Metabolic and Morphologic Characteristics of Adipose Tissue Associated with the Growth of Malignant Tumors

Changes in total body fat and the metabolic and morphologic characteristics of adipose tissue were sequentially investigated in individual rabbits implanted with VX2 tumors to elucidate the pathology of the fat reduction in animals with malignant tumors as compared with that of diet-restricted rabbits. Lipogenesis in normal, VX2–implanted, and diet-restricted rabbit groups on day 40 after the start of the experiments was 19.1±2.9, 13.3±3.5, and 41.7±6.0×l0⁵ cpm/g/h, respectively, and glycerol liberation by their adipose tissue was 199±21, 528±94, and 301±45 nmol/g/h, respectively. In addition, apoptotic cells were noted in the adipose tissue of VX2–implanted rabbits on days 20–30 after implantation, but not in diet-restricted rabbits. The results showed clear differences between the total body fat reduction profiles of VX2–implanted rabbits and diet-restricted rabbits, suggesting a characteristic lipid metabolism with enhanced lipolysis and diminished lipogenesis in VX2–implanted rabbits. The results strongly suggest that adipocyte apoptosis might be involved in these phenomena.     

Probucol decreases total body fat loss in VX2-carcinoma-induced cachectic rabbits

We previously reported the continuous decrease of total body fat in VX2-carcinoma-bearing rabbits after tumor implantation, as well as changes in the serum lipid profile. Probucol, an antioxidant drug, has a cholesterol lowering effect against hyperlipidemic subjects. VX2-carcinoma-bearing rabbits fed with a diet containing 1% probucol did not show any difference in serum lipid compositions as compared with rabbits fed with a control diet. Similarly serum lipolytic activity showed no differences, whether probucol was administered or not, while the decrease in total body fat was significantly less when probucol was administered.     

兔VX2移植瘤PET—CT的显像研究

目的：研究兔VX2移植瘤的PET／CT显像及其应用前景。方法：48只日本大白兔种植VX2肿瘤,随机分为4组,分别于2、4、6和8周进行PET／CT显像,获得注射^18F-FDG后不同时间（20、40、60、80、100和120min）PET／CT图像,以及肿瘤组织和正常组织的SUV值。显像后处死大白兔,进行病理检查,观察肿瘤细胞的核分裂像及平均肿瘤微血管密度。结果：VX2移植瘤总成活率为80％;注射^18F-FDG后40～100min的SUV值与20和120min的SUV值相比,差异有统计学意义,P≤0．001。种植VX2肿瘤细胞后2、4、6和8周的肿瘤组织和正常组织的SUV值差异均有统计学意义,P均〈0．05。肿瘤大小的增殖、病理性核分裂像和平均肿瘤微血管密度与注射^18F-FDG后60min的SUV值密切相关。结论：PET／CT还可以清楚地显示肿瘤的解剖部位、形态、大小和肿瘤细胞的代谢状况,及时发现转移,是一项可靠和有价值的检查手段。     

经皮介入微波热凝治疗实验性VX2肺癌的有效性与安全性

背景与目的:经皮微波热凝治疗(percutaneous microwave coagulation therapy,PMCT)是一种重要的实体肿瘤微创介入治疗方法.本研究评价新型国产微波肿瘤治疗仪及气冷循环微波刀经皮穿刺介入治疗肺VX2移植肿瘤的安全性及有效性.方法:用组织块悬液注射法在30只新西兰大白兔中建立实验性VX2肺癌模型,随机分为对照组、治疗A组(40 W×120 s)、B组(80 W×60 s).在CT引导下经皮穿刺,并按预设参数进行微波热凝治疗;对照组予以假性治疗.观察实验兔术后一般状况,定期CT检查观察肿瘤进展情况,在治疗后第0、1、7天每组随机解剖1只实验兔观察局部组织学改变.结果:肿瘤细胞种植成功率100%.肺癌模型制作成功率为86.7%(26/30).对照组、治疗A组和B组的生存期分别为(39.7±5.3)天、(62.2±4.4)天和(61.7±4.5)天(P＜0.01).气胸的发生情况分别为33.3%(2/6)、55.6%(5/9)和33.3%(3/9)(P＞0.10).结论:PMCT是一种安全、有效、微创的治疗方法,可为肺癌的介入治疗提供一种新的选择.     

