Sequential administration of irinotecan and cytarabine in the treatment of relapsed and refractory acute myeloid leukemia

Purpose: Based on reported synergy of the topoisomerase-I (topo-I) inhibitor irinotecan with antimetabolites, irinotecan and cytarabine (Ara-C) were administered sequentially to patients with acute myeloid leukemia (AML) refractory to or relapsed following high-dose Ara-C and anthracycline therapy. Pharmacokinetic and pharmacodynamic studies were performed with the first irinotecan dose. Experimental Design: In vitro synergy of irinotecan followed by Ara-C was confirmed in a human AML cell line as a basis for the clinical trial. Irinotecan was administered daily for 5 days, with Ara-C 1 g/m² 12 h after each irinotecan dose. Irinotecan was initiated at 5 mg/m², and the dose was escalated by 5 mg/m² increments in cohorts of three patients and in individual patients. Pre-treatment samples were studied for topo-I activity and serial samples after the first irinotecan dose were analyzed for pharmacokinetics and for pharmacodynamic effects, including DNA damage and DNA synthesis rate. Results: The irinotecan dose reached 15 mg/m² in three-patient cohorts without reaching the maximum tolerated dose, and reached 30 mg/m² in individual patients. The AUC and C _max of both irinotecan and its active metabolite SN38 increased linearly in proportion to dose, and the mean half-lives of irinotecan conversion to SN38 and SN38 elimination were 6.2 h (CV 171%) and 7.2 h (CV 48%). Irinotecan rapidly induced DNA damage, and DNA synthesis inhibition varied among patients and treatment cycles. All courses resulted in rapid cytoreduction, and two patients achieved complete remission. Topo-I activity did not predict response. Conclusion: Irinotecan can be safely administered with Ara-C. This combination is active in refractory AML and warrants further study.     

RP-HPLC法测定小鼠各组织中阿糖胞苷及阿糖尿苷浓度

目的:建立在血浆、脑脊液和睾丸组织中同时测定阿糖胞苷及其代谢物阿糖尿苷浓度的反相高效液相色谱法并进行小鼠体检内测定波量长分为析28。0 n方m法,柱:色温谱为柱30为℃X,T进er样ra量C18为,流10动μ相L。为将0.0115 m只o小l.鼠L-随1磷机酸分盐成缓A冲、B液、(Cp H3组=,6分.0)别-乙腹腈腔=注9射5∶阿5,糖流胞速苷为105.09、51 m 0L0.0m、2in 0-010,mg·kg-1,30 min后测定小鼠血浆、脑脊液、睾丸组织中的阿糖胞苷及阿糖尿苷浓度。结果:阿糖胞苷、阿糖尿苷检测浓度线性范围分别为0.25～21.74、0.99～86.96 mg·L-(1r>0.998 8),检测限为0.1～0.4 mg·L-1;平均回收率均≥96%,RSD≤7.19%。阿糖胞苷及阿糖尿苷在小鼠血浆、脑脊液和睾丸组织中的药物浓度有显著性差异,低、中剂量给药组只在血浆中检测出阿糖尿苷。结论:所建立的测定方法简单、快速、准确、重复性好,可为临床上阿糖胞苷和阿糖尿苷血药浓度的监测和药动学研究提供参考。     

Synergy of Irofulven in combination with various anti-metabolites,enzyme inhibitors,and miscellaneous agents in MV522 lung carcinoma cells: marked interaction with gemcitabine and 5-fluorouracil

The novel agent Irofulven (HMAF, NSC 683863) has demonstrated significant antitumor activity against solid tumors in various xenograft models and human clinical trials. The antitumor potential of combining irofulven with 72 different anti-metabolite, enzyme inhibiting, and miscellaneous agents was investigated in this study. The human lung carcinoma MV522 cell line and its corresponding xenograft model were used to evaluate the activity of irofulven in combination with these different agents. Irofulven in combination with select anti-metabolites, notably cytidine or adenine-derived agents, displayed strong synergistic activity in both in vitro and in vivo studies. Agents demonstrating strong synergistic interaction with irofulven included gemcitabine, cyclocytidine, cytarabine, fludarabine phosphate, cladribine, and 5-fluorouracil. Other anti-metabolites, enzyme inhibitors, and a variety of miscellaneous agents failed to interact beneficially when administered in combination with irofulven. The therapeutic activity of irofulven is enhanced considerably when irofulven is combined with select anti-metabolite agents, and further clinical evaluation of these combinations is warranted. The synergistic interaction with these combinations may stem from a variety of actions including inhibition of the nucleotide excision repair (NER) pathway, topoisomerase I activity, and caspase-dependent and independent induction of apoptosis.     

