吉西他滨联合顺铂治疗晚期肝癌的临床研究

目的：了解吉西他滨（健择）联合顺铂治疗晚期肝癌的疗效与不良反应。方法：采用吉西他滨（健择）联合顺铂治疗40例晚期肝癌患者。吉西他滨（健择）1000～1250mg／m^2，平均使用剂量1115mg／m^2，静脉滴注30min，第1，8天，顺铂25mg／m^2，静脉滴注，第1～3天，21d为1周期，至少完成2周期疗效评价。结果：40例患者中无CR患者，PR11例占27．5％，NC25例占62．5％，PD4例占10．0％，总有效率27．5％。中位生存时间为7．2个月，1年生存率为45．8％。主要不良反应为血液毒性，骨髓抑制发生率中白细胞减少占周期数的61％，血红蛋白减少占20％，血小板减少占29％。其余不良反应轻微。结论：吉西他滨联合顺铂治疗晚期肝癌疗效好，不良反应可耐受，可提高患者的生存质量。

复方苦参联合吉西他滨治疗晚期非小细胞肺癌疗效观察

目的:观察复方苦参注射液配合吉西他滨治疗晚期非小细胞肺癌的疗效及安全性。方法:将50例Ⅲa～Ⅳ期非小细胞肺癌随机分为治疗组25例及对照组25例,两组均给予吉西他滨1000㎎/㎡,溶于100mL盐水中,静脉滴注30～60min,分别于第1、8天给药,每次化疗前30min给予托烷司琼5㎎静脉滴注。治疗组于化疗同时静滴复方苦参注射液20mL,每天1次,连用10d,21d为1个周期。两组疗程均以21d为1个周期,重复两个周期后评价疗效及毒副反应。结果:治疗组有效率28.0%,对照组有效率24.0%,两组比较无显著性差异(P﹥0.05),临床受益率治疗组为68.0%,对照组为56.0%,两组比较差异有统计学意义(P﹤0.05)。两组患者毒副反应比较差异有统计学意义(P﹤0.05)。结论:复方苦参注射液联合吉西他滨治疗晚期非小细胞肺癌患者安全有效,复方苦参注射液有一定的增效减毒作用。

Clobenpropit在胰腺癌动物模型中与吉西他滨抗肿瘤的协同作用

目的:探讨Clobenpropit作为一种特定的H_3受体拮抗剂和H_4受体激动剂,在胰腺癌中与吉西他滨共同使用的抗肿瘤作用。方法:通过人胰腺癌细胞株(PANC-1)建立裸鼠模型进行研究,通过尾静脉注射药物,测量肿瘤生长及抑制情况,并最终处死后行进一步研究以评价两种药物对细胞增殖、凋亡的影响。结果:Clobenpropit与吉西他滨联用可显著提高吉西他滨对肿瘤的抑制作用,而单用Clobenpropit的抗肿瘤效果不如单用吉西他滨显著。其联合使用可能是通过抑制细胞迁移、上调钙粘附蛋白E等实现的。结论:Clobenpropit可以增强吉西他滨对胰腺癌细胞的抗肿瘤作用。

姜黄素联合吉西他滨对肝癌细胞HepG2增殖、凋亡的影响

目的:观察姜黄素、吉西他滨单药及联合用药对肝癌细胞HepG2增殖和凋亡的影响。方法:使用不同浓度的姜黄素、吉西他滨以及两药联合分别作用肝癌细胞HepG2 24h、48h、72h。MTT法检测上述药物单用或联用对HepG2细胞的生长抑制作用;采用流式细胞仪检测其对HepG2细胞凋亡率的影响。结果:姜黄素、吉西他滨单药及联合用药对HepG2细胞有明显的生长抑制作用,存在时间剂量依赖关系,均可诱导HepG2细胞凋亡,联合用药有协同作用。结论:姜黄素、吉西他滨能够抑制HepG2细胞增殖,诱导细胞凋亡,两药联用有协同作用。

紫龙金片联合GP方案治疗晚期非小细胞肺癌41例

目的:评价紫龙金片联合吉西他滨(G)、顺铂(P)治疗晚期非小细胞肺癌的临床疗效、毒副反应。方法:85例晚期非小细胞肺癌患者分为治疗组(紫龙金片联合GP方案)和对照组(GP方案)。连用2个周期后,评价近期疗效、生活质量及毒副反应。结果:治疗组客观有效率(RR)为36.6%,对照组为27.3%,两者比较无显著性差异;治疗组疾病控制率(DCR)为78.0%,对照组为56.8%,两者比较有显著性差异;两组KPS评分提高率分别为58.5%、36.4%,两者比较有显著性差异。治疗组的2～4度白细胞、血红蛋白、血小板减少及恶心、呕吐等不良反应发生率分别为17.1%、17.1%、14.6%、17.1%,均低于对照组(分别为43.2%、40.9%、36.4%、40.9%),两者比较有显著性差异。结论:紫龙金片可提高晚期非小细胞肺癌化疗的近期疗效,同时可减轻化疗毒副反应、改善患者的生活质量,无明显毒副作用,是非小细胞肺癌综合治疗的较好选择。