Studies on anticancer treatment with an oily anticancer drug injected into the ligated feeding hepatic artery for liver cancer

In six adult patients with nonresectable liver cancer, as well as in mature New Zealand white rabbits with implanted VX2 carcinoma in the liver, the artery feeding the hepatic lobe with the malignant lesion was ligated, and an oily contrast medium (Lipiodol Ultra-Fluid) was injected into the hepatoproximal lumen of the ligated artery of the liver with carcinoma. The oily contrast medium was detected in all the branches of the artery injected, and thereafter was found only in tumor tissue for 7 days experimentally and for 16 months clinically. Taking advantage of this phenomenon, the therapeutic effect of the injection of an oily anticancer drug (bleomycin oil suspension) into the hepatoproximal lumen of the ligated hepatic artery was investigated in rabbits with VX2 carcinoma of the liver. The mean concentration level of bleomycin in the tumor tissue was 2.4 +/- 0.4 microgram/g 1 week after the injection of bleomycin oil suspension (1.5 mg potency/kg) in three rabbits. However, its concentration level in nontumorous tissue of the liver was undetectably low in two rabbits, but 0.6 microgram/g in the third rabbit. The group of rabbits receiving an injection of bleomycin oil suspension into the ligated artery had a significantly longer mean survival time than those of the experimental group receiving an injection of saline solution of bleomycin into the ligated artery as well as the three other groups treated (P less than 0.02, N = 5 for each group). It may be concluded that an oily anticancer drug injected into the hepatoproximal lumen of the ligated hepatic artery can intensify the anticancer effects of a ligation of the hepatic artery for liver cancer.     

Fatty-acid composition of breast and iliac adipose tissue in breast-cancer patients.

In order to determine to what extent the fatty-acid composition of breast adipose tissue is representative of the body-fat composition in breast carcinoma, we compared the fatty-acid composition of breast adipose tissue to that of iliac fat in breast-cancer patients. Triglycerides from the 2 sites were purified by thin-layer chromatography and fatty-acid composition was determined by capillary gas chromatography. Compared with iliac fat, mammary fat was higher in saturated (33.2 +/- 3.9 vs. 24.4 +/- 1.6%; p = 0.0001) and lower in mono-unsaturated (48.0 +/- 2.2 vs. 54.8 +/- 2.7%; p = 0.0001) and poly-unsaturated fatty acids (16.6 +/- 3.7 vs. 18.0 +/- 3.1%; p = 0.0001). A positive correlation was found between the 2 sites for linoleate (r = 0.95; p = 0.0003), alpha-linolenate (r = 0.83; p = 0.01), palmitate (r = 0.78; p = 0.02) and palmitoleate (r = 0.76; p = 0.02). No relationship was observed for stearic and oleic acids. We conclude that breast and iliac fat differ with regard to fatty-acid composition. The interpretation of fatty-acid composition of the body stores in breast-cancer patients, as an indicator of long-term intake of dietary fat, should take into account the sampling site of stored lipids.     

