化疗药物与LAK细胞联合抗癌的可行性

 采用3H-TDR释放法检测6种常用化疗药物对LAK细胞杀瘤活性的影响。结果显示：不同化疗药物对IL-2诱导LAK细胞活性及对培养好的LAK细胞活性的影响各不相同，同种化疗药物不同浓度时的影响也有差异。卡铂(CARBO)和顺铂(CDDP)对IL-2诱导LAK细胞活性无抑制作用，且可增强培养好的LAK细胞的杀瘤活性；环磷酰胺(CTX)和5-氟尿嘧啶(5-Fu)对诱导及培养好的LAK细胞活性均无抑制作用；阿霉素(ADM)和丝裂霉素(MMC)对诱导及培养好的LAK细胞活性均有抑制作用。由此推论CARBO和CDDP与IL-2/LAK细胞联合抗癌可望产生协同效应；CTX和5-Fｕ与IL-2/LAK细胞联合抗癌可能有相加作用；而ADM和MMC则可能削弱LAK细胞的杀瘤效应。     

硒酸酯多糖增强荷瘤小鼠免疫功能和自身肿瘤杀伤活性的作用

本文研究了硒酸酯多糖(KSC)对荷S180肉瘤小鼠NK细胞活性、LAK细胞活性、IL-2分泌能力和自身肿瘤杀伤活性(ATK)的影响及抑癌效应.结果表明,KSC(40mg/kg·d×9d,ig)能增强荷瘤鼠NK细胞和LAK细胞活性,促进脾细胞产生IL-2,增强ATK活性;加强环磷酰胺(Cy,20mg/kg·d×9d,ip)的抑瘤作用,并能拮抗Cy对免疫活性细胞的抑制效应.体外用rIL-2激活荷瘤鼠脾淋巴细胞可诱生或增强ATK活性.本研究结果提示,KSC上调肿瘤宿主NK细胞和LAK细胞活性及IL-2的分泌水平,增强ATK活性,可作为生物反应调节剂(BRM)应用于肿瘤生物治疗.     

PHA-LAK/rIL-2疗法的应用与评价——60例实体瘤患者临床试验分析

获得较大量高细胞毒活性的LAK细胞,是LAK/IL-2继承性细胞免疫疗法的重要问题之一。为此我们进行了多年的实验研究,采用健康“O”型供血者外周血单个核细胞(PBMC)制备PHA-LAK细胞(即经PHA预刺激48小时然后用rIL-2诱导的LAK细胞),并与直接用rIL-2诱导的常规LAK细胞(C-LAK)的生物学特性进行了较全面的对比。结果发现PHA-LAK的增殖能力强,这与其IL-2R表达水平较高有关;同时PHA-LAK的细胞毒活性也高于常规LAK细胞。FACS表型分析表明:PHA-LAK的表型以CD_3~ⅠCD_8~Ⅰ为主,而常规LAK则以CD_3~ⅠNKH_1~Ⅰ为主,且PHA-LAK IL-2R的表达水平高于常规LAK。在此基础上,我们将PHA-LAK-/rIL-2应用于60例实体瘤患者的治疗,其中肾癌24例、恶性淋巴瘤5例、肝癌5例、肺癌12例、结肠癌5例及其它恶性肿瘤(包括膀胱癌、乳癌、胃癌、食道癌等)9例。     

PHA-LAK／rIL-2疗法的应用与评价——60例实体癌患者临床试验分析

获得较大量高细胞毒活性的LAK细胞，是LAK／IL-2继承性细胞免疫疗法的重要问题之一。为此我们进行了多年的实验研究，采用健康“O”型供血者外周血单个核细胞(PBMC)制备PHA-LAK细胞(即经PHA预刺激48小时然后用rIL-2诱导的LAK细胞)，并与直接用rIL-2诱导的常规LAK细胞(C-LAK)的生物学特性进行了较全面的对比。     