吉非替尼治疗70岁以上老年非小细胞肺癌患者疗效研究

目的:探讨吉非替尼治疗老年晚期非小细胞肺癌(NSCLC)的疗效。方法:选择初治的、病期为IIIB^IV期EGFR突变阳性NSCLC40例患者,随机分为治疗组22例和对照组18例,治疗组给予吉非替尼250mg/d,对照组静脉滴注吉西他滨1250mg/m2联合顺铂75mg/m2,21d1周期,直至病情进展。主要观察用药后的有效率,其次为生存时间、安全性。结果:治疗组总有效率为69.3%,疾病控制率为90.2%;对照组分别为35.1%和75.3%,治疗组显著高于对照组(P<0.05)。治疗组中位无进展生存期为11.5月显著长于对照组6.4月(P<0.05)。药物不良反应治疗组主要是皮疹和肝功能损害,对照组主要是乏力和食欲不振,治疗组白细胞减少显著低于对照组(P<0.05),无1例死亡患者。结论:吉非替尼作为一线方案治疗EGFR突变阳性的老年晚期非小细胞肺癌(NSCLC)是有效的、可行的,尤其可以缓解呼吸短促和咳嗽等症状。

Treatment of Unresectable Carcinoma of Pancreas with ^(125)I Implantation and ^(125)I Plus Gemcitabine

Objective: To study the role of 125 I and 125 I plus gemcitabine (GEM) in treatment of unresectable carcinoma of pancreas. Methods: From April 2000 to April 2003, 38 untreated patients with locally advanced pancreatic cancer (LAPC) were collected and randomized into two groups: Arm A 125 I (18 patients) and Arm B 125 I+GEM (20 patients). Eligibility criteria were: cytologically and pathologically proven pancreatic carcinoma, Karnofsky performance status (kps) 60 80, age 18 75 years, adequate hematological, renal and liver function, and controllable pain. Arm A patients were treated with 125 I implants. Arm B patients started chemotherapy within 10 14 d post operatively following the implant procedure. Chemotherapy doses were as follows: GEM 1 000 mg/m 2 weekly × 3 followed by 1 week of rest for 3 cycles. In addition, all patients underwent laparotomy and surgical staging. The surgical procedures performed were biopsy, gastric bypass and biliary bypass. The total activity and number of seeds used were as recommended by Anderson. The mean activity, minimal peripheral dose (MPD), and volume of implants were 20 mCi, 14 000 cGy, and 53 cm 3, respectively. Results: Overall response rate (CR+PR) in Arm A was 37.6% and in Arm B it was 44.5% ( P >0.05). PR median duration in Arm A was 6.7 months and in Arm B it was 4.8 months ( P <0.05). Clinical benefit response was experienced by 11.7 % of Arm A compared with 42.1% of Arm B ( P <0.05). The incidences of hematological toxicity (such as neutropenia) between Arm A and Arm B were 5.8% and 21.1%, respectively ( P >0.05). The survival rates of 12 and 24 month were 32.5%, 16.3% for Arm A and 61%, 38.7% for Arm B ( P =0.04). The rate of complication of Arm A was lower than that of Arm B without statistical significance. Conclusion: To some extent, 125 I or 125 I plus GEM is able to lead to a moderate objective response for LAPC with obstructive jaundice on the base of biliary bypass or/and gastric bypass, but 125 I plus GEM is more effective than 125 I in improvement of the quality of life and survival rate in patients with LAPC.

Clinical observation of gemcitabine and concomitant three-dimensional conformal radiotherapy in the treatment of locally advanced non-small cell lung cancer

Objective： To evaluate the clinical effect of gemcitabine and concurrent three-dimensional conformal radiation therapy （3D-CRT） for locally advanced non-small cell lung cancer （NSCLC）. Methods： From April 2002 to June 2005, 38 patients with inoperable stage Ⅲ NSCLC were treated with gemcitabine and 3D-CRT simultaneously. Chemotherapy consisted of intravenously gemcitabine 350 mg/m^2 on days 1, 8, 15, 22, 29, 36.3D-CRT was delivered up to a total dose of 60-64 Gy with a 2.0 Gy dose fraction per day, 5 days per week. Results： The overall response rates of primary tumor and mediastinum metastatic node were 86.8% （33/38） and 90.6% （29/32） respectively, and 91.7% （22/24） and 78.6% （11/14） for squamous cell carcinoma and adenocarcinoma respectively. The acute side effects of patients were mostly myelosuppression, nausea, vomiting, radiation-induced esophagitis and pneumonitis （RTOG 1/11）, however, all of them were cured. Conclusion： Concurrent application of gemcitabine and 3D-CRT can improve the overall response rate for locally advanced NSCLC without aggravating the side effects.