小剂量三尖杉酯碱和阿糖胞苷联合粒细胞集落刺激因子治疗老年急性髓细胞白血病疗效观察

目的探讨小剂量三尖杉酯碱（HT,H）和阿糖胞苷（Ara-c,A）联合粒细胞集落刺激因子（G-CSF）治疗老年人急性髓细胞白血病的疗效及不良反应。方法35例AML患者均给予HT1mg·m^-2·d^-1,静脉滴注,第1—14天;Ara—c 10mg·m^-2,静脉滴注,每12h注射1次,第1～14天;G-CSF100—200μg·m^-2·d^-1,皮下注射,在第1次注射Ara—c之前开始使用,至最后1次注射Ara-c之前停用。结果35例AML患者化疗后完全缓解16例（46％）、部分缓解14例（37％）,总有效率83％,未缓解（NR）5例（14％）;2例患者化疗期间死亡。主要不良反应为骨髓抑制。结论小剂量HA方案联合G—CSF治疗老年人急性髓细胞白血病安全、有效。     

FA方案用于急性髓系白血病不同治疗阶段疗效分析

目的：评价氟达拉滨联合阿糖胞苷（FA）方案对急性髓系白血病（AML）不同治疗阶段的临床疗效。方法：根据应用FA方案治疗阶段将75例AML患者分为4组：①第1个疗程诱导化疗未缓解组21例;②2次及2次以上诱导治疗未缓解组21例;③早期复发组14例;④晚期复发组19例;其中后3组为难治复发性AML,比较不同组间疗效。结果：4组患者的完全缓解（CR）率分别为81.0%（17/21）、42.9%（9/21）、28.6%（4/14）及31.6%（6/19）。第1疗程诱导化疗未缓解组CR率明显高于复发难治性AML的CR率35.2%（19/54）（P=0.002）。Logistic回归分析结果显示既往化疗次数与CR率有显著相关性（P=0.027）。主要不良反应为骨髓抑制和继发感染。结论：对于第1个疗程化疗未缓解的AML患者,FA方案可作为一种有效的选择。     

氟达拉滨联合阿糖胞苷及粒细胞集落刺激因子治疗儿童难治及复发性急性白血病

 【摘要】　目的　观察氟达拉滨（Flud）联合阿糖胞苷（Ara-C）及粒细胞集落刺激因子（G-CSF）（FLAG）方案治疗儿童难治及复发性急性白血病（AL）的疗效及患者不良反应。方法　9例复发及难治性AL患儿接受了FLAG方案治疗,Flud 每天30 mg／m2,第1天至第5天,静脉滴注30 min;Ara-C每天2 g／m2,Flud应用后4 h静脉滴注,第1天至第5天。G-CSF 5 μg?kg-1?d-1,中性粒细胞＜0.5×109／L时开始应用,用至中性粒细胞 ≥1×109／L。9例患儿中急性髓系白血病（AML）8例,急性淋巴细胞白血病（ALL）1例;难治性AL 5例,复发性AL 4例。结果　9例患儿中经1个疗程化疗达完全缓解（CR）6例,部分缓解（PR）2例,总有效（CR+PR）率 88.9 %（8／9）。6例CR患者中2例行造血干细胞移植,现均无瘤生存;患者主要不良反应是感染、骨髓抑制和胃肠道反应。结论　FLAG方案治疗儿童难治及复发性AL缓解率高,不良反应可以耐受,是治疗儿童难治及复发性AL的一个选择,为后续的造血干细胞移植提供了机会。     

Studies on the Preparation Properties and Drug Loading of theStarch Nanoparticles

On the basis of studies of starch microspheres, we carried out the research program of starch nanoparticles(SNP)which included preparation, physical and chemical properties and drug loading. The SNP was prepared using reversedphase-microemulsion polymerization method, with soluble starch as raw material. The particle size, quantity ofphosphorous, degradability, scanning electron microgragh, IR spectra and stability of SNP were investigated. Thepharmacodynamics and concentration-time curve of insulin starch nanoparticles were determined.     

