脂质体载药提高阿霉素抗肿瘤活性的初步实验研究

作者采用改良冰冻融溶法制成阿霉素多层脂质体，经冰冻干燥得冻干品。采用６０Ｃｏ辐射消毒获无菌稳定的制剂。包裹率为６０一６６％。平均粒径２．５μｍ。阿霉素脂质体对肝癌腹水型小鼠的实验结果示脂质体载药后肿癌增殖缓慢，动物生存期明显延长。６０天生存延长率为２７１％，明显优于游离阿霉素组的１０１％（Ｐ＜０．０１）。组织细胞培养发现，经阿霉素脂质体作用后的癌细胞失去增殖能力，７２小时后细胞全部死亡，游离阿霉素组仍有７０％细胞存活。鉴于脂质体载药后的生物学特征，可望在肿癌的临床化疗中取得较好的疗效。     

脂质体阿霉素药理研究进展

阿霉素是临床常用的抗恶性肿瘤药,但由于毒性反应较为严重,其临床应用受到限制。近年研究显示,采用脂质体载运阿霉素可减轻阿霉素的毒性作用,而抗肿瘤作用并不减弱。在动物肝转移肿瘤模型上还观察到了抗肿瘤作用的增强。目前,对脂质体阿霉素的临床试验正在进行中。     

隐匿型脂质体阿霉素治疗乳腺癌的临床研究

阿霉素是细胞毒素类抗肿瘤药物,临床应用受到药物相关副作用的限制.羟甲基聚乙二醇(PEG)脂质体包裹的阿霉素的结构是空间稳定性的,不易与血浆蛋白结合,因此称为隐匿型脂质体阿霉素,具有血液浓度高、血浆循环时间长、心脏毒性低、肿瘤靶向性的特征.PEG脂质体阿霉素更易于耐受,心脏毒性及其他副反应较传统阿霉素少,但在生存时间,有效率方面,与传统阿霉素无明显差异.与其他药物联合应用是否能增加有效率,延长生存时间,还需要进一步证实.     

聚乙二醇脂质体阿霉素的研究进展

阿霉素抗瘤谱广,但毒性大,临床应用受到限制。脂质体阿霉素不够稳定,而且脂质体不易进入肿瘤。聚乙二醇包裹的脂质体阿霉素（ＰＬＤ）性质稳定,在血循环中停留时间长,血浆清除率低,分布容积小。ＰＬＤ增加了阿霉素在肿瘤内的分布,提高了抗肿瘤活性,同时减少了对机体的毒性。     

阿霉素脂质体的研究进展

阿霉素作为临床常用的蒽环类恶性肿瘤药物,其心脏毒性、骨髓抑制及消化道不良反应限制了临床应用。自从脂质体被发现,并作为抗肿瘤药物的有效载体后,取得了良好的抗肿瘤效果,并降低毒副作用。文章对阿霉素脂质体的应用优势和研究进展进行综述。     

MRK-16修饰阿霉素免疫脂质体逆转肺癌细胞多药耐药研究

目的：研究MRK-16修饰阿霉素免疫脂质体与阿霉素脂质体对非小细胞肺癌多药耐药的逆转作用。方法：25％的戊二醛偶联MRK-16于阿霉素脂质体，制备MRK-16修饰阿霉素免疫脂质体；以MTS测定细胞存活率，检测SPC—A1／TAX的耐阿霉素指数；以阿霉素脂质体与MRK-16修饰阿霉素免疫脂质体作用于SPC—A1／TAX，设阿霉素组对照；研究两者对SPC—A1／TAX的体外细胞毒与多药耐药逆转作用；流式细胞仪检测用药后2．4、6小时后细胞内药物浓度。结果：免疫脂质体细胞杀伤率（48h）达67．7％，其多药耐药逆转指数达7．45；脂质体对细胞的杀伤率49．2％，逆转指数4．28；流式细胞仪检测细胞内药物浓度，6小时后阿霉素免疫脂质体组细胞内药物浓度是阿霉素组的18．34倍，脂质体组是阿霉素的10．1倍。结论：MRK-16修饰阿霉素免疫脂质体、阿霉素脂质体在体外对非小细胞肺癌多药耐药具有-定的逆转作用。     

半乳糖脂修饰的阿霉素脂质体体外杀伤肝癌细胞的实验研究

目的：合成ｎ－十六烷酰－１硫代－β－Ｄ－半乳糖苷（Ｃｅｔｙ－Ｇａｌ）并用其修饰阿霉素脂质体表面,观察体外对人肝癌细胞系ＳＤＭＭＧ－７７２１的杀伤作用。方法 半乳糖经化学反应制备Ｃｅｔｙ－Ｇａｌ,用１０％摩尔的糖脂整合到超地制备的小单层阿霉素脂质体脂膜上进行体外杀瘤研究了ＭＴＴ法检测杀菌瘤活性,结果 ４８小时细胞毒试验糖脂阿霉素脂质体人肝癌细胞系ＳＭＭＣ－７７２３１的杀伤作用优于无糖脂阿霉素脂质体（     

