Porphyrin-lipoprotein association as a factor in porphyrin localization

Systemic administration of the tumor-localizing product hematoporphyrin derivative (HPD) to mice bearing the Lewis-Lung tumor leads to an initial distribution of porphyrins among plasma lipoproteins and albumin. The more hydrophobic components of HPD (including the tumor-localizing fraction) preferentially bind to plasma low density lipoprotein (LDL) and high density lipoprotein (HDL). After 48 h, the remaining plasma porphyrins are mainly bound to HDL. The distribution pattern of HPD is correlated with the relative numbers of LDL receptors in different tissues.     

A lipoprotein source of cholesteryl esters is essential for proliferation of CEM-CCRF lymphoblastic cell line

Tumour are characterised by a high content of cholesteryl esters (CEs) stored in lipid droplets purported to be due to a high rate of intracellular esterification of cholesterol. To verify whether and which pathways involved in CE accumulation are essential in tumour proliferation, the effect of CE deprivation, from both exogenous and endogenous sources, on CEM-CCRF cells was investigated. Cholesterol synthesis, esterification and content, low-density lipoprotein (LDL) binding and high-density lipoprotein (HDL)-CE uptake were evaluated in cultured in both conventional and delipidated bovine serum with or without oleic or linoleic acids, cholesteryl oleate, LDL and HDL. High content of CEs in lipid droplets in this cell line was due to esterification of both newly synthesised cholesterol and that obtained from hydrolysis of LDL; moreover, a significant amount of CE was derived from HDL-CE uptake. Cell proliferation was slightly affected by either acute or chronic treatment up to 400 μM with Sz-58035, an acyl-cholesteryl cholesterol esterification inhibitor (ACAT); although when the enzyme activity was continuously inhibited, CE content in lipid droplets was significantly higher than those in control cells. In these cells, analysis of intracellular and medium CEs revealed a profile reflecting the characteristics of bovine serum, suggesting a plasma origin of CE molecules. Cell proliferation arrest in delipidated medium was almost completely prevented in the first 72 h by LDL or HDL, although in subsequent cultures with LDL, it manifested an increasing mortality rate. This study suggests that high content of CEs in CEM-CCRF is mainly derived from plasma lipoproteins and that part of CEs stored in lipid droplets are obtained after being taken up from HDL. This route appears to be up-regulated according to cell requirements and involved in low levels of c-HDL during cancer. Moreover, the dependence of tumour cells on a source of lipoprotein provides a novel impetus in developing therapeutic strategies for use in the treatment of some tumours.     

Effect of low-density lipoprotein on the incorporation of benzo(a)pyrene by cultured cells

Benzo(a)pyrene added to human plasma in vitro associated with the plasma lipoproteins, especially the low-density fraction. The influence of plasma low-density lipoprotein on cellular uptake of benzo(a)pyrene was studied using WI-38, a human embryonic lung fibroblast line, and GM 1915, a skin fibroblast line derived from a patient with homozygous familial hypercholesterolemia. The WI-38 cells were low-density-lipoprotein receptor positive, and the familial hypercholesterolemia cells were receptor negative by standard binding studies with 125I-labeled low-density lipoprotein. Following 2 hr of incubation at 37 or 4 degrees, cell association of benzo(a)pyrene was determined with benzo(a)pyrene bound to lipoprotein or added at the same concentration to serum-free medium or medium containing delipidated serum. Uptake from delipidated or serum-free medium by both cell lines was linear with concentration, while incorporation of benzo(a)pyrene bound to low-density lipoprotein was much less and nonlinear at higher concentrations of lipoprotein. While low-density lipoprotein apparently influenced the availability of benzo(a)pyrene to the cell, no differences were noted in the incorporation of benzo(a)pyrene by WI-38 and familial hypercholesterolemia cells. Thus, benzo(a)pyrene entered the cells from low-density lipoproteins despite the absence of specific receptors, apparently by a rapid redistribution between the lipoprotein and cell membrane.     