Synergistic anti-tumor effect of recombinant chicken fibroblast growth factor receptor-1-mediated anti-angiogenesis and low-dose gemcitabine in a mouse colon adenocarcinoma model

AIM： To evaluate whether the combination of recom- binant chicken fibroblast growth factor receptor -1 （FGFR-1） protein vaccine （cFR-I） combined with low- dose gemcitabine would improve anti-tumor efficacy in a mouse CT26 colon adenocarcinoma （CT26） model.METHODS： The CT26 model was established in BABL/c mice. Seven days after tumor ceil injection, mice were randomly divided into four groups： combination therapy, cFR-1 alone, gemcitabine alone, and normal saline groups. Tumor growth, survival rate of tumor-bearing mice, and systemic toxicity were observed. The presence of anti-tumor auto-antibodies was detected by Western blot analysis and enzyme-linked immunospot assay, microvessel density （MVD） of the tumors and tumor cell proliferation were detected by Immunohistochemistry staining, and tumor cell apoptosis was detected by TdT- mediated biotinylated-dUTP nick end label staining.RESULTS： The combination therapy results in apparent decreases in tumor volume, microvessel density and tumor cell proliferation, and an increase in apoptosis without obvious side-effects as compared with either therapy alone or normal control groups. Also, both auto- antibodies and the antibody-producing B cells against mouse FGFR-1 were detected in mice immunized with cFR-1 vaccine alone or with combination therapy, but not in non-immunized mice. In addition, the deposition of auto-antibodies on endothelial cells from mice immunized with cFR-1 was observed by immunofluorescent stain- ing, but not on endothelial cells from control groups. Synergistic indexes of tumor volume, MVD, cell apoptosis and proliferation in the combination therapy group were 1.71 vs 1.15 vs 1.11 and 1.04, respectively, 31 d after tumor cell injection.CONCLUSION： The combination of cFR-l-mediated antiangiogenesis and low-dose gemcitabine synergistically enhances the anti-tumor activity without overt toxicity in mice.

ERK signaling pathway may induce gemcitabine chemoresistance in pancreatic cancer cell line SW1990 by regulating the expression of mdr-1 and RRM1 gene

Objective： To investigate the relationship between extracellular signal-regulated kinase （ERK） pathway, multidrug resistance gene （mdr-1）, ribonucleotide recluctase M1 （RRM1） gene and their roles in gemcitabine （GEM） chemoresistance in pancreatic cancer cell line SW1990. Methods： The GEM-resistance cell model was constructed by a stepwise method. Immunohistochemistry was used to measure the expression of ERK protein （ERK1/2） in the established cell strains in a semiquantitative way. The mRNA expression of mdr-1 and RRM1 were detected by RT-PCR. MTT assay was performed to determine the IC50 value. Results： The established GEM-resistant cell strains were able to gain stable growth and passage ability in the medium contained different concentration levels of GEM （0, 30, 60, 100, 150 and 200 nmol/L）. The expression of ERK protein, mdr-1 and RRM1 gene were elevated accompanied by the increase of GEM concentration. There was a highly positive correlation between mdr-1, RRM1 expression and GEM-resistanca level （r = 0.960, P = 0.002 and r = 0.966, P = 0.002）. The expression of ERK protein also correlated with the mdr-1 and RRM1 level （r = -0.943, P = 0.005 and r = -0.883, P = 0.02）. At the GEM-resistance level of 200 nmol/L, the grey scale value of ERK1/2 was 164.22 ±13.17, mdr-1/β-actin and RRM1/β-actin were 1.41 ±0.04 and 1.45 ± 0.18, respectively; after treated with ERK pathway inhibitor U0126, these values synchronously decreased to 186.85 ± 13.14, 0.2 3± 0.02 and 0.21 ± 0.03, respectively; inversely, the ERK1/2 grey scale value was 106.55 ± 16.45, mdr-l/β-actin and RRMl/β-actin were 1.50± 0.07 and 1.52 ± 0.12, respectively, which presented a tendency of synchronously increase after treated with ERK pathway activator EGF. The IC50 values in GEM-resistant cells of 0 nmol/L and 200 nmol/L levels were 4.104 and 10.20, respectively. After treated with U0126, these values decreased to 3.26 and 4.50, respectively; while treated with EGF, the IC50 values increased to 8.89 and 17.17, respectively. Conclusion： The ERK pathway may induce the GEM-chemoresistance in pancreatic cell line SW1990 through the participation in the regulation of the mdr-1 and RRM1 gene expression.

