高效液相色谱法检测血中表阿霉素的研究

用ＺｏｒｂａｘＣ－８柱成功地分离了阿霉素、表阿霉素及其代谢产物。在此基础上建立了用阿霉素作内标物定量测定表阿霉素的分析方法，其最低检测限为２ｎｇ／ｍｌ，线性范围１０－３００ｎｇ／ｍｌ。     

高剂量与常规剂量表阿霉素联合化疗初治非小细胞肺癌对比研究

目的本实验为一前瞻性随机化对照研究,以高剂量表阿霉素-丝裂霉素-顺铂,常规剂量表阿霉素-丝裂霉素-顺铂作比较,初治非小细胞肺癌(NSCLC),评价其疗效及毒副作用.方法治疗NSCLC共40例.分高剂量组和常规剂量组(A、B)各20例.男性25例,女性15例.病理类型以腺癌为主(26例),Ⅲa期4例,Ⅲb期17例,Ⅳ期19例.全部为初治病人.结果高剂量组(A)总有效率(65%)高于常规剂量组(B)(45%),中位缓解期A组3.1个月,B组2.2个月;中位生存期A组8.7个月,B组7.1个月.表阿霉素的剂量限制毒性为心脏毒性和骨髓抑制,心脏毒性发生率A、B两组均为5%(1例),骨髓抑制A组较B组稍高,白细胞下降率各为65.0%和55.0%.结论高剂量表阿霉素为主的联合化疗治疗NSCLC的有效率比常规剂量组高,毒性相似,可以耐受,是值得推荐的高效低毒的一种给药途径.     

The pharmacokinetics of high-dose epirubicin and of the cardioprotector ADR-529 given together with cyclophosphamide, 5-fluorouracil,and tamoxifen in metastatic breast-cancer patients

A high-pressure liquid chromatographic method for determination of the bisdioxopiperazine derivative ADR-529 (ICRF-187), a compound proven effective in protection against anthracycline-induced cardiotoxicity, has been developed. The limit of quantitation was 5 ng/ml using a narrow-bore 5-m silica column and UV detection. The method was used for determination of pharmacokinetic profiles of ADR-529 after a 3-weekly i.v. administration of different doses of ADR-529 (600–1000 mg/m²) together with different doses of epirubicin (E, 60–100 mg/m²), fixed-dose cyclophosphamide (C, 600 mg/m²), fixed-dose 5-fluorouracil (F, 600 mg/m²), and daily administration of tamoxifen (T, 30 mg; CEF-T) in the treatment of patients with metastatic breast cancer. Pharmacokinetic parameters for epirubicin were also determined. The aim of the study was to determine (1) whether the pharmacokinetics of ADR-529 as part of a combination with CEF-T changes with increasing doses of ADR-529 and increasing doses of epirubicin and (2) whether the pharmacokinetics of epirubicin in the same combinations is altered with the administration of increasing doses of ADR-529. A total of 82 patients were included. A crossover study including 16 of the patients showed no significant difference in epirubicin pharmacokinetic parameters when epirubicin was given with or without concomitant administration of ADR-529. Apart from minor changes in the distributional half-lives, the pharmacokinetic parameters of epirubicin were not altered with increasing doses of ADR-529, nor were the pharmacokinetic parameters of ADR-529 itself. Escalating doses of epirubicin did not significantly alter the pharmacokinetic parameters of ADR-529 with the exception of a 30% increase in the terminal half-life and a decrease in total body clearance when the epirubicin dose was raised from 60 to 100 mg/m². We conclude that concomitant administration of ADR-529 does not alter the distribution and elimination of epirubicin in doses suitable for preventing the anthracycline-induced cardiotoxicity.     

高剂量表阿霉素治疗进展期和晚期乳腺癌

目的评价高剂量表阿霉素（ＨＤ－ＥＰＩ）合并环磷酰胺（ＣＴＸ）、氟脲嘧啶（５－Ｆｕ）治疗进展期和晚期乳腺癌的安全性和有效性。方法对３２例可评价的Ⅲ、Ⅳ期乳腺癌患者静脉给予ＣＴＸ６００ｍｇ／ｍ２、ＥＰＩ９０ｍｇ／ｍ２～１１０ｍｇ／ｍ２、５－Ｆｕ９００ｍｇ／ｍ２,每２１天重复。并与３０例非同期低剂量组比较（ＥＰＩ为５０ｍｇ／ｍ２）。结果高剂量组的总有效率为７１．９％,完全缓解率为１２．５％,明显高于低剂量组（５６．７％和６．７％）;初治的有效率（８０．０％）略高于复治者（６８．２％）。全组中位缓解期７．４个月,中位生存期１２．５个月。白细胞减少为主要的毒副反应,发生率为８９．５％（６８／７６）,Ⅲ、Ⅳ度分别为２７．６％和１８．４％;胃肠道毒性为轻、中度,未见明显的心肝肾毒性。结论ＨＤ－ＥＰＩ＋ＣＴＸ＋５－Ｆｕ方案治疗晚期乳腺癌安全有效,可在临床进一步试用     

