Human bone marrow mesenchymal stem cell-derived exosomes loaded with gemcitabine inhibit pancreatic cancer cell proliferation by enhancing apoptosis

BACKGROUND Pancreatic cancer remains one of the most lethal malignancies,and has limited effective treatment.Gemcitabine(GEM),a chemotherapeutic agent,is commonly used for clinical treatment of pancreatic cancer,but it has characteristics of low drug delivery efficiency and significant side effects.The study tested the hypothesis that human bone marrow mesenchymal stem cell(MSC)-derived exosomes loaded with GEM(Exo-GEM)would have a higher cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis.AIM To investigate the cytotoxicity of MSC-derived Exo-GEM against pancreatic cancer cells in vitro.METHODS Exosomes were isolated from MSCs and characterized by transmission electron microscopy and nanoparticle tracking analysis.Exo-GEM through electroporation,sonication,or incubation,and the loading efficiency was evaluated.The cytotoxicity of Exo-GEM or GEM alone against human pancreatic cancer Panc-1 and MiaPaca-2 cells was assessed by MTT and flow cytometry assays.RESULTS The isolated exosomes had an average size of 76.7 nm.The encapsulation efficacy and loading efficiency of GEM by electroporation and sonication were similar and significantly better than incubation.The cytotoxicity of Exo-GEM against pancreatic cancer cells was stronger than free GEM and treatment with 0.02μM Exo-GEM significantly reduced the viability of both Panc-1 and MiaPaca-2 cells.Moreover,Exo-GEM enhanced the frequency of GEMinduced apoptosis in both cell lines.CONCLUSION Human bone marrow MSC-derived Exo-GEM have a potent cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis,offering a promising drug delivery system for improving therapeutic outcomes.

N-gamboyl Gemcitabine Inhibits Tumor Cells Proliferation and Migration

Gambogic acid(GA) is a natural substance with a good antitumor effect, but it is too lipophilic to be metabolized and excreted, thus accumulating in the body. Gemcitabine(GEM), one of the first-line antitumor drugs, has high hydrophilicity, which greatly shortens its half-life in vivo. We previously reported a compound named N-gamboyl gemcitabine(GAG), derived from the condensation of GEM and GA, whose hydrophilicity is better than GA and stability is better than GEM. Here, the antitumor performance of GAG was investigated for the first time by using several common tumor cell lines as tumor models. The results of in vitro study showed that GAG significantly inhibited the proliferation and migration of the tumor cells. The IC50 values of GAG for the tumor cells were lower than those of GEM and GA. The present study suggests that GAG has a promising potential to be developed into a broad-spectrum antitumor drug.

Efficacy and safety of gemcitabine plus S-1 vs. gemcitabine plus nab-paclitaxel in treatment-na?ve advanced pancreatic ductal adenocarcinoma

Objective:Gemcitabine plus nab-paclitaxel(GnP)is the standard first-line therapy for advanced pancreatic ductal adenocarcinoma(PDAC).S-1,an oral fluoropyrimidine derivative,as compared with gemcitabine,is non-inferior in terms of overall survival(OS)and is associated with lower hematologic toxicity.Accordingly,S-1 is a convenient oral alternative treatment for advanced PDAC.This study was aimed at comparing the efficacy and safety of gemcitabine plus S-1(GS)vs.GnP as first-line chemotherapy for advanced PDAC.Methods:Patients with advanced PDAC who received first-line GS or GnP at the Peking Union Medical College Hospital between March 2011 and November 2022 were evaluated.Results:A total of 300 patients were assessed,of whom 84 received GS and 216 received GnP.The chemotherapy completion rate was higher with GS than GnP(50.0%vs.30.3%,P=0.0028).The objective response rate(ORR)was slightly higher(14.3%vs.9.7%,P=0.35),and the median OS was significantly longer(17.9 months vs.13.3 months,P=0.0078),in the GS group than the GnP group.However,the median progression-free survival(PFS)did not significantly differ between groups.Leukopenia risk was significantly lower in the GS group than the GnP group(14.9%vs.28.1%,P=0.049).Conclusions:As first-line chemotherapy for advanced PDAC,the GS regimen led to a significantly longer OS than the GnP regimen.The PFS,ORR,and incidence of severe adverse events were comparable between the GS and GnP groups.