Role of high-, low- and very low-density lipoproteins in the transport and tumor-delivery of hematoporphyrin in vivo

Free hematoporphyrin administered intravenously to healthy rabbits (1-28 mg/kg body weight) is bound by the 3 major lipoprotein components of plasma (VLDL, LDL and HDL) with different efficiency. In vitro-prepared complexes of hematoporphyrin (Hp) with lipoprotein fractions isolated from mouse serum have been injected intracardiacally into mice affected by MS-2 fibrosarcoma (1 mg of Hp per kg body weight). LDL appear to allow a more specific delivery of the complexed Hp to the tumor tissue as compared with HDL, VLDL or free Hp. The different behavior of VLDL, LDL and HDL as carriers of Hp in vivo is also discussed.     

The pharmacokinetic behavior of the photosensitizer meso-tetra-hydroxyphenyl-chlorin in mice and men

Purpose Meso-tetra-hydroxyphenyl-chlorin (mTHPC) is a hydrophobic photosensitizer that binds to plasma lipoproteins after intravenous injection. In vitro experiments with human plasma have shown that mTHPC initially binds to an unknown protein and subsequently redistributes to lipoprotein fractions. It has been suggested that this might explain the unusual pharmacokinetic profile of mTHPC humans. In humans, unlike in rodents, reappearance of mTHPC has been reported, resulting in a second plasma peak after intravenous injection. However, previous studies analyzed only limited time points during the first 24 h after injection. Our aim was to determine the pharmacokinetics of mTHPC in detail, and to investigate whether the pharmacokinetic behavior of the drug is affected by binding of mTHPC to lipoproteins in vivo. Methods Plasma of cancer patients and mice, intravenously injected with mTHPC, was analyzed for total drug content and drug distribution over the lipoprotein fractions. Results Pharmacokinetic profiles of mTHPC in a group of human subjects showed that apparent steady state drug levels were maintained for at least 10 h. Closer examination of individual profiles showed that the initial (5 min) plasma drug levels were on average 86% of the maximal plasma concentration, which occurred at about 5 h after injection. In mice, however, plasma pharmacokinetics were described by a standard bi-exponential decline of the drug concentration. The majority (>58%) of mTHPC injected into both BALB/c nude mice and patients initially bound to the HDL plasma fraction. We extended our study to ApoE −/− mice, with highly elevated lipoprotein levels, and SR-BI −/− mice, which are lacking the main clearance pathway for HDL associated cholesteryl esters, to take into account the differences between lipoprotein levels and clearance in mice and man. Although mTHPC distribution over the lipoproteins changed in these mice, pharmacokinetic profiles of mTHPC remained the same. Conclusions We conclude that neither lipoprotein levels nor cholesterol metabolism affects the pharmacokinetics of mTHPC in plasma.     

Effects of Cremophor EL on distribution of Taxol to serum lipoproteins.

The clinical formulation of the anti-tumour agent Taxol involves the use of a mixture of ethanol and Cremophor EL. Gel electrophoresis and density-gradient ultracentrifugation were used to detect effects of Taxol infusions on serum lipoproteins. Use of the Cremophor vehicle results in a decrease in the electrophoretic mobility of serum lipoproteins along with the appearance of a lipoprotein dissociation product. These effects persist during a 24 h infusion and for at least 1.5 h afterwards, and can be reproduced in vitro using purified high-density lipoprotein (HDL) or low-density lipoprotein (LDL). In control serum, Taxol binds to albumin > HDL, but after serum is exposed to Cremophor EL in vitro or in vivo substantial binding of Taxol to the lipoprotein dissociation product(s) was observed. The latter could represent an important factor in taxol biodistribution.     

Effects of tamoxifen therapy on lipid and lipoprotein levels in postmenopausal patients with node-negative breast cancer

We conducted a 2-year, randomized, double-blind, placebo-controlled toxicity trial of therapy with tamoxifen (10 mg twice a day) in 140 postmenopausal women with a history of breast cancer and histologically negative axillary lymph nodes. These women had been treated with surgery with or without radiotherapy. At a 3-month evaluation, tamoxifen-treated women showed a significant decrease in fasting plasma levels of total cholesterol and low-density lipoprotein (LDL) cholesterol, which persisted at 6- and 12-month evaluations. During the first 12 months, plasma triglyceride levels increased; small but significant decreases in high-density lipoprotein cholesterol (HDL) were observed in tamoxifen-treated women, but ratios of total cholesterol to HDL cholesterol and of LDL to HDL cholesterol changed favorably. While data relating lipid/lipoprotein profiles and cardiovascular disease are limited in women, current evidence suggests that total cholesterol and possibly low-density lipoprotein cholesterol are risk factors. We conclude that during the first 12 months of treatment, tamoxifen exerts a favorable effect on the lipid profile in postmenopausal women with early stage breast cancer.     