肝癌患者粘附性LAK细胞制备及抗瘤活性研究

本研究在常规LAK细胞制备基础上进行改进，用苯丙氨酸甲酯(PME)去除肝癌患者外周血中抑制LAK细胞活性的单核巨噬细胞。制备抗癌活性较高扩增迅速的粘附性LAK细胞，从实验结果分析。外周血处理后粘附性LAK细胞较未粘性LAK细胞具有较强的扩增能力，最大扩增倍数23～243倍，同时粘附性LAK细胞中TH细胞亚群有增加趋势，Ts细胞亚群有碱少趋势，其IL-2R^ 表达增加至64．3%。此外,在抗瘤活性方面粘附性LAK细胞与非粘附性LAK细胞存在一定差别，分别为64．6%和42．8%．因此。从临床实用出发。制备相对高效的粘附性LAK细胞可以提高LAK疗法的治疗效果。     

灵芝多糖增强人脐血LAK细胞活性机理研究

本研究观察了灵芝多糖(GLP)对人脐血LAK(CB-LAK)杀伤活性的影响,并探讨了其作用机制.结果表明,10～500U/ml rIL-2浓度范围内,随着浓度升高,CB-LAK细胞杀伤活性逐渐增强,当加入10μg/ml GLP时,几乎所有浓度点都诱导出增强溶细胞效应,10μg/mlGLP 50U/ml rIL-2所诱导的杀伤水平与单独使用500U/ml rIL-2所诱导的杀伤水平(71%)相比无显著差异(P>0.05),表明GLP具有较强促进CB-LAK细胞杀伤活性作用.能显著降低诱导CB-LAK细胞所需IL-2用量.IL-2和IL-6是机体重要的免疫调节因子.能提高NK、LAK活性,单独GLP不能刺激CBMC产生IL-2,也     

快速诱导人胎脾LAK细胞的实验研究

本文研究了大剂量IL-2短期冲击人胎脾单个核细胞(FSMC)后,其杀伤活性、增殖活性、表面抗原表达的时间动力学变化。结果表明:快速诱导人胎脾LAK细胞时,IL-2的最适剂量是5000UIL-2/1.0×10~7cell/ml。在第2、3d,快速诱导的人胎脾LAK细胞的杀伤活性及增殖活性均显著高于常规LAK(P<0.05,P<0.05)。且两者表型基本相同。快速诱导后不洗去IL-2的LAK细胞的杀伤、增殖活性显著、极显著地高于常规LAK(P<0.05,P<0.01),在后期,也不低于甚至高于常规LAK细胞。这些结果提示,快速诱导的人胎脾LAK细胞有可能用于临床,从而大大简化操作,减少污染机会;先用5000UIL-2/1.0×10~7cell/ml冲击1h,再按常规方法培养是一种独立且更优的方法。     

硒酸酯多糖增强荷瘤小鼠免疫功能和自身肿瘤杀伤活性的作用

目的:研究硒酸酯多糖(KSC)对荷瘤鼠免疫功能和自身杀伤肿瘤活性(ATK)的作用.方法:测定KSC对荷Sl80肉瘤小鼠NK及LAK细胞活性,IL-2分泌能力,ATK活性和抑瘤的影响.结果:KSC(4Dmg·kg~(-1)·d~(-1)×9d,ig)增强荷瘤鼠NK细胞和LAK细胞活性,促进脾细胞产生IL-2,增强ATK活性;加强环磷酰胺(Cy 20mg·kg~(-1)·d~(-1)×9d,ip)的抑癌作用,并     

癌的细胞免疫疗法

癌的细胞免疫疗法是基于对肿瘤宿主全身给予白细胞介素-2(IL-2)和输入由IL-2激活的自体淋巴细胞。目前,正研究外周血液的活性淋巴细胞(活性淋巴因子杀伤细胞,LAK)和肿瘤组织内的淋巴细胞(肿瘤浸润淋巴细胞,TIL)的作用。 LAK的活性是通过IL-2中孵化外周血液淋巴细胞3～4天而产生。通过短期铬释放实验,这些细胞能溶解各种新生和培养的肿瘤,这证明对自体肿瘤组织没有特异性。小鼠的多种致免疫和非致免疫的肿瘤模型,证明了LAK和IL-2能消除肺和肝肿瘤的早期转移。     