诺维本联合阿霉素一线治疗72例转移性乳腺癌

目的 分析72例接受诺维本加表阿霉素联合化疗方案一线治疗转移性乳腺癌患者的疗效及毒性。方法 72例未经化疗的转移性乳腺癌患者，接受诺维本25mg／m^2每周，静滴d1、d8，表阿霉素静注d1，每3周重复。结果 72例可评价疗效、毒性、生存期，完全缓解12．5％(9／72)，部分缓解65．3％(47／72)，稳定18．1％(13／72)，进展4．2％(3／72)，CR PR77．8％(56／72)。WHO血液血毒性：在360个化疗疗程中，Ⅲ和Ⅳ度粒细胞减少分别是32％和16％，Ⅲ和Ⅳ度非血液血毒性低。中位病变进展时间(TTP)为13个月(1～23月)，中位生存期为25个月(3～34月)。结论 诺维本联合表阿霉素一线治疗转移性乳腺癌疗效高、毒性低。     

榄香烯与化疗药物联合作用对癌细胞株生长的影响

 用肾透明细胞癌细胞株KCC和红白血病细胞林K562作为靶细胞研究了中药榄香烯和化疗药物的体外协同应用对癌株生长的影响。单独用药情况下，KCC对榄香烯、阿霉素、5氟脲嘧啶均呈不同程度的抵抗，K562则相对较敏感。榄香烯合用阿霉素或5氟脲嘧啶后，对KCC的抑制率明显增强，其中榄香烯加阿霉素组效果要强于合用5-Fu，联合用药后对K562的抑制率也明显增强。经统计学分析：单独用药与联合用药之间差异显著（P＜0.01），实验结果对临床应用榄香烯治疗实质性肿瘤时选择良好的协同药物具有参考意义。     

苏拉明联合阿霉素对肺腺癌小鼠移植瘤组织中HIF-1α和VEGF表达的调控及意义

目的研究苏拉明联合阿霉素对肺腺癌小鼠移植瘤组织中缺氧诱导因子-1α(H IF-1α)和血管内皮细胞生长因子(VEGF)表达的调控及对移植瘤增殖的影响。方法复制肺腺癌LA795细胞的T739小鼠异体移植瘤模型。40只实验小鼠皮下移植处均成瘤,接种后4d随机分为4组,10只/组。对照组:生理盐水0.2 m l/只,于接种后第4天开始腹腔注射,1次/d,共16次;阿霉素组:阿霉素(2 mg.kg-1.d-1)溶于0.2 m l生理盐水中,于接种后第4,11,18天各腹腔注射1次;苏拉明组:苏拉明(10 mg.kg-1.d-1)溶于0.2 m l生理盐水中,余同对照组;联合组(阿霉素 苏拉明):按阿霉素组和苏拉明组用药。肿瘤接种后24 d,测量小鼠皮下肿瘤最大长径(a)和横径(b),计算肿瘤体积;处死后剥离皮下肿瘤称湿重,收集肿瘤标本固定,用免疫组化和图像分析系统定量检测肿瘤组织H IF-1α、VEGF、微血管密度(MVD)和增殖细胞核抗原(PCNA)的表达。结果各治疗组肿瘤体积和湿重均低于对照组,其中以联合组最低,差异有统计学意义。苏拉明组和联合组:肿瘤组织中H IF-1α和VEGF的灰度值均高于对照组,MVD的灰度值和PCNA增殖指数均低于对照组;H IF-1α和VEGF的灰度值以联合组最高,MVD和PCNA增殖指数以联合组最低,差异有统计学意义。阿霉素组:H IF-1α和VEGF的灰度值均高于对照组,但差异无统计学意义;低于联合组,差异有统计学意义;MVD低于对照组,但差异无统计学意义;高于联合组,差异有统计学意义;而PCNA增殖指数低于对照组,高于联合组,差异有统计学意义;各组间H IF-1α和VEGF的灰度值与MVD和PCNA增殖指数呈反向变化,直线相关分析显示均呈负相关。结论阿霉素可能协同苏拉明通过抑制H IF-1α和VEGF的表达,从而抑制肿瘤组织新生血管形成和肿瘤细胞增殖。     