Effects of low- and high-density lipoproteins on the proliferation of human breast cancer cells in vitro: differences between hormone-dependent and hormone-independent cell lines

The influence of low- and high-density lipoproteins on the proliferation of human breast cancer cells in culture was studied. We compared total cell number after incubation for 48 hr in culture medium containing or lacking plasma lipoproteins. Marked differences were found between hormone-dependent (MCF-7, T-47-D, ZR-75) and hormone-independent (MDA-MB-231, HBL-100) mammary tumor cell lines. The cells also reacted differently on the different lipoproteins offered in the medium. Human low-density lipoproteins (LDL) exhibited a marked stimulation of the growth of hormone-independent cell lines but no or only toxic effects upon the hormone-sensitive lines. Human high-density lipoproteins (HDL) stimulated the proliferation of all cell lines in a dose-dependent manner but hormone-independent cells showed a higher response. These findings point towards different utilizations of nutrients in hormone-dependent and hormone-independent cells.     

The distribution of porphyrins with different tumour localising ability among human plasma proteins

The distribution among the main fractions of human plasma lipoproteins of a number of porphyrins with different tumour localising ability has been determined by means of ultracentrifugation. A main trend is that the fraction of the dyes that are bound to low density lipoprotein (LDL) increases, and the fraction bound to HSA decreases with decreasing polarity of the dyes. An asymmetric charge distribution, such as in TPPS2a, favours LDL-binding more than expected on the basis of lipophilicity. No correlation between the known tumour localising ability of the drugs tested in the present work and their relative affinity for LDL was found. One of the best tumour localisers reported in the literature, TPPS4, hardly binds to LDL, while Hp and Pp, which are commonly considered inefficient tumour localisers, do have a significant affinity for LDL. On the other hand, the LDL binding capacity for a drug is suggested to be a good index for cellular uptake. Such an index does not necessarily imply that the actual uptake occurs by the LDL pathway.     

Serum lipids and lipoprotein disorders in cancer patients

Total serum cholesterol, free and esterified cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, serum triglycerides and serum lipoproteins were measured in 103 consecutive cancer patients (60 men and 43 women; mean age, 56 years) and 100 age-matched noncancer inpatients. Cancer patients as a group demonstrated significantly lower total cholesterol, esterified cholesterol and LDL cholesterol, compared with noncancer patients. Breast cancer proved to be an exception associated with increased serum total cholesterol, free cholesterol, LDL cholesterol, and triglycerides. a-lipoproteins were constantly increased in cancer patients whereas no differences were found in the other lipoprotein fractions. Finally, the observed overall incidence of hyperlipidemia in cancer patients (23/103) was not significantly different from the controls (29/100).     

Photosensitization with zinc (II) phthalocyanine as a switch in the decision between apoptosis and necrosis

Photodynamic therapy (PDT) of tumors and other diseases is based on the uptake of a photosensitizing dye in target cells, which are damaged by reactive oxygen intermediates generated on irradiation with light in which the wavelengths match the dye absorption spectrum. PDT can induce cell death by necrosis and apoptosis both in vivo and in vitro, but the factors determining the contribution of either mechanism to the overall process are not completely defined. Our studies on the photosensitization of 4R transformed fibroblasts with the second-generation photosensitizer zinc (II) phthalocyanine (ZnPc) aim at determining the effect of important experimental parameters such as time of cell incubation (2 or 24 h) with ZnPc before irradiation and ZnPc concentration in the incubation medium on cell death. Furthermore, we propose possible correlations between the cell death mechanism and primary photo-damage sites; these are mainly determined by the intracellular localization of the photosensitizer. The mechanism of cell death was determined by both electron microscopy analysis of the morphological alterations induced by photosensitization and measurement of caspase 3 activation. The initial photodamage sites were determined by measuring the activities of several functions typical of mitochondria, lysosomes, Golgi apparatus, cytosol, and plasma membrane. The intracellular localization of ZnPc after 2- or 24-h incubation was determined by fluorescence microscopy. Necrosis, associated with early loss of plasma membrane integrity and complete depletion of intracellular ATP, represents the prevailing mode of death for 4R cells dark-incubated for 2 h with ZnPc and irradiated with light doses reducing viability by 99.9%. In contrast, irradiation performed 24 h after ZnPc incubation causes only partial inhibition of plasma membrane activities, and cell death occurs largely by apoptosis. ZnPc is mainly localized in the Golgi apparatus after 2- and 24-h incubation, and in all of the cases this compartment represents a primary target of photodamage. Only after prolonged incubation is mitochondrial localization of ZnPc clearly detected by fluorescence microscopy; this could be a determining factor for promotion of apoptosis. Our data demonstrate that it is possible to modulate the mechanism of cell death by appropriate protocols; this may be relevant for enhancing the therapeutic efficacy of PDT.     

