Influence of dietary fat on the growth of mammary ducts in BALB/c mice

Essential fatty acid (EFA)-deficient diets, when fed to weanling BALB/c mice, retarded the rate of mammary ductal growth. Ductal growth was also markedly retarded in pups fed only EFA-deficient foods from birth (milk from mothers fed EFA-deficient diets for the first 3 wk until weaning, then an EFA-deficient diet for an additional 5 wk). The ability of dissociated mammary epithelial cells to form outgrowths was reduced, and the growth rate of those outgrowths that did form was retarded when such cells were injected into gland-free mammary fat pads in syngeneic hosts fed EFA-deficient diets. Indomethacin, an inhibitor of prostaglandin synthesis, when added at a level of 0.003% to a 15% corn oil-containing diet, resulted in the retardation of ductal growth to about the same extent as did a 15% hydrogenated cottonseed oil-containing diet; however, unlike that associated with EFA-deficient diets, the retardation associated with indomethacin was temporary. EFA appears to be required for normal ductal growth in BALB/c mice, and prostaglandins may be involved in the growth-regulating process.     

Effect of dietary fat on growth kinetics of transplantable mammary adenocarcinoma in BALB/c mice

The growth of mammary adenocarcinomas in BALB/c mice fed a diet containing 10% corn oil (CO), which has about 60% of its fatty acids as linoleate, was significantly greater than that for tumors in mice fed diets containing either 10% hydrogenated cottonseed oil (HCTO), which has no linoleate, or 10% CO plus 0.003% indomethacin (IM). The proportion of the tumor occupied by the various cell types was quantitated from histologic sections for 2 different mammary adenocarcinomas. At 2 weeks post implantation the degree of inflammatory cell (IC) infiltration of the first adenocarcinoma (tumor IX) did not account for the difference in tumor mass induced by dietary fat. This conclusion was confirmed by a study of a group of tumors arising from hyperplastic alveolar nodule transplants, which showed a similar dietary response but in which IC infiltration was minimal even in the largest tumors. Cell cycle parameters of tumor IX were determined by the fraction-of-labeled-mitoses (FLM) procedure. No differences were found in the duration of the G1, S, G2, or M phases of the cell cycle or the total cell cycle time in neoplasms from the CO and HCTO diet groups. The fraction of tumor cells dividing in neoplasms from the 2 diet groups was also identical. The only parameter that was significantly different was the rate of tumor cell loss when determined by both indirect (FLM) and direct [( 125I]iododeoxyuridine) methods. Tumor cell loss for adenocarcinomas from mice fed HCTO or CO plus IM was approximately twice that obtained for tumors from the CO-fed mice. These observations on tumor cell loss were discussed in terms of: the influence of dietary linoleate on the size of mammary tumors and the involvement of prostaglandins in this process.     

Effect of dietary calorie and fat restriction on mammary tumor growth and hepatic as well as tumor glutathione in rats

Effect of dietary calorie restriction and fat reduction on growth of established mammary carcinoma in rats and on glutathione levels in liver and tumor tissue was investigated. Reduced (GSH) and oxidized (GSSG) glutathione were determined enzymatically. Female Sprague-Dawley rats were injected with 25 mg/kg methylnitrosourea (MNU) on day 50 of life for tumor induction, and subsequently fed a diet containing 50 kcal/day with 45% (energy %) fat. When tumors reached approximately 1 cm3, the diet was changed for 10 +/- 2 weeks. Four dietary groups were formed: two high calorie groups (50 kcal/day) with 45% or 25% fat and two calorie restricted groups (35 kcal/day) with 45% or 25% fat, respectively. Tumor growth was significantly inhibited by the 30% calorie restriction, and the inhibition was most effective in the calorie restricted group with low fat level. However, reduction of fat, alone, had no significant inhibitory effect. GSSG levels in both liver and tumor showed no differences among the groups. Hepatic GSH levels tended to be lower in the calorie-restricted groups, and showed no difference between isocaloric groups with different fat levels. In contrast, GSH in tumor tissue tended to be lower in the low fat groups, independently of calorie levels.     

