多柔比星肾病肾损伤早期核因子-κB和血管紧张素ⅠⅡ的表达及关系探讨

目的　探讨在多柔比星 (阿霉素 )肾病综合征 (NS)幼年大鼠肾损伤过程中核因子 (NF) κB和血管紧张素ATⅠ、ATⅡ的表达及其相关性。方法　 4周龄雄性Wistar大鼠单侧肾切除加腹腔注射阿霉素造成NS模型 ,分别以免疫组织化学和原位杂交检测ATⅠ、ATⅡ和NF κB。结果　肾病组随着病变时间的延长 ,NF κB和ATⅠ、ATⅡ表达的强度和部位均呈增强趋势 ,治疗组在相同时间点则两者都有不同程度下调 (P <0 .0 5 )。结论　在阿霉素肾病损伤过程中NF κB和ATⅠ、ATⅡ起着介导作用。     

Bacterial ghosts (BGs)—Advanced antigen and drug delivery system

Bacterial ghosts (BGs) are empty bacterial envelopes of Gram-negative bacteria produced by controlled expression of cloned gene E, forming a lysis tunnel structure within the envelope of the living bacteria. BGs are devoid of cytoplasmic content and possess all bacterial bio-adhesive surface properties in their original state while not posing any infectious threat. BGs are ideally suited as an advanced drug delivery system (ADDS) for toxic substances in tumor therapy. The inner space of BGs can be loaded with either single components or combinations of peptides, drugs or DNA which provides an opportunity to design new types of (polyvalent) drug delivery vehicles. Uptake of BGs loaded with Doxorubicin (Dox) by CaCo2 cells led to effective Dox release from endo-lysosomal compartments and accumulation in the nucleus. Viability and proliferative capacity of the cells were significantly decreased (2–3 orders of magnitude) after internalization of Dox loaded BGs as compared to cells incubated with free Dox. The same effect was observed with leukemia cells. Melanoma cells also revealed a high capability to internalize BGs. These results indicate that BGs are able to target a range of types of cancer. BGs have also been investigated as DNA delivery vectors. Studies show DNA loaded BGs are efficiently phagocytosed and internalized by both professional APCs and tumor cells with up to 82% of cells expressing the plasmid-encoded reporter gene. Our studies with BGs as an ADDS system contribute (i) to optimize drug delivery for the treatment of cancer; (ii) define specific conditions for selection and preparation of BG formulations; (iii) and provide a background for the clinical application of BGs in cancer therapy.     

Scintigraphic evaluation of myocardial uptake of thallium 201 and technetium 99m pyrophosphate utilizing a rat model of chronic doxorubicin cardiotoxicity

To evaluate the usefulness of myocardial scintigraphy as a monitoring tool for chronic doxorubicin (DXR) cardiotoxicity, a rat model was used to investigate the relationship between the myocardial uptake of thallium 201 (Tl) or rechnetium 99m pyrophosphate (^99mTc-PPi) and histological changes of the heart. Although there was no significant difference in myocardial Tl uptake between control and DXR-treated rats at an early phase after Tl injection, late-phase Tl uptake was significantly higher in the DXR-treated rats than in the control rats, indicating a slow wash-out of Tl from the myocardium. The wash-out rate calculated from scintigraphic examination of DXR-treated rats was significantly decreased with increasing degree of cardiomyopathy. Since the Tl wash-out rate was sharply decreased even in animals with minimal histological changes, it may be a possible monitoring tool for the early detection of chronic DXR cardiotoxicity. On the other hand, myocardial^99mTc-PPi images could be obtained only in rats with severe myocardial changes and hence would not useful for early detection.     

以华明产阿霉素为主联合化疗9425例恶性肿瘤临床疗效综合分析

本文综合了全国26个省、自治区、直辖市内180家医院应用鮀滨-华明产阿霉素单剂或联合方案治疗42种癌症患者9425例的近期疗效和毒副反应资料,在可评价的8314例各类恶性肿瘤患者中,完全缓解者1502例,部分缓解者2928例,总有效率为53.3％。其中以恶性淋巴瘤的缓解率最高,达83.8％;小细胞肺癌次之,达73.9％。毒副反应以骨髓抑制、胃肠反应、脱发为多见。相当一部分资料将华明产品与进口同类产品进行了比较,结论为:疗效肯定,毒副反应与进口品相似,价格低廉,值得大力推广应用。     

Complete hepatic venous isolation and extracorporeal chemofiltration as treatment for human hepatocellular carcinoma: A phase I study

Background: We performed a phase I study of a novel system of complete hepatic venous isolation and extracorporeal chemofiltration in patients with unresectable hepatocellular carcinoma (HCC) to determine (a) whether systemic exposure to doxorubicin could be limited after high-dose hepatic arterial infusion (HAI), and (b) the hepatic maximum tolerated dose (MTD) of doxorubicin. Methods: Ten patients with biopsy-proven HCC were treated with 20-min HAI of doxorubicin (17 total treatments). Two patients were treated with doxorubicin 60 mg/m², three patients were treated at 90 mg/m², and five patients received 120 mg/m². A newly developed dual-balloon vena cava catheter was advanced from the femoral vein, and the balloons were inflated to isolate and capture total hepatic venous outflow. The hepatic venous blood was pumped through extracorporeal carbon chemofilters before return of the blood to the systemic circulation. Results: Peak systemic doxorubicin levels were an average 85.6% lower than were peak prefilter levels (p<0.01). Because all catheters were placed percutaneously and because the chemofiltration markedly limited systemic chemotherapy exposure, patients were discharged 1 day after 16 of the 17 treatments. The hepatic and systemic MTD of doxorubicin in this treatment protocol was 120 mg/m². Conclusions: This novel system of complete hepatic venous isolation and chemofiltration limits systemic chemotherapy toxicity and will allow use of higher doses of chemotherapeutic agents to treat HCC. The results of this study were presented at the 46th Annual Cancer Symposium of The Society of Surgical Oncology, Los Angeles, California, March 18–21, 1993.     