Gemcitabine and oxaliplatin combination chemotherapy in 30 patients with advanced pancreatic carcinoma

Objective: To evaluate the activity and safety of combination chemotherapy with gemcitabine plus oxaliplatin (GEMOX regimen) in patients of advanced pancreatic carcinoma. Methods: 30 patients with advanced pancreatic cancer were enrolled into this study. All patients received gemcitabine 1000 mg/m2, given by 30-minute intravenous infusion, on days 1 and 8 of each 21-day cycle. Oxaliplatin 100 mg/m2 was administered as a 2 h infusion on day 1 of each 21 day. Clinical outcomes for patients treated with two cycles of chemotherapy were evaluated according to WHO criteria. Results: All 30 patients were eligible for effectiveness and safety analysis. Objective response rate was approximately 20.0%. Clinical benefit response (CBR) was a composite of assessment of pain, performance status and body weight. The pain relief rate, improve-ment rate of performance status and body weight were 53.3%, 46.7% and 36.7%, respectively. The main adverse effects were bone marrow depression, peripheral nerve toxicity and gastrointestinal reaction. There was no treatment-related death during the chemotherapy. Conclusion: The high response rate with low toxicity observed in this study suggests that GEMOX regimen may be an effective alternative curative treatment for patients with advanced pancreatic carcinoma and can be used more extensively in clinical practice.

Concurrent gemcitabine and cisplatin combined with 3D conformal radiotherapy for stage III non-small cell lung cancer

Objective： To study the toxicities and efficacy of concurrent gemcitabine plus cisplatin combined with three-dimensional conformal radiotherapy for stage Ⅲ non-small cell lung cancer （NSCLC）. Methods： Thirty-six patients with pathologically diagnosed NSCLC received radiotherapy and concurrent chemotherapy. There were 22 patients with stage Ilia and 14 patients with IIIb. Radiotherapy was given a total of 60-70 Gy in conventional fractionation. Chemotherapy included gemcitabine （600 mg/m^2） and cisplatin （20 mg/m^2）, once per week. Results： Thirty-two patients received a total dose of 60-72 Gy. Two patients received 56 Gy and another two patients received 58 Gy. Thirty-four patients received 4-6 weeks of chemotherapy, while two patients received only 2 weeks of chemotherapy. The overall response rate （CR ＋ PR）, complete response rate （CR）, partially response rate （PR） were 83.3% （30/36）, 11.1% （4/36） and 72.2% （26/36） respectively. The median follow-up duration was 18.4 months. The 1- and 2-year overall survival rates were 77.8% （28/36） and 55.6% （20/36）, respectively. Conclusion： Concurrent gemcitabine and cisplatin combined with three-dimensional conformal radiotherapy for stage III non-small cell lung cancer is effective and well tolerated. Lone-term results need further study.

Meta-analysis of gemcitabine at 30 min standard-dose infusion versus prolonged low-dose infusion for advanced non-small cell lung cancer

To evaluate the efficacy and safety of gemcitabine （GEM） at 30 min standard-dose infusion （30 min-SDI） compared with prolonged low-dose infusion （P-LDI） in patients with advanced non-small-cell lung cancer （NSCLC）. Electronic databases including Pubmed, EMbase, Cochrane Library, CNKI, CBM, and VIP were searched using keywords ＂GEM＂, ＂P-LDI＂, and ＂NSCLC＂. Review Manager 5.3 was used to perform the recta-analysis. Primary endpoints were overall response rate （ORR） and 1-year survival rate （1-year SR）. Secondary endpoints were grade 3/4 hematotoxicity and nausea/vomiting. Six randomized controlled trials （RCTs） with a total of 637 patients were included. The results showed that P-LDI was superior in ORR （OR = 1.50, 95% CI： 1.08-2.10, P = 0.02）, but had an equal 1-year SR （OR = 1.27, 95 % CI： 0.90-1.79, P = 0.18） as compared with 30 min-SDl. For grade 3/4 adverse events, there was no significant difference in anemia （OR = 1.84, 95% CI： 0.61-5.57, P = 0.28） and nausea/vomiting （OR = 1.15, 95% CI： 0.63-2.12, P = 0.64） between the two treatments. However, patients with P-LDI experienced less leukopenia （OR = 0.64, 95% CI： 0.43-0.97, P = 0.04） and thrombocytopenia （OR = 0.37, 95% CI： 0.17-0.80, P = 0.01）. P-LDI was superior in terms of ORR, experienced less grade 3/4 thrombocytopenia and leukopenia compared with 30 min-SDI, and could be a viable treatment option for advanced NSCLC.