胃周淋巴结淋巴因子激活的杀伤细胞抗肿瘤研究

淋巴细胞经白细胞介素-2(Interleukin-2,IL-2)体外诱导培养后,可产生明显的杀伤肿瘤细胞活性,此杀伤细胞称为LAK细胞(lymphokine activated killer cells)。本实验取19例胃癌患者胃引流区淋巴结淋巴细胞(gastric drainage lymphnode lymphocytes,GDLNL),在体外经重组白细胞介素-2诱导培养若干天后,对高分化胃腺癌细胞MNK_(28)进行体外杀伤实验。结果提示,无癌转移的淋巴结淋巴细胞在诱导培养3天～2周内,LAK活性较高;而有癌转移的淋巴结淋巴细胞在2周内亦有明显的LAK活性,但较低,以后逐渐升高,3周最高,且至5周时,仍有杀伤肿瘤活性。     

c-myc基因表达与白血病细胞分化诱导及增殖受抑的相关性

选择8例经常规剂量化疗未能完全缓解的难治性非小细胞肺癌患者为观察对象，采用在4个月内完成连续两次大剂量化疗联合自体骨髓、外周造血干细胞和免疫细胞移植的方案进行治疗。化疗方案为CTX 3000mg／m^2；ADM 90mg／m^3、DDPl50mg／m^2．VPl6900mg／m^2,分量于3天静滴。结果显示．所有患者的造血功能均在移植后25天内重建，大多数患者的免疫功能较快重建。经两个疗程治疗后、CR3例，PR3例、NC1例死亡1例。本研究表明，大剂量化疗可提高难治性非小细胞肺癌的疗效，对带瘤患者有必要行二次移植治疗．此方案是安全的。     

Use of temozolomide with other cytotoxic chemotherapy in the treatment of patients with recurrent brain metastases from lung cancer

The use of chemotherapy for the treatment of brain metastases arising from lung cancer has been limited by poor efficacy and high toxicity. Temozolomide, an orally bioavailable alkylating agent that crosses the blood-brain barrier, has activity against brain metastases from both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) when used as a single agent, but response rates are low. Preclinical experiments and early clinical studies in other malignancies indicate that temozolomide may have additive or synergistic effects when used with other chemotherapeutic agents. We report a case of a patient with SCLC with recurrent brain metastases after treatment with multiple chemotherapeutic regimens and whole-brain radiation therapy (WBRT) who was treated with temozolomide (150 mg/m(2) for 5 days in a 28-day cycle) and oral etoposide (50 mg/m(2) for 10 days in a 28-day cycle). A second patient with NSCLC and brain metastases who progressed after treatment with chemotherapy and WBRT was treated with temozolomide (150 mg/m(2) for 5 days in a 28-day cycle) and gemcitabine (1,000 mg/m(2) weekly for 2 weeks in a 3- week cycle). In both patients, the temozolomide regimens were extremely well tolerated and resulted in dramatic and durable responses. The combination of temozolomide with other chemotherapeutic agents represents a promising strategy for treating patients with lung cancer and recurrent brain metastases and merits further study.     

Combination chemotherapy with gemcitabine and vinorelbine in the treatment of patients with relapsed or refractory small cell lung cancer: a phase II trial of the Minnie Pearl Cancer Research Network

The purpose of the study was to evaluate the combination of gemcitabine and vinorelbine in the treatment of patients with relapsed or refractory small cell lung cancer.

Between March 1998 and February 1999, 30 patients with relapsed or refractory small cell lung cancer who had received treatment with one previous combination chemotherapy regimen entered this multicenter, community-based clinical trial. All patients had received previous platinum/etoposide combination chemotherapy; in addition, 12 patients had received paclitaxel as part of their first-line therapy. All patients received gemcitabine 1000 mg/m² and vinorelbine 20 mg/m² on days 1, 8, and 15 of each 28-day cycle. Patients were reevaluated for response after two cycles of therapy; those with objective response or stable disease continued treatment for six courses or until disease progression.

Three of 28 evaluable patients (10%) had partial responses to treatment. None of the 17 patients with refractory disease responded, while 3 of 12 patients (25%) with relapsed disease had partial responses. Median survival was 5 months. Treatment was generally well tolerated; myelosuppression was the major toxicity, but only two patients developed febrile neutropenia, and there were no treatment-related deaths. Non-hematologic toxicity was uncommon; alopecia did not occur with this regimen.

