into three treatment groups (0 Gy, 20 Gy, and 20 Gy + ZA). Left limbs served as non-operated normal bones. Tumor-bearing femora were irradiated 3 weeks later. ZA (100 microg/kg SC) was administered once weekly for 6 weeks. Mice were euthanized at 9 weeks or earlier if severe lameness or pathology occurred. RESULTS: Mice treated with 20 Gy/ZA exhibited higher bone density, bone volume, fractional trabecular bone volume, and biomechanical strength compared to mice treated with 20 Gy only (P < 0.05). Statistical analysis revealed that mice treated with 20 Gy/ZA were not significantly different from normal bones with respect to bone density and strength. Micro-CT reconstructions showed improved microarchitecture in the 20 Gy/ZA group compared to 20 Gy. CONCLUSIONS: Treatment of an osteolytic bone with radiation therapy plus zoledronic acid restores normal bone qualities with respect to bone density, microarchitecture, and biomechanical strength. 相似文献
15.
CD4(+)CD25(+) regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice 总被引:13,自引:0,他引:13
Erdman SE Rao VP Poutahidis T Ihrig MM Ge Z Feng Y Tomczak M Rogers AB Horwitz BH Fox JG 《Cancer research》2003,63(18):6042-6050
Roles for host immune response in carcinogenesis are not well defined. Recent studies have shown that microbially driven inflammation can lead to colon cancer and that prior transfer of regulatory lymphocytes expressing CD4 and CD25 prevents the innate inflammatory events that lead to colon cancer in mice. To further examine the ability of regulatory lymphocytes to inhibit carcinogenesis, 129/SvEv Rag-2-deficient mice were inoculated by gastric gavage with Helicobacter hepaticus, an enteric bacterial pathogen of mice. Mice were then treated at 1, 3, or 12 months after infection with adoptive transfer of CD4(+)CD45RB(lo)CD25(+)-regulatory cells. Mice dosed with regulatory cells at 4 or 12 weeks after H. hepaticus infection had reduced severity of inflammatory bowel disease and significantly lower risk of colon cancer during the 8 month observation period, compared with infected mice that had not received cells. This suggested that regulatory cells were able to interrupt the ongoing innate immune events in the stepwise progression to cancer. Transfer of regulatory cells into chronically infected mice with established cancer reduced severity of colitis, epithelial dysplasia, and cancer, but did not eliminate all tumors. Regulatory cells lacking anti-inflammatory cytokine interleukin (IL)-10 were unable to inhibit inflammatory bowel disease, dysplasia, or cancer, showing that IL-10 was required for the protective effects of lymphocytes in this setting. Taken together, the data suggest that IL-10-mediated suppression of host innate inflammatory response was pivotal in interrupting carcinogenesis. Regulatory lymphocytes and cytokines may have implications for novel therapies for colon cancer in humans. 相似文献
16.
Deng X He G Levine A Cao Y Mullins C 《International journal of cancer. Journal international du cancer》2008,122(1):209-218
Matrix metalloproteinases (MMPs) are proteolytic enzymes that play critical roles in the pathogenesis of human cancers. Clinical trials using synthetic small molecule MMP inhibitors have been carried out but with little success. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors that block the extracellular matrix-degrading activity of MMPs. Here, we investigated the possibilities of genetically modifying human bones with TIMPs to create a high-TIMP bone microenvironment, which is hostile to metastatic prostate cancer cells using adenovirus-mediated gene transfer technology and SCID-hu end-organ colonization mouse model. Two strategies were used to achieve bone-specific TIMP expression: (i) ex vivo bone adenoviral infection followed by in vivo bone implantation; and (ii) ex vivo BMS cell infection followed by injection into in vivo implanted human fetal bones. PC-3 prostate cancer cells were injected into human fetal bones 4 weeks after implantation in SCID mice. In vitro, adenovirus-mediated expression of TIMP-1 or TIMP-2 in bone fragments inhibited MMP-2 activity, bone turnover and prostate cancer cell-induced proteolytic degradation as determined by gelatin zymography, calcium measurement and DQ protein quenched fluorescence assay, respectively. In vivo, immunohistochemistry confirmed TIMP-2 expression in AdTIMP-2-infected bone implants 4 weeks after implantation in SCID mice. Mice receiving AdTIMP-treated bone fragments showed significantly reduced PC-3-induced osteolysis, osteoclast recruitment and bone turnover in the implanted bones. We propose that adenoviral gene transfer of TIMP-1 and TIMP-2 can prevent the proteolytic activity of prostate cancer cells in bone and that enhancing anti-proteolytic defense mechanisms in target organs represents a promising form of prostate cancer gene therapy. 相似文献
17.
Regional response leading to tumorigenesis after sulindac in small and large intestine of mice with Apc mutations 总被引:1,自引:0,他引:1
Yang K Fan K Kurihara N Shinozaki H Rigas B Augenlicht L Kopelovich L Edelmann W Kucherlapati R Lipkin M 《Carcinogenesis》2003,24(3):605-611
Sulindac and other NSAIDs have been widely studied as potential chemopreventive agents for colon cancer. Short-term studies have shown adenomatous polyps to regress in patients with familial adenomatous polyposis (FAP). In this study the effect of sulindac on cancer as an endpoint was evaluated in ApcMin mice, a preclinical model of FAP with an Apc mutation in codon 850 that leads to gastrointestinal adenomas and carcinomas. Three groups of mice were studied all of which were fed AIN-76A diet: one group was fed AIN-76A diet alone, a second group received sulindac 200 p.p.m. premixed in the diet and a third group received sulindac 180 p.p.m. added in drinking water. ApcMin mice were killed 9 weeks after feeding was initiated. Mice receiving sulindac developed fewer tumors in the intestine overall; the major decrease in tumor development after sulindac was seen in the small intestine regardless of route of administration. In the large intestine, however, sulindac significantly increased the incidence, multiplicity and volume of tumors in the colon of ApcMin mice, a regional response to sulindac differing from previous reports. Quantitative measurements of apoptosis, Bax and Bcl-xL protein expression in the ApcMin mice revealed the ratio of Bax/Bcl-xL expression and apoptosis increased in the small intestine but decreased in the cecum, consistent with the regional tumorigenesis observed after sulindac. These findings thus suggest involvement of Bax and apoptosis in tumors developing after sulindac treatment in this mouse model. 相似文献
18.