Effect of dietary fat on human breast cancer growth and lung metastasis in nude mice

Results from epidemiological studies have generally indicated an association of dietary saturated animal fats with human breast cancer risk. Some studies, however, have suggested a similar association for some polyunsaturated vegetable fats shown to promote both rodent mammary carcinogenesis and metastasis. This study was performed to evaluate the effects of corn oil on growth and metastasis of MDA-MB-435 human breast cancer cells, which have a propensity for metastasis. Corn oil is rich in the omega-6 fatty acid linoleic acid. Fifty-eight female athymic nude mice (NCr-nu/nu) were fed a high-fat diet (23% wt/wt corn oil; 12% linoleic acid) or a low-fat diet (5% wt/wt corn oil; 2.7% linoleic acid). Seven days after diets were started, tumor cells (1 x 10(6) were injected into a mammary fat pad. The time to appearance of solid tumors and the tumor size were recorded. After 15 weeks, the study was terminated, and autopsies were performed to determine the weight of the primary tumor and the extent of metastasis. The latent interval for tumor appearance in the animals fed the high-fat diet was shorter than that in the low-fat diet group, and the tumor growth rate in the high-fat diet group showed a small but statistically significant increase compared with the low-fat diet group. Primary tumors developed in 27 of the 29 mice on the high-fat diet and in 21 of the 29 on the low-fat diet. Of the mice with palpable primary tumors, 18 of 27 in the high-fat diet group and eight of 21 in the low-fat diet group had macroscopic lung metastases. The extent of metastasis in the high-fat diet group was independent of the primary tumor weight, but only those in the low-fat diet group with primary tumors weighing more than 2 g developed metastases. These results suggest that a high-fat diet rich in omega-6 polyunsaturated fatty acid can enhance metastasis of human breast cancer cells in this mouse model. The findings support the need for further study of the relationship between dietary polyunsaturated fats and breast cancer risk and for experiments to determine the effect on metastasis of only a 50% difference in fat intake--the dietary goal of the proposed clinical trials of low-fat dietary intervention in breast cancer patients.     

INHIBITORY EFFECT OF DEMO ON THE GROWTH OF TRANSPLANTED HUMAN COLON CANCER IN NUDE MICE

A human colon cancer cell line Hce- 8693 was heterotransplanted in nude mice. Polyamine blosythesis Inhibitor a- dlfiuoromethylomithine (DFMO ) show a marked reproducible inhibition in this model. The size and weight of transplanted tumor In DFMO group were smaller than those of the control group and the average inhibition rate was 72.8% (P < 0.001) . DFMO showed higher tumor inhibitory rate than 5-Fu (35. 4%) (P<0. 001) . Furthermore. DFMO demonstrated less severe bone marrow inhibition in the nude mice than 5-Fu (20. 0% Vs 53. 2%. P<0. 001) .There was no synergistic action in these two drugs at the experimental dose. The concentration of putrescine and spermidine in the plasma and tumor tissue in the DFMO group were 70% lower than those of the control group (P<0. 001) . These results indicate that the anti-tumor effect of DFMO might be explained by the inhibition of polyamine biosynthesis and this study provides an experimental basis for future clinical application of DFMO.     

Enhanced growth rate of transplanted mammary adenocarcinoma induced in C3H mice by dietary linoleate.

Three-month-old C3H female mice were given injections of 5-mg pieces of mammary adenocarcinoma and were then fed diets that either were fat free or contained saturated fat (15% hydrogenated cottonseed oil) or linoleate (1-15% corn oil). After 6 weeks, the tumors in mice fed the linoleate diet weighed 3-4 times more than those in mice fed the fat-free or saturated-fat diets. Despite a linoleate-free diet, tumors contained appreciable amounts of linoleate and arachidonate (approximately 2 and 9% of the total fatty acids, respectively). When the level of dietary corn oil was increased from 1 to 15%, the linoleate content of the tumors increased from 4 to 18% of the total fatty acids. However, in these instances, the tumor arachidonate levels increased to maximum values even when the 1% corn oil diet was used. These observations showed that mammary tumor growth was depressed by a fat-free or saturated-fat diet and enhanced by dietary linoleate. Furthermore, they suggested that the growth rate was related to the arachidonate content rather than the linoleate content of the tumors.     