脂质体阿霉素热化疗对食管癌细胞的毒性实验研究

目的了解脂质体阿霉素体外不同温度热化疗对食管癌细胞株的细胞毒性作用。方法以体外培养食管癌细胞株EC9706为靶细胞,以游离阿霉素作为阳性对照,未加药物组作为阴性对照,采用WST-1法测定阿霉素和脂质体阿霉素对EC9706的半数抑制浓度(IC50)。再使用此IC50时药物的浓度,在37℃、41℃、43℃下水浴加温1 h进行热化疗,同样使用WST-1法测定其细胞杀伤率。结果阿霉素、脂质体阿霉素对食管癌细胞株EC9706的IC50分别为19.064 μg/ml、51.359 μg/ml(含阿霉素的量为5.707 μg/ml)。在37℃条件下,阿霉素与脂质体阿霉素对EC9706细胞株的杀伤率分别为(49.29±2.14)%、(49.39±6.07)%（P>0.05）。在41℃条件下,单纯加热、阿霉素、脂质体阿霉素对EC9706的杀伤率分别为(25.25±2.52)%、(64.80±5.01)%、(76.39±3.42)%,两种药物加热条件下的细胞杀伤作用均较单纯加热组高(P<0.01),且脂质体阿霉素较阿霉素的细胞毒作用提高了11.59% (P<001)。在43℃条件下,虽脂质体阿霉素的杀伤作用(79.05 ± 3.09)%较阿霉素(71.89±2.30)%提高了716% (P<0.05),但与该药在41℃条件下的杀伤作用比较仅提高2.66%,且差异没有统计学意义(P>0.05)。结论食管癌细胞株EC9706对阿霉素和脂质体阿霉素都很敏感。在热化疗作用上,阿霉素和脂质体阿霉素对食管癌细胞较单纯热疗具有更强的杀伤作用;在37℃条件下,脂质体阿霉素对细胞的杀伤作用与阿霉素相当,在41℃和43℃条件下脂质体阿霉素对细胞的杀伤作用强于阿霉素,但脂质体阿霉素在43℃与41℃对细胞的杀伤作用相当,两种药物联合热疗都具有协同增敏作用。     

阿霉素脂质体治疗晚期肝癌45例

:〔目的〕对比观察阿霉素(ADM)多相脂质体与游离ADM治疗晚期肝癌近期疗效及副作用。〔方法〕1997年3月～1998年6月87例晚期肝癌患者,随机分成两组,A组为ADM多相脂质体介入化疗组(治疗组),B组为游离ADM介入化疗组(对照组)。〔结果〕平均生存期1年生存率两组无明显差别,近期疗效A组优于B组,毒副反应A组较B组轻。〔结论〕两种治疗方法平均生存期无明显差别,ADM多相脂质体介入化疗可提高近期疗效,降低毒副反应,提高病人生活质量。     

Pharmacokinetics of Adriamycin and cisplatin for anhepatic chemotherapy during liver transplantation

We investigated the pharmacokinetics of cytotoxic anticancer agents administered under anhepatic conditions. Beagle dogs underwent either a sham operation consisting of laparotomy only (control group, n = 11) or a laparotomy and total hepatectomy under venovenous bypass (anhepatic group, n = 12). Each dog received a bolus intravenous injection of either Adriamycin (1 mg/kg) or cisplatin (1 mg/kg). The plasma and urine concentrations of each drug were measured at intervals for up to 2 h after drug injection. The dogs given Adriamycin were then sacrificed to determine tissue drug concentrations in the liver (controls only), spleen, kidney, heart, lung, skeletal muscle and small intestine. The control and anhepatic groups showed similar Adriamycin profiles during the initial 5 min after drug injection. However, subsequently, the plasma Adriamycin concentrations remained persistently higher in the anhepatic dogs than in the controls, yielding a two-fold elevation of the mean area under the concentration-time curve in the anhepatic group (P<0.01 vs controls). The renal clearance values did not significantly differ between the two groups. The tissue Adriamycin concentrations in all measured organs, excluding the liver, were higher in the anhepatic group than in the controls. In a second set of experiments with cisplatin, the plasma platinum concentrations did not significantly differ between the two groups throughout the time course. However, the renal clearance of platinum in the anhepatic dogs showed a fourfold increase compared with that in the controls (P<0.01). These pharmacokinetic data suggest that Adriamycin carries the risk of increased systemic toxicities, while cisplatin may be associated with increased renal toxicity when administered during the anhepatic period of liver transplantation. Received: 17 July 1996 / Accepted: 5 March 1997     