The activity of gemcitabine and vinorelbine in patients with previously treated small cell lung cancer is modest and is limited to patients with relapsed (versus refractory) disease. In patients with relapsed small cell lung cancer, this regimen provides an additional treatment option, with decreased toxicity when compared to other second-line options. However, novel treatment approaches are necessary before substantial improvements in treating this patient population will be realized.     

Limited small cell lung cancer: possible prognostic impact of initial chemotherapy doses

While the effect of chemotherapy dose on tumor response in small cell lung cancer has been fairly well established, the effect on survival has been retrospectively analyzed only in some series. This particular point was studied in a series of 52 consecutive patients with limited small cell lung cancer treated by an alternating radiotherapy-chemotherapy schedule. The induction treatment consisted of 6 chemotherapy cycles (the planned doses were: doxorubicin 40 mg/m2 day 1, VP16213 75 mg/m2 days 1-3, cyclophosphamide 300 mg/m2 days 3-6, and cisplatinum 100 mg/m2 day 2) alternated after the first 2 cycles with 3 courses of thoracic radiotherapy delivering a total dose of 55 Gy. Eighty-one percent of patients went into complete remission and the 3-year relapse-free survival was 24%. A multivariate analysis of prognostic factors took into account age, sex, T stage, performance status, delayed hematological toxicity to the first course of chemotherapy, actual dose/m2 of each drug during the first course and mean dose/course delivered during the induction treatment after the first cycle of chemotherapy. It was possible to identify 3 independent factors influencing overall survival and relapse-free survival: actual initial dose of cisplatinum, actual initial dose of cyclophosphamide and the T stage. The effect of the initial dose of cisplatinum and cyclophosphamide proved to be linear on relapse-free survival. The results of this analysis show a possible effect of initial doses of chemotherapy in the management of limited small cell lung cancer in terms of both distant metastasis and overall survival rates.     

异长春花碱与顺铂联合治疗晚期非小细胞肺癌近期疗效观察

目的 观察异长春花碱(NVB)联合顺铂(DDP)治疗晚期非小细胞肺癌(NSCLC)的近期疗效与毒副反应。方法 共治疗52例晚期NSCLC患者：NVB25mg/m^2静滴，第1、8天，DDP80mg／m^2，第1天，同时水化3天。21天为一周期，化疗2周期后评价疗效，化疗期间记录毒副反应。结果 本组52例患者完全缓解(CR)2例，部分缓解(PR)26例，稳定(SD)17例，进展(PD)7例，总有效率(CR PR)为53．8％，NVB限制性毒性为自细胞下降、恶心呕吐及静脉炎。结论 以NVB和DDP联合化疗NSCLC有效率较高，毒副反应易耐受，可作为晚期非小细胞肺癌的一线方案。     

洛铂联合吉西他滨治疗晚期肺癌安全性的临床观察

目的观察评价新一代铂类抗癌药物洛铂（labaplatin，LBP）联合吉西他滨（gemicitabine，GEM）组成的GP方案治疗晚期肺腺癌和晚期小细胞肺癌（SCLC）的安全性。方法开放性、单试验组、Ⅰ期临床研究，共入组2例，均为常规放化疗效果差的患者，男性1例，女性1例，年龄分别为79岁、53岁。病理类型分别为小细胞肺癌（广泛期）、肺腺癌（Ⅳ期）。应用GP方案，即LBP30mg／m^2，静滴，d1；GEM1000mg／m^2，静滴，d1.8，21d为1个周期。其中男性SCLC患者接受1个周期化疗、女性NSCLC患者接受1．5个周期化疗，按照WHO和NCI标准评价客观疗效和毒副反应，定期随访。结果2例毒副反应主要表现为可逆性的骨髓抑制、胃肠道反应、一过性肝损害、脱发，未见明显心肾毒性。结论LBP联合GEM组成GP方案治疗晚期NSCLC和SCLC的毒副反应可以耐受，可进一步研究观察。     

