Primary glial tumor patients treated by combining cis-platin and etoposide

Summary Thirty eight patients with malignant gliomas (27 GBM and 11 AA) were treated with up to 7 cycles of CDDP + VP16 every month after surgery. Chemotherapy was planned as two cycles before and 5 cycles after radiation (42 Gy) using a three times daily fractionation schedule. No severe toxicity was observed. The object of our study was to investigate the antitumor effectiveness by combining CDDP plus VP16 against primary malignant glial tumors. The time to tumor progression (TTP) and survival time (ST) of the GBM patients in the present study were 38.5 and 68,5 weeks respectively. The TTP of the AA patients was 73 weeks and the ST was not calculated as most patients are still alive. By the 18th. month after surgery, 38% of GBM and 74% of AA patients treated with (CDDP + VP16) are still alive. This study demonstrates that the combination of CDDP and VP16 is effective in patients with malignant gliomas.     

Phase II Studies of Bleomycin, Ifosfamide and Cis-Platinum in Advanced and Recurrent Cervical Carcinoma

We report the results of phase II studies using a combination of ifosfamide, cis-platinum and bleomycin (BIP) in advanced and recurrent cervical cancer. Fifty-one patients have been studied. In 37 patients with disease not amenable to radical local therapy 27 objective responses (73%) were seen with 7 complete responses. Eleven of 14 patients (79%) with primary inoperable disease had at least a 50% reduction in tumour bulk prior to radical local radiotherapy. All patients experienced alopecia, nausea and vomiting. Other toxicity included myelosuppression, infection, reduction in renal function and disturbance of consciousness. There was no evidence that primary chemotherapy enhanced the acute toxic effects of pelvic radiotherapy. These data indicate that BIP is highly active in cervical cancer and can be used for effective palliation and cytoreduction in more than 70% of patients.     

改良原子吸收光谱法测定组织中载顺铂磁性纳米药物中的顺铂含量

目的建立改良组织消化和原子吸收光谱测定组织中铂浓度的方法。方法应用岛津原子吸收光谱系统,条件:AA-6300型原子吸收分光光度计、GFA-Ex7i石墨炉、ASC-6100自动进样器、铂元素空心阴极灯,含载顺铂磁性纳米药物的组织烘干后经硝酸和双氧水水浴消化后直接采用原子吸收光谱仪在265.9nm处测定。结果各不同组织顺铂线性范围均是54～283.5μg.L-1,相关系数r均大于0.999,日内变异系数均小于5%,日间变异系数均小于10%。结论采用改良原子吸收光谱法可高效、准确的检测湿化消化法处理的组织样本中铂元素的含量,该改良方法适用于顺铂药物动力学的研究。     

重组人血管内皮抑素联合顺铂胸腔内注射治疗肺腺癌恶性胸腔积液的临床研究

目的研究重组人血管内皮抑素(恩度)联合顺铂胸腔内注射治疗肺腺癌恶性胸腔积液的近期疗效与安全性。方法 90例肺腺癌恶性胸腔积液患者随机分为恩度联合顺铂组、恩度组和顺铂组,具体方法:恩度30mg/次,顺铂30mg/次,每两天一次,连续3次为1疗程,最多可连续接受2疗程治疗。评估三组的近期疗效、生活质量(QOL)和不良反应。结果恩度联合顺铂组有效率、QOL改善率分别为83.3%、76.7%,恩度组53.3%、63.3%,顺铂组50%、60%。恩度联合顺铂组有效率高于恩度组、顺铂组,组间差异有统计学意义(P=0.014)。三组QOL改善率差异无统计学意义。恩度联合顺铂组、顺铂组不良反应发生率比较差异无统计学意义,恩度组低于上述两组,差异具统计学意义(P0.017)。结论恩度联合顺铂胸腔内注射治疗肺腺癌胸腔积液可明显提高缓解率,改善生活质量,且不良反应小,具有较好的临床疗效及用药安全性。     

Flow cytometric analysis of micronuclei in peripheral blood reticulocytes: II. An efficient method of monitoring chromosomal damage in the rat.