Effects of Methylxanthine Derivatives on Adriamycin Concentration and Antitumor Activity

We studied the mechanism whereby caffeine acts as a biochemical modulator of adriamycin, and examined various methylxanthine derivatives to determine whether they would be of value as biochemical modulators. In an in vitro study of adriamycin efflux in Ehrlich ascites carcinoma cells, theophylline, pentoxifylline, and theobromine inhibited this efflux, while caffeine metabolites did not. The effects of several methylxanthine derivatives on the antitumor activity of adriamycin and on adriamycin concentration in tissue were also examined in CDF₁ tumor-bearing mice. Theobromine, which inhibited adriamycin efflux in vitro , increased the antitumor activity of adriamycin and the concentration of adriamycin in tumors. The caffeine metabolites, which had no effect on the adriamycin efflux, did not increase antitumor activity. These results suggest that the metabolism of caffeine may weaken its effect as a biochemical modulator, and that pentoxifylline and theobromine would be of value as biochemical modulators of adriamycin.     

Adriamycin in localized and metastatic uterine sarcomas.

Seventeen women with metastatic uterine sarcomas were treated with Adriamycin chemotherapy. Only one (6%) had an objective response. In addition, 12 patients with early uterine sarcomas were randomized to Adriamycin versus no adjuvant chemotherapy in order to evaluate the effect of Adriamycin in reducing the incidence of subsequent distant recurrences. Of those women receiving Adriamycin, two developed distant metastasis and two developed life-threatening congestive heart failure. Also, two of the six women who did not receive Adriamycin developed distant metastasis. Therefore, continuation of the randomized trial was considered unjustified.     

阿霉素联合治疗恶性肿瘤236例的近期临床观察

本文采用华明产ADM联合方案治疗癌瘤236例,在可评价的175例中,达CR35例,PR62例,有效率55.4％。其中恶性淋巴瘤有效率86.5％,白血病82.3％,乳腺癌53.8％,肺癌43.9％。236例毒性反应在消化道、脱发和骨髓抑制,Ⅰ°～Ⅱ°居多。心电图异常7.2％,转氨酶升高6.3％,未见不可逆性毒性反应。再次临床验证表明,华明产ADM的疗效,毒性与过去使用的进口ADM相似。     

HPLC测定细胞中阿霉素及其在筛选耐药逆转剂中的应用

 阿霉素(简称ADM)是肿瘤化疗中常用的药物。 本文介绍一种用高效液相色谱(HPLC)测定耐药细胞中ADM的方法, 该方法处理简单、灵敏度高, 仪器的最低检出量为8.621pmol, 在20～344.8pmol范围内呈现良好的浓度一峰高线性关系, 并利用该方法时行ADM耐药逆转剂的筛选研究, 认为潘生丁、环抱菌素A可作为ADM耐药的逆转剂。     

阿霉素每周给药治疗恶性肿瘤的临床观察

目的：评价阿霉素每周给药或每3周给药治疗多种晚期恶性肿瘤的疗效及不良反应。方法：阿霉素15－20mg/m^2每周1次或50mg/m^2每3周1次静脉推注,同时加其他抗癌药联合化疗。结果：共316例患者接受了2个疗程以上联合化疗,其中113例接受阿霉素每周化疗,203例接受阿霉素每3周化疗。阿霉素每周化疗的有效率为：非霍奇金淋巴瘤71％,非小细胞肺癌44％,小细胞肺癌80％,乳腺癌54％,胃癌30％,软组织肉瘤33％,原发性肝癌15％,阿霉素每3周化疗的有效率为：非霍奇金淋巴瘤76％,非小细胞肺癌40％,小细胞肺癌83％,乳腺癌47％,胃癌27％,软组织肉瘤29％,原发性肝癌14％,阿霉素每周化疗的不良反应主要为骨髓抑制、恶心呕吐和脱发,其发生率与阿霉素每3周化疗较为接近,阿霉素每周化疗病人的心电图改变比每周化疗的病人少见,结论：阿霉素每周化疗的疗效与阿霉素每3周化疗相似,阿霉素每周给药的不良反应病人容易耐受, 心脏毒性较轻。     

阿霉素抑制骨巨细胞瘤的机理

 目的 探讨敏感性相对最高的阿霉素（ADM）抑制骨巨细胞瘤的机理,方法 用阿霉素与骨巨细胞瘤细胞悬液共同培养72小时（阿霉素最浓度分别为0.04μg/ml,0.4μg/ml）,搜集细胞,用电镜观察及用流式细胞仪、DNA电泳进行分析。结果 电镜及流式细胞分析均可获取一定数量的凋亡细胞,且较高浓度（0．4μg／ml以上）阿霉素处理的细胞DNA电泳可见典型的梯形条带。研究的结果提示：阿霉素抑制骨巨细胞瘤的机理是诱导骨巨细胞瘤细胞凋亡。     