阿霉素肝动脉热化疗治疗兔肝VX2移植癌

背景与目的:研究表明,加热可提高兔VX2细胞对阿霉素(adriamycin,ADM)的增敏作用,可促进ADM进入细胞内,从而提高ADM的抗癌作用。作者在兔VX2细胞行ADM热化疗研究和兔肝VX2细胞移植瘤模型建立基础上,进行ADM兔肝动脉热灌注,以评价介入性化疗与介入性热化疗对兔肝癌的抑瘤效果。方法:将VX2细胞接种于60只新西兰白兔肝右叶,建立兔肝VX2移植癌模型。随机分4组,每组15只。利用导管经肝动脉分别给各组37℃生理盐水(第1组)、37℃ADM溶液(第2组)、60℃生理盐水(第3组)、60℃ADM溶液(第4组),1周后观察各组肿瘤体积及血清AST水平,观察荷瘤兔的存活期。结果:第4组肿瘤生长率(0.53±0.21)%,与第1组(3.48±1.17)%相比有显著性差异(P<0.01),与第2组的(1.09±0.26)%、第3组的(3.32±1.28)%相比亦有显著性差异(P<0.05)。第4组存活期(87.0±2.0)天,与第1组(40.5±3.0)天相比差异有显著性(P<0.05)。第4组血清AST水平给药前后变化与其它各组相比无显著性差异(P>0.05),与对第1组相比有显著性差异(P<0.05)。结论:60℃ADM溶液热灌注可降低肿瘤生长率,延长存活期,而对肝功能的损害是可逆的。     

Induction of VX2 para-renal carcinoma in rabbits: generation of animal model for loco-regional treatments of solid tumors

Background

Animal models of para-renal cancer can provide useful information for the evaluation of tumor response to loco-regional therapy experiments in solid tumors. The aim of our study was to establish a rabbit para-renal cancer model using locally implanted VX2 tumors.

Methods

In order to generate a rabbit model of para-renal cancer, we established four hind limb donor rabbits by using frozen VX2 tumor samples. Following inoculation, rabbits were monitored for appetite and signs of pain. Viable tumors appeared as palpable nodules within 2 weeks of inoculation. Tumor growth was confirmed in all rabbits by high-resolution ultrasound analysis and histology. Once tumor growth was established, hind limb tumors extraction was used for tumor line propagation and para-renal tumor creation. Twenty-one rabbit models bearing para-renal cancer were established by implanting VX2 tumor into the para-renal capsula. Tumors developed into discreet 2–3 cm nodules within 1–3 weeks of implantation. Serial renal ultrasonography follow-up, starting 1 week after tumor implantation, was performed. Two weeks after tumor implantation, rabbits were euthanized and tumors and other organs were collected for histopathology.

Results

Tumor growth after VX2 tumor fragment implantation was confirmed in all rabbits by high-resolution ultrasound (US) imaging examinations of the para-renal regions and was measured with digital caliper. The para-renal injection of VX2 tumor fragments, achieved tumor growth in 100% of cases. All data were confirmed by histological analysis.

Conclusions

We generated for the first time, a model of para-renal cancer by surgical tumor implantation of VX2 frozen tumor fragments into rabbit’s para-renal region. This method minimizes the development of metastases and the use of non-necrotic tumors and will optimize the evaluation of tumor response to loco-regional therapy experiments.

     

Selective expansion of 5,10-methylenetetrahydrofolate pools and modulation of 5-fluorouracil antitumor activity by leucovorin in vivo

Expansion of CH2THF pools in tissues of BALB/c mice bearing s.c.-implanted EMT6 mammary adenocarcinomas was measured after leucovorin administration. Twenty-four mice were treated with leucovorin at doses of 0, 45, 90, or 180 mg/kg/injection x 8 injections spaced over 48 h. Tumor and bone marrow cytosols were assayed for CH2THF by forming ternary complexes with thymidylate synthase and [3H]FdUMP. Tumor CH2THF pools were expanded significantly at the two higher doses. Marrow levels were not different from controls. Groups of tumor bearing mice were treated with saline, leucovorin, 5-fluorouracil or 5-fluourouracil plus leucovorin on an optimal dosage schedule. Measured plus leucovorin on an optimal dosage schedule. Measured from the last day of treatment, these tumors grew to 10 mm root-mean-square diameters in 3.5 +/- 1.4, 5.0 +/- 1.2, 6.5 +/- 1.5, and 9.3 +/- 1.2 days, respectively. Growth rates were significantly different from controls only in the latter two groups.     