托瑞米芬和他莫昔芬对血脂影响的对比研究

目的　探讨托瑞米芬 (TOR)在乳腺癌术后辅助治疗中对血脂的影响程度。方法　 10 3例乳腺癌患者分为治疗组和对照组。治疗组包括TOR组和TAM组 ,TOR组口服TOR 60mg/天 ,TAM组口服TAM 2 0mg/天。在内分泌治疗前 ,治疗 3、6、9和 12个月后 ,分别晨取患者空腹静脉血进行血脂检测。结果　TOR治疗组血总胆固醇平均水平下降 11.0 % ,S LDL平均水平下降 11.1% ,血甘油三酯平均水平下降 10 .7% ;TAM治疗组血总胆固醇平均水平下降 9.0 % ,S LDL平均水平下降 17.4% ,而血甘油三酯水平无明显变化 (P =0 .491)。结论　TOR对血脂的影响程度与TAM相近 ,2组血总胆固醇和S LDL平均水平均较治疗前下降。不同的是 ,TOR治疗组血甘油三酯水平下降 ,而TAM治疗组无明显变化。提示TOR可影响与冠心病发病相关的血脂水平。     

Liposome-delivered Si(IV)-naphthalocyanine as a photodynamic sensitiser for experimental tumours: pharmacokinetic and phototherapeutic studies

The pharmacokinetic behaviour and phototherapeutic effectiveness of bis(di-isobutyloctadecylsil-oxy)-2,3-naphthalocyanatosilicon (iso-BOSiNc) incorporated into dipalmitoyl-phosphatidylcholine (DPPC) liposomes have been studied in Balb/c mice bearing an MS-2 fibrosarcoma. We found that iso-BOSiNc i.v.-injected at a dose of 0.5 mg kg-1 b.w. is preferentially transported by serum lipoproteins; in particular, the photosensitiser is associated with LDL (57.8% of total recovery in the serum) and HDL (35.7%) while minor amounts are associated to VLDL (2.63%) and other serum proteins (3.89%), Iso-BOSiNc concentrations greater than 1 microgram g-1 of tissue are recovered from the tumour at 12-48 h after administration while the ratio of iso-BOSiNc concentration in tumour and peritumoral tissue is greater than 10. Upon increasing the injected dose, the additional iso-BOSiNc is almost exclusively bound by HDL, which leads to large uptake of the photosensitiser by liver and spleen. The efficiency of iso-BOSiNc as a photodynamic agent was measured upon irradiation with a different dose-rate for a total light dose of 450 J cm-2. The extent of tumour necrotic area increases as a function of the time after the end of PDT treatment and reaches a maximum level after about 24 h. Moreover, the necrotic area is linearly dependent on the irradiation dose-rate up to 100 mW cm-2. In all there is substantial evidence that iso-BOSiNc delivered in a liposomal dispersion is a highly effective photosensitizer for PDT of tumours.     

Systemic excretion of benzo(a)pyrene in the control and microsomally induced rat: the influence of plasma lipoproteins and albumin as carrier molecules