国产紫杉醇治疗恶性肿瘤的Ⅲ期临床研究报告

目的考察紫杉醇治疗多种恶性肿瘤的疗效及毒副作用。方法紫杉醇单药化疗每次剂量１７５ｍｇ／ｍ２，联合化疗紫杉醇每次剂量１３５ｍｇ／ｍ２，３ｈ静脉输注，每３周重复，在紫杉醇治疗前常规给予地塞米松、苯海拉明和西米替丁预防过敏反应。结果共３３３例进入了临床研究。１６７例接受了紫杉醇单药化疗，１６６例接受了紫杉醇加顺铂或阿霉素或其他药物联合化疗。紫杉醇单药化疗的有效率如下：卵巢癌３７％，乳腺癌３９％，非小细胞肺癌３１％，小细胞肺癌４０％，鼻咽癌６７％。紫杉醇联合化疗的有效率如下：卵巢癌３８％，乳腺癌４４％，非小细胞肺癌３１％，小细胞肺癌４０％，鼻咽癌４４％。患者毒副反应主要为白细胞减少、肌肉及关节疼痛、感觉异常和脱发。结论本研究所用的紫杉醇制剂及剂量安全有效，患者能够耐受。紫杉醇可与其他化疗药物联合应用，治疗恶性肿瘤病人。     

奈达铂治疗耐药性鼻咽癌和非小细胞肺癌

目的：研究国家二类新药奈达铂单药治疗顺铂(DDP)耐药性晚期鼻咽癌和非小细胞肺癌的临床疗效及安全性。方法：奈达铂单药治疗耐药性鼻咽癌鼻咽癌6例、非小细胞肺癌3例。奈达铂100mg／m^2加入500ml无菌生理盐水中，静脉滴注2小时，每3--4周重复一次。结果：9例入组患者均可评价疗效。鼻咽癌6例中1例CR，2例PR，有效率为50％；非小细胞肺癌3例中有1例PR。总RR为45．5％。主要毒副作用是对血小板及白细胞生成的抑制作用，恶心、呕吐反应较小，对肾脏的损伤、胃肠道性毒性作用及周围末梢神经等毒性较轻，肝肾功能影响不明显。结论：奈过铂单药对DDP耐药的鼻咽癌或非小细胞肺癌仍有较高的疗效，且多数患者耐受良好．     

A phase I study of STEALTH cisplatin (SPI-77) and vinorelbine in patients with advanced non small-cell lung cancer

STEALTH cisplatin (SPI-77) is a liposomal formulation of cisplatin that has activity in animal models of non small-cell lung cancer (NSCLC). Vinorelbine has documented clinical activity in NSCLC. The purpose of this study was to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of SPI-77 when administered in combination with a fixed dose of vinorelbine to patients with stage IIIB or IV NSCLC refractory to or recurrent following previous chemotherapy. SPI-77 was given on day 1 in combination with vinorelbine at a fixed dose of 25 mg/m2 on days 1 and 8 of a 3-week treatment cycle. Dose escalation of SPI-77 progressed as follows: 20, 40, 80, 100, 120, and 140 mg/m2. Twenty patients were entered (11 men and nine women; median age, 63 years). Sixty-four complete cycles of therapy were administered, and 19 of 20 patients completed at least 1 cycle of combination chemotherapy. Neutropenia was dose limiting at a SPI-77 dose of 140 mg/m2. Neuropathy and nephrotoxicity were minimal and not dose related. A partial response was observed in three of 17 patients eligible for a response evaluation and response duration ranged from 6 weeks to 5 months. In conclusion, treatment with combination SPI-77 and vinorelbine was well tolerated, and our recommended phase II dose is 120 mg/m2 of SPI-77 in combination with vinorelbine at 25 mg/m2. Activity was observed in this patient population, and additional phase II testing of this regimen in a less extensively pretreated cohort of patients with NSCLC is indicated.     

拓扑替康联合卡铂治疗复发性小细胞肺癌临床观察

目的：观察盐酸拓扑替康联合卡铂治疗复发性小细胞肺癌的疗效及不良反应。方法：对29例复发的小细胞肺癌患者采用CT方案化疗：拓普替康1.2mg/m^2,d1-5;卡铂300mg/m^2,d5,21天为1周期,至少治疗2周期。结果：CR 1例,PR 11例,SD 12例,PD 5例,总有效率为41.38%,其中敏感型和难治型复发患者的有效率分别为47.62%和25%。结论：拓普替康与卡铂作为二线方案治疗复发性小细胞肺癌,疗效确切。主要不良反应为血液学毒性,及时应用集落刺激因子,可耐受治疗。