Comparison between the effects of dietary fat level and of calorie intake on methylnitrosourea-induced mammary carcinogenesis in female SD rats

The aim of this study was to separate the effects of calorie intake on tumorigenesis from those of fat content and fat composition in an animal model. Our principal observations were the following. Decreasing the calorie level by 30% significantly inhibited tumor development in any observed parameter of tumorigenesis, independently of the level of fat. The fat content of semi-synthetic diets, although varying by 44.4%, did not significantly influence mammary tumorigenesis; in fact, carcinogenic expression was discontinuously related to the fat level. A plateau of tumor incidence was observed at the level of 35 energy percentage of fat. Fat composition did not influence tumorigenesis or body weight gain. The role of caloric restriction is thus stressed in relation to possible dietary prevention of cancer.     

Hepatectomy accelerates the growth of transplanted liver tumor in mice.

To study the effect of hepatectomy on the growth of liver tumor, Shionogi Carcinoma 42, a mammary tumor, was transplanted into the liver of mice which had undergone 40% hepatectomy. The liver tumor and the number of pulmonary metastases in hepatectomized mice were significantly larger than those in nonhepatectomized mice. Responses to lectins and IL-2, subpopulations, and cytotoxicity to YAC-1 and P815 cells of splenocytes were assessed to evaluate immunological status. At the initial phase after hepatectomy and tumor transplantation into the remaining liver, NK activity transiently increased, and function of B and T cells, especially of helper T cells, decreased, while B-cell function recovered beyond normal levels in a later phase. These results suggest that liver may play an important immunological role and that the immunological modification after hepatectomy may be responsible for the accelerated growth of liver tumor. Accordingly, some adjuvant immunotherapy may be recommended for the prevention of recurrence after hepatectomy for liver tumor.     

X-linked dominant growth suppression of transplanted tumors in C57BL/6J-scid mice

Tumor susceptibility, angiogenesis, and immune response differ between mouse strains. We, therefore, examined the growth rates of tumor xenografts in three genetically isolated strains of severe combined immunodeficient mice (C.B-17, C57BL/6J, and C3H). Tumors grew at significantly reduced rates in the C57BL/6J-scid strain. Engrafting bone marrow from the C57BL/6J-scid strain onto C.B-17-scid mice did not transfer the slow-growing tumor phenotype to the recipient mice; this counters the supposition that the slow-growing tumor phenotype is caused by a greater immune response to the xenograft in the C57BL/6J-scid strain. To establish the inheritance pattern of the slow-growing tumor phenotype, we reciprocally crossed C.B-17-scid mice and C57BL/6J-scid mice. Tumor growth was suppressed in all of the F1 progeny except the male mice derived from the cross between C.B-17-scid female and C57BL/6J-scid male mice. The F1 male mice that received the X chromosome from the C.B-17 strain displayed a fast-growing tumor phenotype. These results confirm that there are significant strain differences in capacity to support the growth of tumor xenografts. In addition, these results reveal the existence of a dominant allele involved in host suppression of tumor growth on the X chromosome of C57BL/6J mice.     

染料木素对人卵巢癌裸鼠皮下移植瘤抑制作用及其机制的探讨

目的:探讨染料木素对人卵巢癌裸鼠皮下移植瘤的抑制作用及其机制。方法:建立人卵巢癌裸鼠皮下移植瘤模型,通过腹腔注射的给药方式探讨染料木素对卵巢癌的抑制作用,并用蛋白质印迹法检测染料木素作用后移植瘤组织Cyclin B1和Cyclin D1蛋白的表达情况。结果:染料木素对人卵巢癌裸鼠皮下移植瘤具有抑制作用且呈剂量效应正相关,与对照组比较,染料木素低、中、高剂量组肿瘤生长抑制率差异均有统计学意义,t值分别为9.103、51.226和91.735,P均<0.001。染料木素可下调Cyclin B1蛋白的表达并上调Cyclin D1蛋白的表达。结论:染料木素对人卵巢癌裸鼠皮下移植瘤的抑制作用可能通过下调Cyclin B1蛋白表达并上调CyclinD1蛋白表达而实现。     

