Antitumor activity of prolonged as compared with bolus administration of 2′,2′-difluorodeoxycytidine in vivo against murine colon tumors

2′,2′-Difluorodeoxycytidine (gemcitabine) is a cytidine analogue with established antitumor activity against several experimental tumor types and against human ovarian and non-small-cell lung cancer. Both preclinical studies and most clinical trials involving patients with solid tumors have focused on short-term administration schedules; however, mechanistic studies indicate that a continuous-infusion schedule may be more effective. We determined the maximal tolerated dose (MTD) of gemcitabine in mice using various schedules. At these MTDs we observed considerably better antitumor activity of gemcitabine in two of three murine colon carcinoma lines using a prolonged administration as compared with a standard bolus protocol (i.p. 120?mg/kg q3d×4). On the latter schedule, Colon 26–10 grown in BALB/c mice was the most sensitive tumor line, showing a growth-delay factor (GDF, number of doubling times gained by the treatment) of 6.7, whereas Colon 38 (grown in C57/B16 mice) was the least sensitive tumor, displaying a GDF of 0.9. Prolonged treatment (q3d×6) of Colon 26–10 at a lower dose (100?mg/kg) enhanced the antitumor activity (GDF 9.6) while producing similar toxicity. A similar weight loss was found following the continuous infusion (c.i.) of gemcitabine using Alzet osmotic pumps s.c. for 3 or 7 days (2?mg/kg), but the GDF increased to 2.4 in Colon 38 (C57/B16) as compared with that provided by the bolus injections. Continuous infusion of gemcitabine at 15?mg/kg per 24?h q7d×2 i.v. via the tail vein was more effective than bolus injection against Colon 26–10, with the GDF being >17.7 and 73% of the tumors regressing completely. However, against Colon 38 tumors this schedule was not effective (GDF 0.4), even with a 25% higher dose. The plasma pharmacokinetics of gemcitabine was determined after one bolus dose (120?mg/kg). The peak concentration of gemcitabine was 225?μM and that of the deaminated catabolite 2′,2′-difluorodeoxyuridine (dFdU) was 79?μM. The elimination of gemcitabine was much faster than that of dFdU, with the t _1/2ß values being 15?min and 8?h, respectively. For the c.i. schedules, plasma concentrations were below the detection limit of the assay (<0.5?μM). Our results suggest that prolonged infusion of gemcitabine can give a better antitumor activity than bolus injections and shows promise of being active in clinical trials.     

What's new in pancreatic cancer treatment?

Pancreatic cancer represents a major challenge to oncologists because of its high chemoresistant nature and dismal outcomes. Conventional therapy for advanced disease relied for a long time on palliative 5-fluorouracil (5-FU)-based chemotherapy, but with unsatisfactory results. The introduction of the novel antimetabolite gemcitabine provides new optimism for patients with advanced pancreatic cancer, as multiple clinical trials have demonstrated the superiority of gemcitabine over 5-FU and other agents for these patients. The benefits of gemcitabine over conventional therapies include improved response rate and enhanced survival, as well as improvement in disease-related symptoms and quality of life in these patients. With these data, gemcitabine is widely accepted worldwide as the therapy of choice by many oncologists for advanced pancreatic cancer. The current review presents an overview of the clinical studies of gemcitabine over the past decade for the treatment of patients with advanced pancreatic cancer. Other investigational regimens or uses (e.g., fixed dose-rate infusion, intraarterial infusion, adjuvant use, chemo-radiation, etc) are also reviewed. Received: October 27, 2001 / Accepted: November 16, 2001     

胰腺区域性动脉灌注治疗胰腺癌的实验研究

目的：为了探讨进展期胰腺癌介入治疗的作用机制。方法：选用10条毕格犬随机分实验组和对照组,每组5条,实验组在数字减影动脉造影术（DSA）引导下分别置管至腹腔动脉干和肠系膜上动脉并注射吉西他滨（45mg/kg),对照组经外周静脉注射吉西他演（45mg/kg),给药后采集外周静脉血,胰腺,胰周,心,肺和肝肾等组织,测定吉西他滨的血药浓度和组织内匀浆浓度,并观察组织病理改变。结果：给药2,4,8,h后,实验组吉西他滨西浓度明显高于对照组。实验组经剂量校正后的曲线下面积也明显高于对照组;经剂量校正后的药物在故事片腐朽 内的平均滞留时间实验组比对照组明显延长。给药4,8h后,实验组胰腺组织内药物浓度明显高于对照组,病理检查提示;对照组犬肾小球毛细血管及肾小管内见大量红细胞,肺毛细血管及心肌明显瘀血,出血,而实验组无明显病理改变,实验组胰周脂肪中见大量中性白细胞浸润,出血及纤维素样渗出,对照组无此病理改变。结论：区域性动脉灌注能使吉西他滨在胰腺内浓度明显提高,体内滞留时间明显延长,对全身其他重要脏器的毒作用较小,适用于胰腺癌的介入治疗。     

健择联合卡铂治疗卵巢癌疗效观察

目的探讨健择(GEM)联合卡铂(CBP)治疗卵巢癌的的疗效和毒副作用。方法24例晚期卵巢癌患者给予GEM 1.2g/m2,静脉滴入,30m in,第1、8天;CBP 400mg/m2,静脉滴入,第1天。每3周为1个周期,2~3个周期后评价疗效和毒副反应。24例可评价疗效患者中,共计62个化疗周期。结果完全缓解(CR)3例,部分缓解(PR)8例,稳定(SD)9例,进展(PD)4例,总有效率(CR PR)45.8%(11/24)。10例初治患者有效率为60%(6/10),14例复治患者有效率为35.7%(5/14);化疗后白细胞减少发生率为100%,其中Ⅲ~Ⅳ度白细胞下降发生率为29.2%(7/24)。Ⅲ~IV度血小板下降20.8%(5/24),Ⅲ~IV度血红蛋白下降16.7%(4/24)。非血液学毒性较轻。结论GEM联合CBP是治疗卵巢癌疗效较好方案,主要毒性反应为血液学毒性。     