In vitro studies have previously indicated that benzo(a)pyrene distributes primarily into the plasma lipoprotein fraction when incubated with whole plasma. Hydroxylated metabolites of benzo(a)pyrene distribute increasingly into the albumin fraction as the degree of metabolite hydroxylation increases. This report assesses the influence of plasma lipoproteins and albumin as carriers for benzo(a)pyrene on carcinogen excretion in the control and microsomally induced rat. Male Sprague-Dawley rats cannulated in the bile duct received i.v. injections of radiolabeled benzo(a)pyrene noncovalently bound to the very-low-density, low-density, or high-density lipoproteins in equimolar amounts. Bile was collected and measured for radioactivity. Cumulative biliary excretions of benzo(a)pyrene complexed with rat lipoproteins were 39.6 +/- 9.7 (S.D.), 24.6 +/- 1.3, and 21.2 +/- 8.8% for very low-density, low-density, and high-density lipoprotein, respectively. Values for excretion of benzo(a)pyrene complexed with rat or human lipoproteins were comparable. These data suggest that the transport molecule can effect a 2-fold difference in benzo(a)pyrene excretion under conditions of the present study. We infer that metabolism of the plasma lipoprotein molecules determines, in part, the extent of benzo(a)pyrene excretion. Cumulative biliary excretions of albumin-bound benzo(a)pyrene, 3-hydroxybenzo(a)pyrene, benzo(a)pyrene 7,8-dihydrodiol, and benzo(a)pyrene-4,5-epoxide were 28.0 +/- 2.7, 39.8 +/- 0.5, 46.9 +/- 2.5, and 49.8 +/- 1.2%, respectively. Thus, excretion increased as the degree of benzo(a)pyrene hydroxylation increased. The effect of microsomal enzyme induction on excretion of lipoprotein-bound benzo(a)pyrene was also assessed. Contrary to expectation, excretion of benzo(a)pyrene bound to the very-low-density, low-density, or high-density lipoproteins in Aroclor-induced rats was not greater than that of control animals. Hence, under the conditions of the present study, 60 to 80% of the injected benzo(a)pyrene and 50 to 60% of the injected benzo(a)pyrene metabolites were not excreted immediately in control or microsomally induced animals. This benzo(a)pyrene may represent a carcinogen pool that is slowly excreted.     

Photokilling mechanisms induced by zinc(II)-phthalocyanine on cultured tumor cells

The photosensitizing effects of liposomal zinc(II)-phthalocyanine (ZnPc) on HeLa cells, with emphasis on morphological changes and mechanisms for cell death, have been studied. No dark toxicity for ZnPc alone was found. Incubation for 1 h with ZnPc followed by red light irradiation induced a variable decrease in the surviving of cells, which was related to both drug concentration and irradiation time. A lethal photodynamic effect (100% of the cells are killed: LD100) was induced by 5 x 10-6 M ZnPc and 5-min irradiation, whereas a sublethal effect (60% of the cells are killed: LD60) was detected with 10 7 M ZnPc and 3 min of red light. Toluidine blue and Hoechst 33258 staining showed characteristic alterations of cell morphology. Numerous bubbles on the plasma membrane were found immediately after an LD100 treatment, and a necrotic morphology appeared 24 h later. On the contrary, severe cell shrinkage with nuclear fragmentation. characteristic of apoptosis. was observed 8 and 24 h after LD60 treatments. In this case, propidium iodide-acridine orange labeling and the TUNEL assay confirmed the occurrence of apoptosis. The highest amount of apoptotic cells appeared 24 h after LD60 treatments, particularly in detached cells, as revealed by cell counting and DNA electrophoresis. Both apoptotic and necrotic mechanisms for cell death occur in HeLa cells in dependence on the experimental protocol of ZnPc photodynamic treatments.     

Hypocholesterolemia and acute myelogenous leukemia. Association between disease activity and plasma low-density lipoprotein cholesterol concentrations

Plasma total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol concentrations were determined in 32 patients admitted with either acute nonlymphocytic leukemia or chronic myelogenous leukemia in blast crisis. Measurements were repeated in 15 of these individuals during a leukopenic period induced by chemotherapy and in 6 of the latter group when they had achieved remission. Initial plasma total, LDL, and HDL cholesterol levels in 15 male (111.9 +/- 27.9; 53.7 +/- 10.4; 23.7 +/- 22.5 mg/dl) and 17 female (124.0 +/- 42.0; 68.6 +/- 32.0; 29.4 +/- 13.9 mg/dl) patients were markedly reduced compared with age and sex-matched control values (all P less than 0.01). Remission in six subjects was associated with significant increases in total cholesterol (162.0 +/- 61.0 vs. 111.5 +/- 47.9 mg/dl; P less than 0.02) and LDL cholesterol (106.8 +/- 51.2 vs. 43.5 +/- 31.3 mg/dl; P less than 0.05) compared with their baseline values. Chemotherapy-induced leukopenia was associated with inconsistant changes in plasma cholesterol levels although LDL cholesterol increased in all patients who subsequently achieved remission. LDL cholesterol levels fell dramatically in two patients who relapsed. These results indicate that LDL cholesterol concentrations may be of value in assessing disease activity in individuals with acute myelogenous leukemia.     