Biochemical modulation of cytarabine triphosphate by clofarabine

Purpose Clofarabine has proven to be effective in the treatment of adult and pediatric acute myelogenous leukemia (AML). To investigate if clofarabine could be used with success in biochemical modulation strategies, we investigated the biochemical modulation of cytarabine triphosphate (ara-CTP) by clofarabine in a myeloid leukemia cell line and the effect of this combination on cytotoxicity.Experimental design K562 cells were incubated with clofarabine and ara-C either sequentially or simultaneously to evaluate the combination effect on their phosphorylated metabolites. Clonogenic assays were used to determine the cytotoxicity of each agent alone and in combination. Deoxynucleotide analysis was performed to assess the effect of clofarabine on dNTPs.Results Clofarabine added either simultaneously or in sequence increased ara-CTP accumulation. The maximal modulation of ara-CTP accumulation occurred with 1 M clofarabine. This level was achieved at the maximum tolerated dose for adult and pediatric patients with AML. With 10 M ara-C alone, 86 M ara-CTP had accumulated after 3 h. The optimal sequence for the drug combination, i.e., clofarabine followed 4 h later by ara-C, resulted in 248 M ara-CTP at 3 h. Clofarabine accumulated maximally in the monophosphate form. Preincubation with ara-C did not affect the triphosphate form, but it lowered clofarabine monophosphate. Clofarabine resulted in the intracellular decrease of dATP and dGTP levels. Clonogenic assays revealed that the combination of clofarabine and ara-C produced synergistic killing of myeloid leukemia cells.Conclusions These findings demonstrate that combination of clofarabine followed by ara-C results in a biochemical modulation of ara-CTP and synergistic cell kill. These studies provide a compelling rationale for clinical trials using this combination regimen for adult and pediatric patients with AML.     

减低剂量IA方案联合司莫司汀治疗急性髓细胞白血病的临床观察

目的 探讨减低剂量去甲氧柔红霉素、阿糖胞苷联合司莫司汀(IAS)方案治疗急性髓细胞白血病(AML)的临床疗效和不良反应.方法 将58例初诊AML患者采用随机数字表法分为两组,其中IAS组30例,DA组(柔红霉素+阿糖胞苷)28例.IAS方案具体为去甲氧柔红霉素8～10mg/(m2·d),第1～3天,静脉注射;阿糖胞苷100～150 mg/(m2·d),第1～7天,静脉滴注;司莫司汀200 mg,化疗前1d口服.DA方案具体为柔红霉素40 ～60 mg/(m2·d),第1～3天,静脉注射;阿糖胞苷100～150 mg/(m2·d),第1～7天,静脉滴注.以完全缓解率和总有效率作为疗效观察指标.结果 1个疗程化疗结束后IAS组完全缓解率为80.0％ (24/30),总有效率为86.7％ (26/30);DA组完全缓解率为57.1％ (16/28),总有效率为64.3％ (18/28),两组间完全缓解率、总有效率差异均有统计学意义(x2值分别为4.167和3.962,P均＜0.05).化疗的不良反应主要为骨髓抑制和粒细胞缺乏所致的感染,未见严重的非血液系统不良反应,两组不良反应发生率差异无统计学意义[ 96.7％( 29/30)、92.9％( 26/28),x2=0.004,P＞0.05].结论 IAS诱导方案疗效优于DA方案,不良反应可耐受,可以作为初治AML患者高效安全的化疗方案.     

预激CAG方案治疗老年初治急性髓系白血病的临床分析

目的:评价CAG(阿糖胞苷、阿柔比星、粒细胞集落刺激因子)方案治疗老年初治急性髓系白血病(AML)的疗效及不良反应。方法:64例老年初治AML作为观察对象,其中39例患者予以CAG预激方案治疗,完全缓解(CR)后序贯予原方案、HA(高三尖杉酯碱和阿糖胞苷)、DA(柔红霉素和阿糖胞苷)、MA(米托蒽醌、阿糖胞苷)、中剂量阿糖胞苷巩固治疗至少2个循环;25例患者予以标准方案DA或HA方案化学治疗(化疗),CR后序贯予HA或DA、MA、中剂量阿糖胞苷至少2个循环。观察其疗效及不良反应。结果:CAG预激治疗组1个疗程CR 17例,2个疗程CR 6例,总CR率为59%,7例部分缓解(PR),总有效率77%。常规化疗组患者中1个疗程CR 7例,2个疗程CR 4例,总CR率为44%,2例PR,总有效率52%,与CAG预激治疗组相比差异有统计学意义(P<0.05);CAG组的胃肠道反应、感染、出血、脱发、肝功能及肾功能受损、心毒性、骨髓抑制不良反应发生率均明显少于常规化疗组,差异均有统计学意义(均P0.05)。结论:CAG预激方案治疗初治老年AML患者较之传统常规治疗具有有效率高、不良反应较小、患者生活质量高的优点,适合老年AML患者使用。