Tran K Risingsong R Royce D Williams CR Sporn MB Liby K 《Cancer prevention research (Philadelphia, Pa.)》2012,5(5):726-734
Novel drugs are needed for the prevention and treatment of breast cancer. Synthetic triterpenoids are a promising new class of compounds with activity in a variety of preclinical cancer models. We tested activity of the methyl ester derivative of the synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me), in a relevant model of estrogen receptor-negative breast cancer, the polyoma-middle T (PyMT), in which the oncoprotein drives carcinogenesis. The developing tumors recapitulate key features of the human disease. Mice were fed CDDO-Me (50 mg/kg diet), starting at 4 weeks of age. CDDO-Me significantly increased the age of mice at onset of first tumor (P < 0.001) by an average of 4.3 weeks and overall survival (P < 0.001) by 5.2 weeks. The drug also inhibited the infiltration of tumor-associated macrophages into mammary glands of PyMT mice at 12 weeks of age and reduced levels of the chemokines CXCL12 and CCL2 in primary PyMT mammary tumor cells. Treatment with this multifunctional drug also inhibited secretion of matrix metalloproteinase-9 in primary tumor cells from PyMT mice and decreased proliferation of these cells by inhibiting cyclin D1 and decreasing phosphorylation of epidermal growth factor receptor and STAT3. 相似文献
19.
Raju J Swamy MV Cooma I Patlolla JM Pittman B Reddy BS Steele VE Rao CV 《International journal of cancer. Journal international du cancer》2005,113(5):798-802
Epidemiological studies suggest that carotenoids such as beta-carotene and lutein play an important role in reducing the risk for several cancers. However, in colon cancer there is ambiguity with regard to the role of these compounds in that both preventive effects and tumor promotion have been observed. In the present study we observed that male F344 rats were able to tolerate up to 2,500 ppm of beta-carotene as well as of lutein. We have then assessed the chemopreventive efficacy of beta-carotene and lutein at dose levels of approximately 4 and 8% of the 2,500 ppm tolerated dose (TD) and also approximately 40 and 80% of the TD on azoxymethane (AOM)-induced colon carcinogenesis, using aberrant crypt foci (ACF) as a surrogate biomarker for colon cancer. Throughout the experiments, 5-week-old male F344 rats were fed the control diet (modified AIN-76A) or experimental diets containing 100 or 200 ppm (approximately 4 or 8% of the 2,500 ppm TD), or 1,000 or 2,000 ppm ( approximately 40 or 80% of the 2,500 ppm TD) of beta-carotene and lutein (n=10 rats/group). After 2 weeks on the experimental or control diets, all animals were injected with AOM (15 mg/kg body wt., once weekly for 2 weeks). At 14 weeks of age, all rats were killed, and their colons were evaluated for ACF. Administration of 100 or 200 ppm of beta-carotene inhibited AOM-induced total colonic ACF formation by 24% (p<0.01) and 36% (p<0.001), respectively, whereas lutein at 200 ppm produced a 27% inhibition (p<0.01) yet had no significant effect at the 100 ppm dose level. Surprisingly, administration of 1,000 or 2,000 ppm of beta-carotene and lutein increased colonic ACF formation in a dose-dependent manner, i.e., to 124% and 144% for the former and 110% and 159% for the latter. These results clearly suggest that further studies are warranted to determine whether the increase in ACF incidence by high doses of beta-carotene and lutein will also lead to an increase in tumor outcome. Taken together these data indicate that the chemopreventive activity of beta-carotene and lutein against colon carcinogenesis depends on the dose level. 相似文献
20.
Preneoplastic and neoplastic liver and lung lesions were studied in male B6C3F1 mice given a single injection (80 mg/kg) of N-nitrosodiethylamine (DEN) intraperitoneally at 4 weeks of age, followed 1 week later by oral exposure to di(2-ethylhexyl)-phthalate (DEHP; at 6000 ppm in the diet), butylated hydroxyanisole (BHA; 7500 ppm in the diet) or indomethacin (10 ppm in the drinking water) alone or in combination (DEHP and BHA or DEHP and indomethacin), and continued for 29 weeks. DEHP or BHA alone and the combination of DEHP and BHA increased the incidence of DEN-initiated focal hepatocellular proliferative lesions (FHPL), including both microscopic hyperplastic foci and hepatocellular adenomas. Mice that received BHA alone or DEHP plus BHA had FHPL that were composed predominantly of eosinophilic hepatocytes, while FHPL in DEHP-exposed mice were basophilic. Indomethacin showed neither promotional or antipromotional effects, except for lung tumors. Mice receiving DEHP and indomethacin after DEN had significantly fewer lung lesions. A high incidence of renal papillary necrosis and nephropathy was observed in the indomethacin-DEHP exposed mice, while these lesions were not found in mice treated with indomethacin alone or DEHP alone. These findings suggest that BHA, an antioxidant, promoted pre-neoplastic liver lesions while indomethacin, a known inhibitor of prostaglandin synthesis and a chemopreventive agent for colon and mammary tumors in other studies, had no effect on liver tumor promotion by DEHP. 相似文献