Boronated protoporphyrin (BOPP): localization in lysosomes of the human glioma cell line SF-767 with uptake modulated by lipoprotein levels.

PURPOSE: Boronated protoporphyrin (BOPP) is a candidate for use in both boron neutron capture therapy (BNCT) and photodynamic therapy (PDT) of glioblastoma multiforme (GBM). Our objectives are to identify factors that influence the uptake and retention of BOPP in vitro and to determine BOPP distribution in a human glioma cell line in vitro. This information will aid the development of compounds and treatment strategies that increase the effectiveness of BNCT therapy for GBM. METHODS AND MATERIALS: The amount, distribution pattern, and site of internalization of BOPP were assessed using fluorescence microscopy. Living human glioma (SF-767) cells were imaged after a 24-h exposure to BOPP (20-135.6 microg/ml, normal serum). Dose-dependent uptake of BOPP was determined using both fluorescence microscopy of individual living cells and inductively-coupled plasma-atomic emission spectroscopy (ICP-AES) analysis of cell pellets. Lysosome- or mitochondria-specific fluorescent probes were used to identify the cellular compartment containing BOPP. Two human fibroblast cell lines, AG-1522 (LDL receptor-positive) and GM019-15C (LDL receptor-deficient), were used to investigate LDL receptor-dependent BOPP uptake. The dependence of BOPP uptake on lipoproteins in the media was determined by exposing each of the three cell types to BOPP in medium containing either normal (NS) or lipoprotein deficient serum (LPDS). RESULTS: BOPP accumulated in the lysosomes of human glioma cells in vitro, and not in the mitochondria, as reported for C6 rat glioma cells in vitro. BOPP uptake was concentration-dependent and was also dependent on the amount of lipoproteins in the medium. Over the range of incubation concentrations studied and at the single exposure duration time point investigated (24 h), all cells retained a similar amount of BOPP. At the lowest incubation concentration (20 microg/ml, NS), the amount of boron retained was near 10(9) atoms per cell (15 microg B/g cells). Lysosomes containing high concentrations of BOPP were randomly distributed throughout the cytoplasm; however, larger lysosomes containing BOPP were concentrated around the cell nucleus. Little or no BOPP accumulated in the cell nucleus. At incubation concentrations of 20 and 40 microg/ml (24-h time point), BOPP uptake in SF-767 cells was reduced in LPDS compared with NS (66% reduction). A similar result was observed for normal human fibroblasts (AG-1522 cells, 40 microg/ml, 24 h). At 40 microg/ml, in both NS and LPDS at 24 h, BOPP accumulation in LDL receptor-deficient human fibroblasts (GM019-15C cells) was reduced relative to AG-1522 cells. BOPP accumulation in GM019-15C cells (40 microg/ml, 24 h) was not affected by serum lipoprotein levels. CONCLUSION: In cell culture, BOPP is taken up by human glioma cells via the LDL pathway and is compartmentalized into cellular lysosomes. Knowledge of this mechanism of BOPP uptake and retention will be important in attempts to modify toxicity and efficacy of this drug.     