Kinetics of cell proliferation and growth of transplanted hepatoma in mice]

The authors compared the parameters of the growth and kinetics of the cell proliferation of five strains of transplantable mice hepatoma. By means of autoradiography and 3H-thymidine the curves of labeled mitoses and these of persistently labeled cells were obtained and analysed. Of all the mitotic cycle parameters: the time of G2 period and duration of phase S are mostly constant and not related with the rate of tumors growth. Hepatoma 46 is characterized by an extremely low intensity of cell production in relatively low their death rate. On the contrary, in hepatoma 48 possessing the same rate of growth the cell production was much more intensive, the rate of cell death being very high.     

Epidermal growth factor suppresses the tumor growth of human breast cancer transplanted in nude mice

The present work was performed in order to clarify the effects of epidermal growth factor (EGF) and transforming growth factor-beta (TGF-beta) on the tumor growth of human breast cancer transplanted in nude mice. A local injection of 2 micrograms EGF significantly suppressed the tumor growth of human breast cancer MX-1 and primary breast tumor (UM-1) which was first isolated from a human female breast cancer patient in our laboratory. On the other hand, TGF-beta did not suppress the growth of those tumors. Our result indicates that human EGF may be useful as a therapeutic agent for some human breast cancers. Human EGF may lead to a new trend of therapy in the treatment of cancer.     

Effects of dietary menhaden oil and retinyl acetate on the growth of DU 145 human prostatic adenocarcinoma cells transplanted into athymic nude mice

The effects of feeding menhaden oil (MO), rich in -3 fatty acids,or supplemental vitamin A [as retinyl acetate (RA)], on thegrowth of DU 145 human prostate cancer cells were studied inathymic nude mice. The mice were fed AIN-76A diets containingeither 23% corn oil (CO), a mixture of 17% MO and 6% CO, or23% CO plus RA. After irradiation sterilization, the RA-supplementeddiet was found to contain 15 times the amount of vitamin A presentin the control diet. There were 24 mice in each dietary group.Three weeks after commencement of feeding the experimental diets,1x10⁶ or 5x10⁶ DU 145 cells were inoculated into subgroups of12 animals, and the appearance and growth of solid tumors followedover a 6-week period. There was no significant difference intumor latency between mice fed MO plus CO, and those fed COalone, regardless of the inoculum size. However, the appearanceof palpable tumors was more rapid in mice inoculated with 5x10⁶cells and fed the RA-supplemented CO diet (91% after 17 days)compared with mice receiving the same tumor cell load but fedthe unsup-plemented CO diet (55% after 17 days). Growth of thesolid tumors was retarded significantly in mice inoculated with1x10⁶ cells and fed the MO-containing diet compared with theCO controls; this effect was not evident in animals who received5 10⁶ cells. RA supplementation caused accelerated tumor growth,which, again, only achieved statistical significance in thegroupinoculated with 1 10⁶ cells.     

白藜芦醇对小鼠移植宫颈癌的抑制作用及机制研究

背景与目的:白藜芦醇(resveratrol,Res)是天然存在于葡萄等植物中的一种多酚类化合物,具有抗癌、抗氧化等作用.体外研究发现Res可抑制宫颈癌细胞的生长,但在体内是否有作用尚未见报道.本研究观察Res对小鼠宫颈癌细胞株U14移植瘤的抑制作用,并初步探讨Res的抗肿瘤作用机制.方法:建立615近交系小鼠U14移植瘤动物模型,并随机分成4组:对照组(0.9％的NaCl溶液)、Res低剂量组(每日剂量2.5 mg/kg)、Res高剂量组(每日剂量10 mg/kg)和顺铂组,每组10只.连续给药20 d,于接种后第26天处死小鼠,检测肿瘤体积及质量,计算抑瘤率,采用RT-PCR和Western blot分析肿瘤组织巨噬细胞移动抑制因子(migration inhibitory factor,MIF)的表达水平,通过免疫组织化学法检测肿瘤组织微血管密度(microvessel density,MVD),并用原位末端标记法(TUNEL)检测肿瘤细胞凋亡指数(apoptosis index,AI).结果:Res高剂量组、顺铂组肿瘤的生长明显受到抑制,肿瘤体积缩小,肿瘤质量明显低于对照组(P＜O.01);Res高剂量组和顺铂组抑瘤率分别为52.94％、56.44％,明显高于Res低剂量组(P＜0.01).Res高剂量组和顺铂组MIF mRNA与蛋白表达水平及MVD明显降低,AI则明显升高,与对照组相比,差异均有统计学意义(P＜O.01),但低剂量Res对MIF表达、MVD及AI无明显影响(P＞0.05).结论:Res可明显抑制小鼠宫颈癌的生长,机制可能与抑制MIF表达、降低MVD和促进细胞凋亡有关.     