Angiogenesis in the adipose tissue of tumor-bearing rabbits treated by cyclic plasma perfusion

The mechanisms of cancer cachexia have not been elucidated. We previously reported that cyclic plasma perfusion using non-coated charcoal was effective in cancer cachexia. In the present study we investigated the angiogenic effect of cyclic plasma perfusion on adipose tissue. Twenty rabbits were divided into two groups, i.e., tumor-bearing rabbits subjected to cyclic plasma perfusion (n=10, PP group), and tumor-bearing rabbits subjected to sham-perfusion (n=10, SP group). The changes in body weight, total body fat, and expression of angiogenic factors were investigated. Loss of body weight and total body fat was significantly suppressed in the PP group. Apoptosis of adipocytes was seen in both groups only in the early stage of tumor bearing. Lipolytic activity in the PP group showed a lower ratio than that in the SP group. In the PP group, increased microvessel density and expression of vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) were seen at 40 days after transplantation. Similar findings were not seen in the SP group. These results suggest that cyclic plasma perfusion not only decreased lipolytic activity but induced angiogenesis in the adipose tissue.     

Alterations in whole body, muscle, liver, and tumor tissue protein synthesis and degradation in Novikoff hepatoma and Yoshida sarcoma tumor growth studied in vivo

The rate of protein synthesis in vivo was assessed in tumor tissue, skeletal muscle, liver, and the whole body of rats bearing either the Yoshida sarcoma or Novikoff hepatoma after 18 days of tumor growth and compared to tumor-free controls. Changes in size of the whole animal and tumor (i.e., growth) were measured, and fractional rates of growth, synthesis, and degradation were estimated. Muscle protein synthesis and whole-body growth were significantly reduced in both groups of tumor-bearing rats after 18 days of tumor growth. In addition to reductions in muscle protein synthesis, whole-body protein synthesis was significantly reduced in the Yoshida tumor-bearing group (587 +/- 36 versus 401 +/- 40 mg/h; mean +/- SEM; control versus Yoshida group, respectively, P less than 0.01). Tumor protein synthesis was not statistically different between the Yoshida tumor (76 +/- 21 mg/h) and the Novikoff tumor (50 +/- 8) after 18 days of growth despite the fact that the Yoshida tumors were significantly larger (33.9 +/- 4.2 g versus 11.9 +/- 1.2 g; P less than 0.01). The fractional synthesis rate (Ks) was, in fact, significantly slower in the Yoshida versus the Novikoff tumor (36.8 +/- 7.6 versus 55.1 +/- 4.8%/day). Tumor growth (Kg) followed first order growth rates for both tumor types (r = 0.945, 0.869; Kg = 17.2 +/- 1.6, 15.5 +/- 1.9%/day; Yoshida and Novikoff, respectively). The fractional degradation rate of tumor protein (Kd) was determined as the difference between the two first order rate constants Ks and Kg. The tumor protein degradation rate was significantly reduced in the Yoshida tumors compared to the Novikoff tumors (19.6 +/- 8.2% versus 39.6 +/- 4.2%/day, respectively). The greater size in the Yoshida sarcoma can be attributed to reduction in fractional protein degradation rather than change in synthesis rates, which supports the theory that some tumors can regulate their growth by alteration in tumor protein degradation rates (J. A. Tayek et al., Cancer Res., 46:5649-5654, 1986).     

Effective targeting of solid tumors in patients with locally advanced cancers by radiolabeled pegylated liposomes.