胃癌患者血脂变化及总胆固醇的临床意义

目的　测定胃癌患者血清中甘油三酯（ＴＧ）、总胆固醇（ＴＣ）、高密度脂蛋白（ＨＤＬ）和低密度脂蛋白（ＬＤＬ）的含量,探讨胃癌患者血清ＴＣ水平与胃癌临床病理特征之间的关系。方法　采用日立７６００-１２０Ｅ全自动生化分析仪检测１５７例胃癌、１３０例胃溃疡患者及６４例正常人外周血血脂及脂蛋白。用酶法测定血清ＴＧ和ＴＣ,用沉淀法测定血清ＨＤＬ和ＬＤＬ。结果　正常人组血清ＴＧ和ＴＣ分别为（１.５９±０.８１）ｍｍｏｌ／Ｌ和（４.６５±０.８７）ｍｍｏｌ／Ｌ,明显高于胃癌组的（１.４３±０.６６）ｍｍｏｌ／Ｌ和（４.３５±０.８２）ｍｍｏl／Ｌ及胃溃疡组的（１.５３±０.６３）ｍｍｏｌ／Ｌ和（４.４３±１.１４）ｍｍｏｌ／Ｌ,其中正常人组与胃癌组血清ＴＣ比较,差异有统计学意义（Ｐ＜０.０５）;正常人组血清ＨＤＬ和ＬＤＬ分别为（１.３０±０.３６）ｍｍｏｌ／Ｌ和（２.７３±０.６６）ｍｍｏｌ／Ｌ,明显高于胃癌组的（１.１０±０.２７）ｍｍｏｌ／Ｌ和（２.２７±０.５７）ｍｍｏｌ／Ｌ及胃溃疡组的（１.１３±０.３１）ｍｍｏｌ／Ｌ和（２.４５±１.０４）ｍｍｏｌ／Ｌ,差异均有统计学意义（Ｐ＜０.0５）。胃癌患者血清ＴＣ水平与性别、年龄、肿瘤大小和浸润深度无关,与淋巴结转移、组织学类型及ＴＮＭ分期有关（Ｐ＜０.０５）。结论　测定胃癌患者血清ＴＧ、ＴＣ、ＨＤＬ及ＬＤＬ水平有助于判断胃癌患者的病程及预后。     

Effect of letrozole on the lipid profile in postmenopausal women with breast cancer

Hormonal therapy plays a central role in the overall treatment of breast cancer. Aromatase inhibitors can inhibit the aromatase enzyme system resulting in a reduction of oestrogens. Letrozole is a non-steroidal aromatase inhibitor that effectively blocks aromatase activity without interfering with adrenal steroid biosynthesis. The drug can significantly reduce the levels of plasma oestrogens, which remain suppressed throughout the treatment. Data are scarce concerning the influence of these drugs on serum lipid levels. In the present study, we evaluated the effects of letrozole on the serum lipid profile in postmenopausal women with breast cancer. A total of 20 patients with breast cancer were treated with letrozole, 2.5 mg once daily. After an overnight fast, serum lipid parameters (total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, apolipoproteins A1, B and E and lipoprotein (a)) were measured before treatment and at 8 and 16 weeks afterwards. A significant increase in total cholesterol (P=0.05), LDL cholesterol (P<0.01) and apolipoprotein B levels (P=0.05) in the serum, as well as in the atherogenic risk ratios total cholesterol/HDL cholesterol (P<0.005) and LDL cholesterol/HDL cholesterol (P<0.005) was noticed after letrozole treatment. We conclude that letrozole administration in postmenopausal women with breast cancer has an unfavourable effect on the serum lipid profile.     

Role of plasma lipids and lipoproteins in predicting amphotericin B-induced nephrotoxicity in pediatric oncology patients

Purpose: The objective of this study was to determine if total plasma and lipoprotein cholesterol (C) and triglyceride (TG) concentrations could predict the degree of nephrotoxicity caused by the antifungal agent amphotericin B (AmpB); and to use the average amount of potassium supplementation received daily as a indicator of nephrotoxicity in pediatric oncology patients. Patients and methods: Plasma samples from 18 patients (ages<17 years) who were receiving AmpB due to suspected or confirmed fungal infection at British Columbia Children’s Hospital were analyzed for lipid concentrations. The high density lipoprotein (HDL) fractions were separated by precipitation; total (TOT) plasma and fraction C and TG concentrations were measured by enzymatic colorimetric assays; and low density lipoprotein (LDL) C levels were determined by Friedewald’s formula. Changes in serum creatinine levels from baseline and amounts of potassium supplementation were used as indicators of nephrotoxicity; both were obtained from patients’ medical charts. Pearson correlation coefficients (r) were determined and considered significant if P<0.05. Results: The total cumulative AmpB dose, adjusted for weight, does not seem to predict AmpB-induced nephrotoxicity. Positive but relatively weak correlations were found between total potassium supplementation and LDL C (r=0.489, P<0.02); and TOT C (r=0.551, P<0.01). In addition, a positive but relatively weak correlation between the average amount of potassium supplementation per day above baseline and HDL C (r=0.407; P<0.02) was observed. Conclusion: Differences in total plasma and LDL cholesterol concentrations may be used as predictors of AmpB-induced nephrotoxicity in pediatric oncology patients.