地塞米松影响Lewis肺癌小鼠移植瘤生长及微血管生成的研究

背景与目的:近年来研究发现糖皮质激素与多种肿瘤发生、发展密切相关,本研究旨在探讨地塞米松对Lewis肺癌小鼠移植瘤生长及微血管生成的影响.方法:将Lewis肺癌细胞接种于C57BL/6小鼠右腋皮下,按数字表法随机分为3组:对照组、顺铂组和地塞米松组.于接种后第7天起分别连续给药10 d,密切监测皮下移植瘤体积变化.于接种后第17天处死全部小鼠,剥离皮下肿瘤称质量并计算抑瘤率,采用免疫组化法检测肿瘤缺氧诱导因子(hypoxia inducible factor 1α,HIF-1 α)、血管内皮生长因子(vascular endothelial growth factor,VEGF)表达与微血管密度(microvessel density,MVD)计数水平.结果:各用药组肿瘤的生长明显受到抑制,瘤质量明显低于对照组(F=11.593,P＜0.05);与对照组比较,各用药组肿瘤组织中HIF-1α、VEGF表达与MVD计数水平显著降低(F值分别为4.788、8.220和12.456,P均＜0.05);而地塞米松组与顺铂组比较,差异无统计学意义(P＞0.05).结论:地塞米松可通过抑制肿瘤组织中HIF-1 α、VEGF的表达,从而抑制Lewis肺癌的生长和微血管生成.     

Differences in progression of BALB/cfRIII and BALB/cfC3H mammary hyperplastic alveolar nodules transplanted into the gland-free fat pads of BALB/c mice

In BALB/cfC3H and BALB/cfRIII virgin female mice, i.e., BALB/c mice carrying milk-transmitted C3H and those carrying RIII murine mammary tumor virus infection, respectively, mammary noduligenesis and tumorigenesis are remarkably different. Focal hyperplastic alveolar changes or hyperplastic alveolar nodules were removed from BALB/cfRIII or BALB/cfC3H breeding female donors and transplanted into the gland-free mammary fat pads of syngeneic BALB/c virgin female recipients with or without hormonal supplementation. The results obtained have shown significant differences in: (a) the morphological type of outgrowths; (b) the incidence of malignant transformations; and (c) the hormonal responsiveness of the tumors arisen after pituitary transplants.     

重组肿瘤抑素血管生成抑制相关肽对裸鼠移植性卵巢癌的抑制作用

目的 观察肿瘤抑素改造后所得血管生成抑制相关肽(21肽)的抗血管生成活性及对裸鼠移植卵巢癌的抑制作用.方法 用亲和层析法纯化21肽.观察接种SKOV3细胞系的裸鼠经21肽治疗后的肿瘤生长情况,检测21肽对肿瘤组织的微血管密度和免疫组织化学指标的影响.结果 经21 d的治疗后,21肽组平均抑瘤率可达53.17%.21肽组肿瘤组织微血管密度(CD34表达)为6.324±1.643,与对照组(16.127±2.535)比较明显降低(P＜0.05).21肽组肿瘤组织的增殖细胞核抗原(PCNA)、血管内皮生长因子(VEGF)、基质金属蛋白酶2(MMP-2)呈低表达(P＜0.01),而基质金属蛋白酶抑制因子2(TIMP-2)呈高表达(P＜0.01).结论 21肽具有显著的抗血管生成活性,对卵巢癌具有较好的抑制作用,其抑制卵巢癌的作用机制可能与其降低新生血管形成和调解血管生成相关因子的表达有关.