We have evaluated a flow cytometric method that allows assessment of micronucleated reticulocytes (MN-RETs) in microliter quantities of peripheral blood and compared results using this assay with those of established microscopic methods of scoring bone marrow and peripheral blood from rats treated with well-characterized genotoxic agents. Young reticulocytes (RETs) are labeled with FITC-anti-CD71 (transferrin receptor) and micronuclei with propidium iodide (with RNase treatment). Red blood cells parasitized with Plasmodia serve as a calibration standard for DNA content. Microscopic scoring used acridine orange (AO) staining of methanol-fixed slides or supravital AO staining. The effect of the rat spleen on the parameters evaluated was determined by comparing age- and sex-matched normal and splenectomized rats treated with cyclophosphamide, cis-platin, or vinblastine under treatment conditions that established a steady-state frequency of MN-RETs in the bone marrow and peripheral blood compartments. The data demonstrate the sensitivity and reproducibility of the flow cytometric assay in the Sprague-Dawley rat, and comparative studies using identical blinded samples at multiple laboratories show that inter- and intra-laboratory reproducibility is much higher with the flow method than with the microscopic methods currently employed for regulatory studies. A significant effect of splenic selection against genotoxicant-induced MN-RETs was observed with each of the three scoring methodologies, despite the fact that the flow and supravital AO techniques restrict analysis to the youngest fraction of RETs. The high precision of flow-based measurements also demonstrated a slight but statistically significant level of selection against spontaneously arising MN-RET. Despite these spleen effects, assay sensitivity for blood-based analyses was maintained by the flow method as it was shown to have superior counting statistics, lower variability, and higher sensitivity than manual scoring. The data suggest that flow cytometric assessment of micronucleus induction can be integrated into routine toxicity testing, eliminating the need for a separate bioassay.     

顺铂磁性纳米药物体内靶向性研究

目的 研究顺铂磁性纳米药物(CDDP-MNP)在正常小鼠体内的磁靶向性分布.方法 正常昆明种小鼠32只,随机分为4组,每组8只.于小鼠一侧肾脏区域设置强度为4100～4200Gs的体外磁场,自尾静脉注射CDDP-MNP并保持体外磁场一定时闻:A、B、C、D组分别在注药后维持磁场30 min和1、2、4 h.以原子吸收光谱分析法检测小鼠肾脏内顺铂含量,MRI监测肾脏信号强度变化,普鲁士蓝铁染色及扫描电镜检查纳米粒子在肾脏组织内的分布.结果 小鼠磁靶侧肾脏内CDDP含量高于非靶向侧,经尾静脉注射后0.5、1、2 h靶向侧药物浓度分别为非靶向侧的1137、1.31、1.22倍(p<0.05).MRI显示注射CDDP-MNP后,T2WI中小鼠磁靶向侧肾脏区域信号强度较对侧明显降低.病理切片普鲁士蓝铁染色显示含氧化铁的纳米粒分布于肾脏毛细血管管腔、内皮细胞等部位,透射电镜下见纳米粒主要被内皮细胞吞噬.结论 具有超顺磁性的CDDP-MNP在体外磁场作用下能实现体内靶向性分布,并可通过MRI进行监测,该纳米药物具有临床靶向抗肿瘤应用潜力.     

甲苯与顺铂联合作用对豚鼠内耳的损伤

究甲苯与顺铂对豚鼠听力的影响，发现甲苯或顺铂单独作用后可造成豚鼠一定程度的听力损失，甲苯与顺铂联合作用后，除高频区引起明显的听力损失外，中低频区听力更为明显，阈移大于甲苯和顺铂单独作用后阈移的总和，表明甲苯与顺铂联合作用后毒性效应呈协同或相加，耳蜗病理亦表明联合作用后外毛细胞总损较明显。     

Physiological model for the pharmacokinetics ofcis-dichlorodiammineplatinum(II) (DDP) in the tumored rat

A physiological model has been developed to describe the disposition of cisdichlorodiammine-platinum(II) (DDP) following i.v. dosing in the female rat bearing the Walker 256 carcinoma. The model simulates concentrations of DDP and its mobile and fixed metabolites in plasma, liver, gut, skin, muscle, tumor, carcass, and kidney, and DDP and mobile metabolite excretion following a 4 mg/kg dose. In the kinetic model, DDP binds irreversibly to low MW nucleophiles and macromolecules (largely proteins) within the plasma and tissue compartments to form mobile and fixed metabolites, respectively. Reaction rates for the formation of each metabolite are tissue/organ specific. The rate constant for the biotransformation of DDP to fixed metabolite in plasma (k _2p=0.0082 min^–) was determined from in vitro incubation studies. This rate was used as the basis for estimating the biotransformation rate constants for DDP to fixed and mobile metabolites in other compartments. Both DDP and mobile metabolite are assumed to follow flowlimited transport, to freely traverse compartmental barriers, and to partition equally in all compartments. Both are excreted in the urine, the major route of Pt elimination. Urinary excretion is modeled as a linear process involving filtration only; an assumption based on a calculated renal clearance of 1.1 ml/min, a value very similar to the estimated GFR. Biliary excretion is a minor route of mobile metabolite elimination and is modeled as a linear process occurring in the liver. Four hours after dosing, approximately 60% of the administered Pt remains in the tissues and plasma. Of this, over 75% of the plasma Pt and 90% of the metal ion in every other compartment is fixed (protein bound). Fixed Pt can be eliminated from a compartment only after its biotransformation to mobile metabolite. In most compertments this rate of elimination corresponds closely to the average rate of protein turnover in that compartment.     