The biodistribution and pharmacokinetics of (111)In-DTPA-labeled pegylated liposomes (IDLPL) were studied in 17 patients with locally advanced cancers. The patients received 65-107 MBq of IDLPL, and nuclear medicine whole body gamma camera imaging was used to study liposome biodistribution. The t(1/2beta) of IDLPL was 76.1 h. Positive tumor images were obtained in 15 of 17 studies (4 of 5 breast, 5 of 5 head and neck, 3 of 4 bronchus, 2 of 2 glioma, and 1 of 1 cervix cancer). The levels of tumor liposome uptake estimated from regions of interest on gamma camera images were approximately 0.5-3.5% of the injected dose at 72 h. The greatest levels of uptake were seen in the patients with head and neck cancers [33.0 +/- 15.8% ID/kg (percentage of injected dose/kg)]. The uptake in the lung tumors was at an intermediate level (18.3 +/- 5.7% ID/kg), and the breast cancers showed relatively low levels of uptake (5.3 +/- 2.6% ID/kg). These liposome uptake values mirrored the estimated tumor volumes of the various tumor types (36.2 +/- 18.0 cm3 for squamous cell cancer of the head and neck, 114.5 +/- 42.0 cm3 for lung tumors, and 234.7 +/- 101.4 cm3 for breast tumors). In addition, significant localization of the liposomes was seen in the tissues of the reticuloendothelial system (liver, spleen, and bone marrow). One patient with extensive mucocutaneous AIDS-related Kaposi sarcoma was also studied according to a modified protocol, and prominent deposition of the radiolabeled liposomes was demonstrated in these lesions. An additional two patients with resectable head and neck cancer received 26 MBq of IDLPL 48 h before undergoing surgical excision of their tumors. Samples of the tumor, adjacent normal mucosa, muscle, fat, skin, and salivary tissue were obtained at operation. The levels of tumor uptake were 8.8 and 15.9% ID/kg, respectively, with tumor uptake exceeding that in normal mucosa by a mean ratio of 2.3:1, in skin by 3.6:1, in salivary gland by 5.6:1, in muscle by 8.3:1, and in fat by 10.8:1. These data strongly support the development of pegylated liposomal agents for the treatment of solid tumors, particularly those of the head and neck.     

Organ distribution and tumor uptake of liposome entrapped cis-bis-neodecanoato trans-R,R-1,2 diaminocyclohexane platinum (II) administered intravenously and into the proper hepatic artery

Summary Blood and tissue levels of elemental platinum (Pt) were measured after the administration of a liposomally entrapped cisplatin analogue, cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (L-NDDP). In mice bearing subcutaneous B16 melanoma tumors, Pt tumor levels were not significantly different in animals treated i.v. with an equimolar dose of L-NDDP or cisplatin. In rabbits bearing liver tumors of VX2 carcinoma, i.v. administration of L-NDDP resulted in 2- to 20-fold higher Pt levels in all tissues (including VX2 tumors) except the brain and peripheral nerve than in animals treated with an equimolar dose of cisplatin. Compared with i.v. administration, inoculation of either drug into the proper hepatic artery resulted in a severalfold increase of Pt levels in the VX2 tumors. Blood and other tissue levels were not substantially changed by intraarterial (i.a.) administration. These studies show that (1) multilamellar lipid vesicles can adequately deliver a lipophilic cisplatin analogue (NDDP) to nonphagocytic tumors when administered i.v. and (2) the inoculation of L-NDDP into the proper hepatic artery results in higher Pt tumor levels than with i.v. administration but does not decrease the systemic distribution of the drug.Supported in part by NIH grant CA41581 to ARK and a grant from The Liposome Co., Inc., Princeton, NJ     

Treatment of isografted 9L rat brain tumors with beta-5-o-carboranyl-2'-deoxyuridine neutron capture therapy.