Wbselen and gemcitabine synergistically inhibited the viability of JF305 and MiaPaCa-2 human pancreatic cancer cells

Gemcitabine （GEM） is a cell-cycle specific inhibitor of DNA synthesis and repair, and has been applied as the first-line therapy for patients with locally advanced or metastatic pancreatic cancers. However, the median survival time is only 5.65 mon when GEM was administrated as a monothearpy. Therefore, novel therapeutic agents and/or combinations with GEM are needed for the treatment of pancreatic cancer. In this study, we aim to evaluate the efficacy of treatment with wbselen （WB）, GEM, and combination treatment with GEM and WB in two pancreatic cancer cell lines, JF305 and MiaPaCa-2 cells. The combination index （CI） and the dose-reduction index （DRI） of combined treatment with different dose and time regimes were analyzed based on median-effect theory. Compared with single treatment with GEM, combination treatment displayed decreased response time and IC 50 , and increased maximum inhibition. Among the different combination regimes, the most significant synergistic effect was achieved when the dose ratios of WB to GEM was 2：1 in JF305 cells and 1：1 in MiaPaCa-2 cells after 48 h of drug treatment. When combinations of WB and GEM were used in these two cell lines, the dose of GEM was significantly reduced while the total drug concentration increased, especially after 48 h of drug treatments. Our results indicated that the combination treatment with WB and GEM had synergistic effect against pancreatic cancer in vitro.

Cost-effectiveness analysis of second-line chemotherapy strategies for patients with advanced non-squamous non-small cell lung cancer

Lung cancer is the most widespread type of cancer and the primary cause of cancer-related death in the world.In this study,we aimed to analyze the cost-effectiveness of second-line chemotherapy strategies based on gemcitabine,pemetrexed,and docetaxel for advanced non-squamous non-small cell lung cancer patients in China.A Markov model based on three states,progression-free survival,progressed survival and death,was constructed to simulate the progression of the disease in a 6-year horizon.Sensitivity analysis was performed to evaluate the robustness of the model.The primary outcome of the model was the incremental cost-effectiveness ratio at a willingness-to-pay threshold of 3×per capita GDP of China in 2018($29383).The baseline model results showed that the quality-adjusted life years over the course of the disease associated with second-line chemotherapy strategies were 0.233,0.417 and 0.272 for gemcitabine,pemetrexed and docetaxel,respectively,and the corresponding total costs were$5321.02,$12143.94,and$9479.42.Gemcitabine,pemetrexed and docetaxel resulted in the incremental cost-effectiveness ratios of$37081.09 and$106625.64 per quality-adjusted life year gained.The incremental cost-effectiveness ratio of pemetrexed and docetaxel compared with gemcitabine exceeded the willingness-to-pay threshold.One-way sensitivity analysis showed that the utility value of gemcitabine in the progressed survival state was the most influential parameter.

Gadofullerene nanoparticles extend survival rate and down-regulate thrombin expression in orthotopic pancreatic cancer

Pancreatic cancer is a devastating malignant disease with 5-year survival rate less than 8%.The impenetrable desmoplastic stroma of pancreatic tissue and serious side-effects of existing drugs hinder the effective treatment for pancreatic carcinoma.Thus,it is imperative to exploit much more safe and efficient methods to prolong the survival of pancreatic cancer patients.In this study,we explored a superior anti-pancreatic cancer strategy based on gadofullerene nanoparticles(GFNPs)using an orthotopic human pancreatic carcinoma(PANC-1)tumor model.It was demonstrated that GFNPs could efficiently suppress orthotopic pancreatic cancer in a dose manner,and significantly extend the survival rate of tumor-bearing mice.Of note,the proteomic profiling of tumor tissues revealed that GFNPs ameliorated the coagulation cascade dysfunction and downregulated the thrombin expression in pancreatic tumor tissues.The regulation of abnormal thrombin by GFNPs was validated in vitro and in vivo.More importantly,GFNPs suppressed orthotopic pancreatic cancer with negligible adverse effects,superior to the widely recognized clinical antipancreatic cancer drug,gemcitabine.Together,this study provides a promising therapeutic for intractable pancreatic cancer as well as a potential to alleviate the cancer-associated thromboembolic diseases.