改性载顺铂磁性纳米药物治疗鼻咽癌的体外实验*****★

背景：近年来载抗癌药物磁性纳米微粒作为一种新型靶向给药系统，利用其高载药量、靶向定位输送、以及磁粒的热效应、可生物降解等优点，为高效、低毒副作用的化疗带来了新的希望。 目的：观察顺铂耦合海藻酸钠改性磁性纳米球载体后对人鼻咽癌CNE2细胞的体外毒性效应。 设计、时间及地点：体外对比观察实验，于2005-03在中山大学北校区药理实验室完成。 材料：顺氯氨铂(CDDP)由山东齐鲁制药厂提供，海藻酸钠改性载顺铂四氧化三铁磁性纳米球(CDDP-SAMNP)，粒径大小43~52 nm，可逆释放的CDDP量(或利用率)约65%。鼻咽癌CNE2细胞株由中山大学肿瘤医院细胞病理实验室提供。 方法：实验分药物处理组及对照组，药物处理组分为CDDP组和CDDP-SAMNP组，CDDP和CDDP-SAMNP均用RPMI-1640培养液稀释，加药浓度按CDDP的含量计。对照组分别为RPMI-1640培养液组和单纯SAMNP组(加入四氧化三铁，磁核质量浓度为7 g/L，以培养液稀释)。 主要观察指标：采用MTT法分别观察1.89~11.34 mg/L的CDDP及相应剂量的CDDP-SAMNP对鼻咽癌CNE2细胞作用24, 48 h后的杀伤率；并通过透射电镜观察CNE2对CDDP-SAMNP的摄取。 结果：①单纯SAMNP对鼻咽癌CNE2细胞无杀伤作用，与培养液组相似(P > 0.05)。②随着CDDP和CDDP-SAMNP药物浓度的增加，药物对CNE2细胞的杀伤率呈明显的量效关系。同一药物相同浓度下，随着作用时间的延长，杀伤率提高，呈明显的时效关系。作用24 h，CDDP-SAMNP对鼻咽癌CNE2的杀伤率与CDDP相似(P > 0.05)。作用48 h，中低浓度(1.89~5.04 mg/L)时，CDDP-SAMNP的杀伤率低于CDDP(P < 0.05)，当达到6.93 mg/L时，杀伤率接近同浓度的CDDP。③CNE2细胞能够摄取CDDP-SAMNP和SAMNP。 结论：在高浓度下阴离子海藻酸钠改性载顺铂磁性纳米球对鼻咽癌CNE2细胞的体外毒性与同浓度单纯顺铂相近，杀伤作用来源于载体释放的顺铂。改性后顺铂的稳定性提高，药效没有降低。     

Porosified Silicon Wafer Structures Impregnated With Platinum Anti-Tumor Compounds: Fabrication, Characterization, and Diffusion Studies

In this work, the incorporation and characterization of cis-platin (cis-diammine dichloroplatinum(II)), carbo-platin [cis-diammine(cyclobutane-1,1-dicarboxylato] platinum(II)), and Pt(en)Cl₂ (ethylenediamminedichloro platinum(II)) within layers of calcium phosphate on porous Si/Si substrates are described. These materials have been characterized by scanning electron microscopy, secondary ion mass spectrometry, and X-ray energy dispersive spectroscopy. The diffusion of platinum species from the doped calcium phosphate layers has also been investigated by UV-visible absorption spectrometry and inductively-coupled plasma spectroscopy. The influence of initial platinum concentration, the impact of thermal annealing of the calcium phosphate/porous Si/Si matrix, as well as the effect of varying the ligand coordination sphere of the Pt complex on its ability to be delivered to the surroundings have also been analyzed. For the case of cis-platin, it is found that increasing the concentration of platinum complex in the electrolyte during cathodic growth of calcium phosphate results in a relatively greater concentration of Pt incorporated into the calcium phosphate layers and a larger amount of Pt which subsequently can be delivered to the surrounding medium upon exposure to solvent.