beta-5-o-Carboranyl-2'-deoxyuridine (D-CDU) is a nontoxic pyrimidine nucleoside analogue designed for boron neutron capture therapy of brain tumors. In vitro studies indicated that D-CDU accumulates to levels 92- and 117-fold higher than the extracellular concentration in rat 9L and human U-251 glioma cells, respectively, and persists for several hours at levels 5-fold higher than the extracellular concentration. Furthermore, D-CDU was not toxic to rats injected i.p. with up to 150 mg/kg. On the basis of these studies, D-CDU was evaluated as a neutron capture therapy agent using rats bearing stereotactically implanted intracranial 9L tumors at single i.p. doses of 30 mg/kg and 150 mg/kg of D-CDU (20% 10B enriched), given 2 h before irradiation with thermal neutrons. Boron concentrations in tumors 2 h after dosing were 2.3 +/- 1.6 and 7.4 +/- 1.3 micrograms boron/g tissue (mean +/- SD), corresponding to tumor/brain ratios of 11.5 +/- 3.6 and 6.8 +/- 2.0 micrograms boron/g tissue for the low and high doses, respectively. All untreated animals died within 28 days, whereas half survived at days 32, 55, and 38 for groups receiving neutrons only, 30 mg/kg D-CDU, and 150 mg/kg D-CDU, respectively. Odds ratios of all treatment groups differed significantly from the untreated group (P < 0.002; logrank test). The median survival time for the 30 mg/kg-treated group but not for the 150 mg/kg-treated group was significantly longer than for rats treated with neutrons only (P = 0.036), which may correlate with the decreased tumor selectivity for D-CDU observed at the higher dose. Additional pharmacodynamic studies are warranted to determine optimal dosing strategies for D-CDU.     

兔VX2肝癌介入治疗后早期发生凋亡的流式细胞术检测

目的研究经肝动脉插管灌注碘油抗癌药乳液化疗栓塞和单纯灌注化疗后的早期兔肝VX2肿瘤发生凋亡。方法27只新西兰大白兔瘤组织块种植肝VX2肿瘤,A组(n=9)经肝动脉灌注碘油抗癌药乳液,B组(n=9)肝动脉灌注化疗,C组(n=9)肝动脉灌注生理盐水,每组分别在处理后第24h、72h、120h处死实验兔各3只,采用FITC-AnnexinV/PI流式细胞术分析介入处理后早期的肿瘤细胞凋亡。结果肿瘤边缘部的凋亡早期细胞百分率(PapE)与凋亡晚期细胞百分率(PapL)及峰值时间点分别为:A组(9.48±4.58)%、(33.46±8.81)%、24h、72h,B组(4.46±1.47)%、(11.65±3.51)%、24h、24h,C组(2.50±1.39)%、(5.99±1.22)%。肿瘤中心部的PapE、PapL与峰值时间点分别为:A组(16.48±6.32)%、(43.56±18.51)%、24h、72h,B组(7.50±3.10)%、(18.53±14.04)%、24h、24h,C组(5.61±1.92)%、(14.63±12.23)%。结论Lp-THACE诱导肝癌肿瘤细胞早期大量凋亡是其有效的主要作用机制,...     

Body composition and time course changes in regional distribution of fat and lean tissue in unselected cancer patients on palliative care--correlations with food intake, metabolism, exercise capacity, and hormones