顺铂+氟尿嘧啶与吉西他滨同期放化疗治疗Ⅲ～Ⅳa期鼻咽癌的临床研究

目的 评价顺铂＋氟尿嘧啶（DF）和吉西他滨（GEM）两组同期放化疗方案治疗Ⅲ～Ⅳa期鼻咽癌的疗效和不良反应。方法 病理确诊的Ⅲ～Ⅳa期鼻咽癌患者187例分为两组，DF组94例,GEM组93例。DF组化疗于放疗第1、5周给予DDP25mg／m^2，d1～5；5-FU500mg／m^2，d1～5，均静脉滴入。GEM组化疗在放疗1～6周中同步进行，每周1次，每次GEM200mg／m2，静脉滴入。两组病例放疗方案相同。结果 DF与GEM两组同期放化疗方案的有效率分别为100％和100％。1年生存率分别为94％和96％，3年生存率分别为71％和76％。血液系统毒副反应中Ⅲ～Ⅳ级血红蛋白降低及Ⅰ～Ⅱ级粒细胞减少发生率DF组较GEM组为高（P〈0．05）。结论 同期GEM单药放化疗组与DF放化疗组的近期疗效、1年生存率及3年生存率方面相近。GEM单药放化疗组不良反应较轻，患者耐受较好。     

晚期非小细胞肺癌的化放疗序贯治疗

目的探讨吉西他滨联合顺铂治疗晚期非小细胞肺癌3周方案并序贯化放疗的疗效和不良反应。方法经病理和细胞学证实的晚期非小细胞肺癌患者，既往未进行化疗和放疗，临床上有可测量病灶（根据WHO标准），美国东部肿瘤协作组（ECOG）评分为0—2分，肝、肾功能基本正常。均给予吉西他滨和顺铂的联合化疗并序贯化放疗方案治疗。按照WHO的标准评价疗效和不良反应，并随访生存期。结果共入组43例患者，其中39例可评价疗效：19例（48．72％）部分缓解、13例（33．33％）病情稳定和7例（17．95％）疾病进展。生存期为3．7—21．4个月，中位生存期为10．1个月。主要的不良反应为血液毒性，表现为白细胞、中性粒细胞、血小板和血红蛋白下降；其次为消化道症状。结论吉西他滨联合顺铂治疗晚期非小细胞肺癌3周方案并序贯化放疗是晚期非小细胞肺癌的标准一线化疗方案之一，患者可较好耐受。     

吉西他滨联合长春瑞滨治疗晚期非小细胞肺癌的临床研究

目的:观察吉西他滨联合长春瑞滨治疗晚期非小细胞肺癌(NSCLC)的临床疗效及毒副反应。方法:38例初治NSCLC给予吉西他滨1000mg/m2,d1、d8,静脉滴注30分钟,长春瑞滨25mg/m2,d1、d8,静脉推注,21d为1个周期,至少治疗2个周期。结果:全组38例均可评价,无CR,PR13例,总有效率(CR PR)34·2%(13/38),SD31·6%(12/38),PD21·1%(8/38),中位生存期为11个月,疾病进展时间为5·9个月;1年生存率及2年生存率分别为44·7%(17/38)和23·7%(9/38)。血液学毒性反应主要是Ⅰ~Ⅱ度白细胞下降占73·7%(28/38),Ⅲ~Ⅳ度白细胞下降占10·5%(4/38),Ⅰ~Ⅱ度血红蛋白及血小板下降分别占26·3%(10/38)和31·6%(12/38),非血液毒性包括食欲减退、Ⅰ~Ⅱ度恶心及呕吐、局部静脉炎等,所有不良反应经对症处理及支持治疗后均恢复正常。结论:吉西他滨联合长春瑞滨组成GN方案对于晚期NSCLC疗效较好,毒副反应可耐受,值得临床推广。     

健择对人鼻咽癌细胞系放射增敏机制的实验研究

目的：观察单纯放射及放射联合健择（gemcitabine）对人鼻咽癌细胞系（CNE-2）细胞周期改变的影响，探讨健择对CNE-2细胞的放射增敏机制。方法：用流式细胞仪技术分析^60Coγ射线单纯照射和照射联合健择对CNE-2细胞周期的影响。结果：单纯照射导致CNE-2细胞G1期阻滞，照射剂量〈6Gy时与照射剂量呈正相关，〉6Gy时G1期阻滞基本稳定在一定水平。5mg／L、10mg／L、15mg／L健择与CNE-2细胞共育24h后照射2Gy，以S期阻滞为主；随着单次照射剂量的提高，以G1阻滞明显。CNE-2细胞与健择15mg／L共育12h后照射2Gy，开始时以G1阻滞为主，但24h后以S期阻滞明显。且至少维持36h以上。结论：健择对CNE-2细胞有中度放射增敏作用；其机制可能与健择引起S期或G1期阻滞有关。     

吉西他滨联合顺铂治疗晚期非小细胞肺癌的临床观察

目的观察吉两他滨（健择）联合顺铂（GP方案）对晚期非小细胞肺癌的疗效。方法对30例晚期非小细胞肺癌采用21天GP方案治疗。结果30例中，无CR，PR12例，SD12例，PD6例，总有效率CR＋PR为40．0％（12／30）。巾位卡存期（MST）为8个月。Ⅲ～Ⅳ度白细胞下降占10．0％（6／26）。结论治疗晚期非小细胞肺癌，吉西他滨联合顺铂21天方案是有效、经济和安全的。