含泰素的联合化疗治疗阿霉素耐药的转移性乳腺癌

１９９５年７月～１９９７年１２月，用含泰素的联合化疗方案治疗了阿霉素抗药的晚期乳腺癌２０例，其中ＥＴＰ方案治疗１２例，ＴＩＭ方案治疗４例，ＴＥ方案治疗２例，ＣＴＦ方案、ＴＩ方案治疗各１例。全组化疗共７４周期，中位周期数３．５周期（２～６周期）。结果，ＣＲ４例，ＰＲ１０例，ＭＲ２例，ＳＤ１例，ＰＤ３例，总有效率（ＣＲ＋ＰＲ）７０％。全组中位缓解期７个月（２～１３个月）。主要剂量限制毒性为骨髓抑制，以白细胞减少为主，Ⅲ度～Ⅳ度白细胞减少发生率为４３％。与泰素相关的常见不良反应为脱发、肌肉／关节痛和周围神经痛，发生率分别为１００％、８０％和４０％，均为轻、中度，停药后可恢复。我们认为含泰素的联合化疗对阿霉素耐药的转移性乳腺癌有很好的疗效，可以考虑作为第二线治疗方案     

Effect of Combined Intrapleural Administration of Lactobacillus casei (LC9018) and Adriamycin on Experimental Malignant Pleurisy in Mice

The combined effect of Lactobacillus casei YIT9018 (LC9018) and adriamycin (ADR) on malignant pleurisy was investigated using an experimental model in BALB/c mice in which Meth A fibrosarcoma cells were intrapleurally implanted. The control mice died from dyspnea due to pleural effusion, before significant growth of tumor nodules could be achieved in the thoracic cavity. Intrapleural (ipl) administration of LC9018 (20–200 μg/head) on days 1 and 5 reduced the effusion volume and induced pleural adhesions in a dose-related manner. A statistically significant and reproducible prolongation of survival was observed at a dose of LC9018 200 μg/head: increase of lifespan (ILS) values of 15–39% were obtained. An ipl administration of ADR (2–4 mg/kg) on day 1 was also effective in prolonging survival without severe toxicity (ILS values of 100–122%). The combined use of ADR and LC9018 induced a high incidence of pleural adhesions, a delay in effusion accumulation, and an additive prolongation of lifespan (ILS values of 133–178%), compared with ADR monotherapy. In the combination therapy group, a marked and continuous ipl exudation of neutrophils, macrophages, and lymphocytes was observed with a significant decrease in pleural tumor cells. These findings suggest that ipl administration of LC9018 enhances the effect of ADR, probably through both host-mediated tumoricidal activity and sclerosing effects on the pleura.     

Investigation of the enterohepatic recirculation of Adriamycin and its metabolites by a linked-rat model

We investigated the possible role of enterohepatic recirculation in prolongation of the half-life of elimination for Adriamycin, a commonly prescribed anticancer agent. We sought to determine whether enterohepatic recirculation of Adriamycin and its metabolites occurs using a linked-rat model. Two rats, a donor and a receiver, were linked via a catheter from the bile duct of the donor rat to the duodenum of the receiver. Control experiments were conducted with intact rats (without a bile duct cannula, control A) in order to estimate the half-life of elimination and with bile duct-cannulated rats (control B) to determine the amounts of Adriamycin and its metabolites in the bile. [¹⁴C-14]-Adriamycin was injected intravenously via the femoral vein to control A, control B and donor rats. The biological half-life of Adriamycin in the intact rats (control A, 10 h) was significantly higher than in the bile-duct-cannulated rats (control B, 4 h). The cumulative amount of Adriamycin and its metabolites excreted in the urine of the control A rats was also greater than from control B rats, indicating higher levels of the drug in their systemic circulation. Biological samples (bile, urine, plasma, blood cells and the major organs heart, liver and kidney) of the receivers contained significant amounts of Adriamycin and its metabolites. The total radioactivity recovered in the bile of the receivers accounted for 0.1% to 8% of the Adriamycin dose that was administered to the donors. Adriamycin and its metabolites appeared there only after a lag time that was consistent among all the receivers. Doxorubicinol aglycone was the major metabolite found in the bile and urine of the receivers. Low but constant levels of radioactivity were also detected in the plasma and blood cells of the receivers. The presence of unchanged Adriamycin in the bile and urine of the receivers suggested absorption of the parent drug from the intestine of the receivers. Overall, we estimated that about 22% of the dose injected to the donors was absorbed from the intestine of the receivers. Taken together, these findings clearly demonstrate a significant role for enterohepatic recirculation of Adriamycin and its metabolites, which may contribute to the ability of these compounds to induce cumulative cardiac damage and/or to increase the efficacy of Adriamycin. Received: 21 January 1997 / Accepted: 14 July 1997