BACKGROUND: Several investigations that yielded different results in terms of net changes in body composition of weight-losing cancer patients have been reported that employed a variety of methods based on fundamentally different technology. Most of those reports were cross-sectional, whereas to the authors' knowledge there is sparse information available on longitudinal follow-up measurements in relation to other independent methods for the assessment of metabolism and performance. METHODS: For the current report, the authors evaluated time course changes in body composition (dual-energy X-ray absorptiometry) with measurements of whole body and regional distribution of fat and lean tissue in relation to food and dietary intake, host metabolism (indirect calorimetry), maximum exercise capacity (walking test), and circulating hormones in cancer patients who were receiving palliative care during 4-62 months of follow-up. The entire cohort comprised 311 patients, ages 68 years +/- 3 years who were diagnosed with solid gastrointestinal tumors (84 colorectal tumors, 74 pancreatic tumors, 73 upper gastrointestinal tumors, 51 liver-biliary tumors, 3 breast tumors, 5 melanomas, and 21 other tumor types). RESULTS: Decreased body weight was explained by loss of body fat, preferentially from the trunk, followed by leg tissue and arm tissue, respectively. Lean tissue (fat-free mass) was lost from arm tissue, whereas trunk and leg tissue compartments increased, all concomitant with declines in serum albumin, increased systemic inflammation (C-reactive protein, erythrocyte sedimentation rate), increased serum insulin, and elevated daily caloric intake; whereas serum insulin-like growth factor 1 (IGF-1), resting energy expenditure, and maximum exercise capacity remained unchanged in the same patients. Serum albumin levels (P < 0.001), whole body fat (P < 0.02), and caloric intake (P < 0.001) predicted survival, whereas lean tissue mass did not. Daily intake of fat and carbohydrate was more important for predicting survival than protein intake. Survival also was predicted by serum IGF-1, insulin, leptin, and ghrelin levels (P < 0.02 - P < 0.001). Serum insulin, leptin, and ghrelin (total) levels predicted body fat (P < 0.001), whereas IGF-1 and thyroid hormone levels (T3, free T3) predicted lean tissue mass (P < 0.01). Systemic inflammation primarily explained variation in lean tissue and secondarily explained loss in body fat. Depletion of lean arm tissue was related most to short survival compared with the depletion of lean leg and trunk tissue. CONCLUSIONS: The current results demonstrated that body fat was lost more rapidly than lean tissue in progressive cancer cachexia, a phenomenon that was related highly to alterations in the levels of circulating classic hormones and food intake, including both caloric amount and diet composition. The results showed importance in the planning of efficient palliative treatment for cancer patients.     

热盐水灌注对兔肝VX2肿瘤血管内皮细胞的影响

目的：研究将60℃生理盐水经肝动脉灌注兔肝VX2肿瘤对肿瘤血管内皮细胞及通透性的影响。方法：20只VX2肝荷瘤兔,随机分为2组,分别经兔肝动脉灌注37℃生理盐水60ml（对照组）、60℃生理盐水60ml（治疗组）。灌注后再经导管推注1% Evans Blue （EB）,2ml/kg。24小时后处死荷瘤兔,取小块瘤组织,称重后,放入1ml甲酰胺液中,置于50℃恒温水浴箱60h,提取液用722型光栅分光光度计测出620nm下的OD值,从标准曲线上测出相应的伊文思蓝含量,以反映该组织血管的通透性。切取肿瘤边缘血管组织包埋,行电镜检查观察肿瘤血管内皮细胞形态变化。结果：60℃生理盐水灌注组肿瘤组织EB含量［（10.71±0.84）μg/100mg］与37℃灌注组［（3.42±0.87）μg/100mg］相比有差异（P〈0.01）。电镜观察热灌注组肿瘤血管内皮细胞,细胞间隙增大。结论：60℃灌注可增大肿瘤内皮细胞间隙从而增加肝肿瘤组织的血管通透性。     

Specific inhibitory effect of dietary eicosapentaenoic acid on N-nitroso-N-methylurea-induced mammary carcinogenesis in female Sprague-Dawley rats

We have investigated the effects of two qualitatively different types of unsaturated fatty acids on N-nitroso-N-methylurea (NMU)-induced mammary carcinogenesis in female Sprague-Dawley rats. Semipurified diets containing 4.7% eicosapentaenoic acid (EPA) plus 0.3% linoleic acid or 5% linoleic acid were prepared. Animals maintained on these diets were given an i.v. injection of NMU (50 mg/kg body wt) at 50 days of age and killed 20 weeks later. Both tumor incidence and tumor number per rat were significantly lower in the EPA diet group (60.0% and 2.3 +/- 2.5 versus 93.3% and 5.1 +/- 4.5 respectively) for the 5% linoleic acid diet. Furthermore, the average weight of tumor material (total) per rat was significantly lower in the EPA as compared to linoleic acid diet group (2.9 +/- 4.2 g and 11.4 +/- 12.2 g respectively). Analysis of phospholipid fatty acids in the mammary tumors in the EPA diet group showed a higher proportion of C16:0, C18:2, omega-3 fatty acids C20:5 and C22:6 and a lower proportion of C20:4. Furthermore, mammary tumors in rats fed the EPA diet demonstrated significant reduction in prostaglandins. The results thus suggest that inhibition by EPA of NMU-induced mammary carcinogenesis may be mediated via the modulation of lipid metabolism and associated reduction in prostaglandin synthesis.     