以国产紫杉醇为主的方案治疗转移性乳腺癌

目的评价以国产紫杉醇为主的方案治疗转移性乳腺癌的近期疗效和不良反应。方法12例乳腺癌根治术后患者发生一处或多处转移,均有可评价客观指标,采用紫杉醇+表阿霉素方案或紫杉醇+顺铂方案化疗。具体为紫杉醇135mg/m2,第1天,静脉滴注3小时;表阿毒素60mg/m2第1天静脉推注或分2天静脉推注;顺铂80mg/m2分3天静脉滴注,并适量水化、利尿等。紫杉醇使用前12小时、6小时分别口服地塞米松20mg,且给药前30分钟予非那根25mg肌肉注射和西米替丁400mg静脉推注。表阿霉素在紫杉醇前使用,顺铂在紫杉醇后使用。结果本组12例CR1例、PR5例、NC2例、PD4例,总有效率50%。主要不良反应为骨髓抑制和脱发,其次为消化道反应和肌肉关节酸痛。结论以国产紫杉醇为主的方案治疗转移性乳腺癌有效率较高,不良反应可耐受。     

Protective effects of silymarin on epirubicin-induced mucosal barrier injury of the gastrointestinal tract

Mucositis is a serious disorder of the gastrointestinal tract that results from cancer chemotherapy. We investigated the protective effects of silymarin on epirubicin-induced mucosal barrier injury in CD-1 mice. Immunohistochemical activity of both pro-apoptotic Bax and anti-apoptotic Bcl-2 markers, together with p53, cyt-P450 expression and DNA damage analysis on stomach, small intestine and colon were evaluated. Our results indicated stronger expression for cyt P450 in all analyzed gastrointestinal tissues of Epi group, which demonstrate intense drug detoxification. Bax immunopositivity was intense in the absorptive enterocytes and lamina connective cells of the small intestine, surface epithelial cells of the stomach and also in the colonic epithelium and lamina concomitant with a decreased Bcl-2 expression in all analyzed tissues. Epirubicin-induced gastrointestinal damage was verified by a goblet cell count and morphology analysis on histopathological sections stained for mucins. In all analyzed tissues, Bax immunopositivity has been withdrawn by highest dose of silymarin concomitant with reversal of Bcl-2 intensity at a level comparable with control. p53 expression was found in all analyzed tissues and decreased by high dose of silymarin. Also, DNA internucleosomal fragmentation was observed in the Epi groups for all analyzed tissues was almost suppressed at 100?mg/kg Sy co-treatment. Histological aspect and goblet cell count were restored at a highest dose of Sy for both small and large intestine. In conclusion, our findings suggest that silymarin may prevent cellular damage of epirubicin-induced toxicity and was effective in reducing the severity indicators of gastrointestinal mucositis in mice.     

表阿霉素纳米胶束靶向治疗大鼠移植性肝癌

目的 探讨键合表阿霉素纳米胶束(EPI-NPs)在大鼠移植性肝癌模型肝内的分布及药效.方法 制备具有靶向控释作用的EPI-NPs,Walker-256细胞直接注射法制作大鼠移植性肝癌模型,通过肝动脉灌注给药(EPI含量均为2 mg/kg),利用组织荧光和匀浆荧光技术对比分析EPI-NPs和表阿霉素(EPI)在肝内的分布特点,并作药效对比.结果 EPI-NPs组肿瘤组织的EPI荧光强度高于肝组织(P＜0.05),而EPI组则表现为平均分布;EPI-NPs组在肿瘤及肝内的EPI荧光强度均高于EPI组(P＜0.05).EPI-NPs组大鼠肝移植瘤的体积抑瘤率及质量抑瘤率分别为72.96％和68.19％,EPI组的体积抑瘤率及质量抑瘤率分别为39.16％和35.33％,两者差异均有统计学意义(P＜0.05).EPI-NPs组生存率高于EPI组(P＜0.05).结论 EPI-NPs具有良好的肿瘤组织靶向性和抑瘤效果.