磁性阿霉素纳米微球的制备及在高频磁场中的发热研究

制备一种在高频磁场中能感应发热的用于治疗肿瘤的阿霉素纳米微球，研究其在磁场中的热效应。用超声搅拌冷冻干燥的方法制备药物微球，平均粒径200nm左右。电镜观察其形态为球囊状。将其置于不同介质中于高频磁场中测其温度变化值，实验表明该微球在交变磁场中使介质升温。升温速度与平稳时的温度和微球的量及磁场强度成正比，介质流动性好，升温快。     

Phase I and pharmacokinetics studies of prochlorperazine 2-h i.v. infusion as a doxorubicin-efflux blocker

In an earlier phase I study, we reported that the maximal tolerated dose (MTD) of prochlorperazine (PCZ) given as a 15-min i.v. infusion was 75 mg/m². The highest peak plasma PCZ concentration achieved was 1100 ng/ml. The present study was conducted to determine if PCZ levels high enough to block doxorubicin (DOX) efflux in vitro could be achieved and sustained in vivo by increasing the duration of i.v. infusion from 15 min to 2 h. The treatment schedule consisted of i.v. prehydration with at least 500 ml normal saline (NS) and administration of a fixed standard dose of 60 mg/m² DOX as an i.v. bolus over 15 min followed by i.v. doses of 75, 105, 135, or 180 mg/m² PCZ in 250 ml NS over 2 h. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose. Toxicities attributable to PCZ were sedation, dryness of mouth, anxiety, akathisia, hypotension, cramps, and confusion. The MTD of PCZ was 180 mg/m². Large interpatient variation in peak PCZ plasma levels (91–3215 ng/ml) was seen, with the plasma half-life (t1/2) being approximately 57 min in patients given 135–180 mg/m² PCZ. The volume of distribution (V_d), total clearance (Cl_T), and area under the curve (AUC) were 350.1±183.8 l/m², 260.7±142.7 l m² h^–1 and 1539±922 ng ml h^–1, respectively, in patients given 180 mg/m² PCZ and the respective values for patients receiving 135 mg/m² were 48.9±23.76 l/m², 33.2±2.62 l m² h^–1, and 4117±302 ng ml h^–1. High PCZ plasma levels (>600 ng/ml) were sustained in all patients treated with 135 mg/m² PCZ for up to 24 h. DOX plasma elimination was biphasic at 135 and 180 mg/m² PCZ, and a>10-ng/ml DOX plasma level was maintained for 24 h. Partial responses were seen in three of six patients with malignant mesothelioma, in two of ten patients with non-small-cell lung carcinoma, and in the single patient with hepatoma. Our data show that PCZ can be safely given as a 2-h infusion at 135 mg/m² with clinically manageable toxicities. The antitumor activity of the combination of DOX and PCZ needs to be confirmed in phase II trials.This work was supported by NIH grant R01 CA-29360 and S1488, CRC grant M01 RR-05280, and the Joan Levy Cancer Foundation. This paper was presented at the meeting of the American Association for Cancer Research, Orlando, Florida, May 19–22, 1993     

磁导向载体阿霉素介入治疗原发性肝癌的临床研究

目的：观察磁导向载体阿霉素(MTC-DOX)肝动脉介入治疗原发性肝癌的有效性和安全性。方法：将Seldinger导管超选择插入肿瘤供血肝动脉，以脉冲给药的方式注入MTC-DOX，21天为一周期，连续用药2周期以上按照WHO标准进行评价。结果：不能手术的原发性肝癌患共11例入组，10例可以评价疗效，治疗后NC7例，PD3例，中位肿瘤进展时间(TTP)为182天，有3例临床症状减轻，有4例生活质量改善，1年生存率达到54．5％；11例可以评价毒性，毒副反应均较轻，主要为轻中度的肝区疼痛和发热，少数患有胃肠道反应和一过性转氨酶升高。结论：采用磁导向载体阿霉素介入治疗原发性肝癌靶向性特别好，疗效明显，同时毒性反应轻微，值得进一步研究。     

阿霉素脂质体淋巴管灌注的靶向效果

目的：探讨阿霉素脂质体经淋巴管灌注后的体内动力学过程以及靶向效果。方法：将６０只家兔随机分为阿霉素脂质体和阿霉素水溶液两组，从家兔足背淋巴管给药，采用高效液相色谱（ＨＰＬＣ）法检测给药后各时点外周血及腹膜后淋巴结中阿霉素药物浓度，并将摘取的淋巴结作病理检查。结果：水溶液组腹膜后淋巴结阿霉素峰浓度（Ｃｍａｘ）为４６．８１μｇ／ｇ，药时曲线下面积（ＡＵＣ）为３１．８６μｇ／ｄａｙｇ－１；而脂质体组阿霉素峰浓度为９１．２３μｇ／ｇ，ＡＵＣ为１３８．３４μｇ／ｄａｙｇ－１。在外周血中脂质体组的峰浓度只有水溶液组的１／５。淋巴结病理检查结果表明，脂质体组的水肿、坏死、纤维化较水溶液组明显，而心肌病理反应较轻或不存在。结论：脂质体对淋巴结具有高度靶向性，阿霉素脂质体淋巴管灌注有可能成为治疗淋巴结转移的有效且副作用少的新方法。