Tumor angiogenesis of low-grade astrocytomas measured by dynamic susceptibility contrast-enhanced MRI (DSC-MRI) is predictive of local tumor control after radiation therapy

PURPOSE: To assess regional cerebral blood volume (rCBV) as a surrogate marker of angiogenesis in patients with low-grade fibrillary astrocytoma before radiation therapy and to correlate measured values with clinical outcome after fractionated stereotactic radiotherapy (FSRT). METHODS: Twenty-five patients with histologically proven fibrillary astrocytomas were examined using dynamic susceptibility contrast-enhanced MRI before radiotherapy. Radiotherapy was delivered to mean and median total doses of 60.9 and 60 Gy, respectively (range 55.8-66 Gy). During MRI for treatment planning, 55 T2*-weighted gradient echo images were acquired before, during, and after i.v. contrast-bolus injection. The acquired signal-time curves were converted into concentration-time curves. By normalization to an arterial input function, absolute and relative rCBV values were calculated. Measured pretherapeutic rCBV data were correlated to outcome in terms of local control after FSRT. RESULTS: Mean pretherapeutic rCBV for astrocytomas was 6.5 +/- 3.7 ml/100 g tissue. Mean and median follow-up times were 47.8 and 52 months, respectively. Fifteen tumors recurred during the period, with a mean and median latency of 39.1 and 42 months, respectively. Tumors recurring earlier than 42 months after FSRT showed a higher pretreatment rCBV than tumors recurring later and tumors in continued local control (8.12 +/- 4.48 ml/100 g vs. 6.0 +/- 2.3 ml/100 g and 4.73 +/- 2.47 ml/100 g; p = 0.02 and p = 0.03). The respective ratios of tumor rCBV in early recurrent tumors to gray matter and white matter rCBV were 0.98 +/- 0.38 and 2.17 +/- 1.36 as compared with 0.79 +/- 0.14 and 1.44 +/- 0.29 in locally controlled tumors (p = 0.074 and p = 0.056). CONCLUSIONS: In fibrillary low-grade astrocytomas, a noninvasive assessment of angiogenesis as indicated by rCBV measurement was feasible. The present data suggest that high pretherapeutic angiogenic activity in low-grade astrocytomas indicates a subgroup of tumors at higher risk for early local recurrence or malignant transformation after FSRT.     

低频超声辐照联合微泡抑制兔VX_2肿瘤生长的实验研究

目的：探索低频超声辐照联合静脉注射微泡抑制肿瘤生长的非创伤性治疗肿瘤的新方法。方法：24只新西兰大白兔后腿肌肉内接种VX2肿瘤,瘤体长至1cm左右随机分为对照组、单纯微泡组、单纯超声组和超声微泡组。各组经相应处理后,超声检测肿瘤大小、观察瘤体内血流灌注情况,绘制肿瘤生长曲线,计算肿瘤增长百分率。病理学观察治疗后各组瘤体组织的病理学损伤。结果：治疗后2周结果显示超声微泡组瘤体体积和肿瘤增长百分率均明显小于其余各组（P〈0.01）,瘤体内血流灌注明显减少,瘤体组织大部分坏死;单纯微泡组、单纯超声组的瘤体体积和肿瘤增长百分率与对照组间均无显著性差异（P〉0.05）。结论：20kHz超声辐照联合微泡造影剂SonoVue可有效抑制兔VX2肿瘤的生长。