Discussion on gemcitabine combined with targeted drugs in the treatment of pancreatic cancer

Pancreatic cancer is a malignant tumor with poor prognosis.The treatment of pancreatic cancer depends on the tumor stage and type,and includes local treatment(surgery,radiotherapy and ablation intervention)and systemic therapy(chemotherapy,targeted therapy and immunotherapy).We read with great interest the review“Effective combinations of anti-cancer and targeted drugs for pancreatic cancer treatment”published on World J Gastroenterol and intended to share some of our perspectives in pancreatic cancer treatment.This review presents the therapeutic effects of the combination of gemcitabine and targeted drugs,which gives us a deeper insight into the combination treatments for pancreatic cancer.

Nuclear PLD1 combined with NPM1 induces gemcitabine resistance through tumorigenic IL7R in pancreatic adenocarcinoma

Objective:Pancreatic ductal adenocarcinoma(PDAC)is a highly malignant gastrointestinal cancer with a 5-year survival rate of only 9%.Of PDAC patients,15%-20%are eligible for radical surgery.Gemcitabine is an important chemotherapeutic agent for patients with PDAC;however,the efficacy of gemcitabine is limited due to resistance.Therefore,reducing gemcitabine resistance is essential for improving survival of patients with PDAC.Identifying the key target that determines gemcitabine resistance in PDAC and reversing gemcitabine resistance using target inhibitors in combination with gemcitabine are crucial steps in the quest to improve survival prognosis in patients with PDAC.Methods:We constructed a human genome-wide CRISPRa/dCas 9 overexpression library in PDAC cell lines to screen key targets of drug resistance based on sgRNA abundance and enrichment.Then,co-IP,ChIP,ChIP-seq,transcriptome sequencing,and qPCR were used to determine the specific mechanism by which phospholipase D1(PLD1)confers resistance to gemcitabine.Results:PLD1 combines with nucleophosmin 1(NPM1)and triggers NPM1 nuclear translocation,where NPM1 acts as a transcription factor to upregulate interleukin 7 receptor(IL7R)expression.Upon interleukin 7(IL-7)binding,IL7R activates the JAK1/STAT5 signaling pathway to increase the expression of the anti-apoptotic protein,BCL-2,and induce gemcitabine resistance.The PLD1 inhibitor,Vu0155069,targets PLD1 to induce apoptosis in gemcitabine-resistant PDAC cells.Conclusions:PLD1 is an enzyme that has a critical role in PDAC-associated gemcitabine resistance through a non-enzymatic interaction with NPM1,further promoting the downstream JAK1/STAT5/Bcl-2 pathway.Inhibiting any of the participants of this pathway can increase gemcitabine sensitivity.

Targeting mitochondrial transcription factor A sensitizes pancreatic cancer cell to gemcitabine

Background:The survival of pancreatic cancer cells,particularly cancer stem cells which are responsible for tumor relapse,depends on mitochondrial function.Mitochondrial transcription factor A(TFAM)is critical for the regulation of mitochondrial DNA and thus mitochondrial function.However,the possible involvement of TFAM in pancreatic cancer is unknown.Methods:Human samples were obtained from pancreatic cancers and their adjacent tissues;human pancreatic cell lines were cultured in RPMI1640 medium.TFAM expressions in pancreatic tissues and cultured cells were determined using immunohistochemistry,ELISA,and reverse transcription polymerase chain reaction(RT-PCR).The effect of TFAM on cell growth,migration,colony formation and apoptosis were evaluated.Mitochondrial biogenesis in pancreatic cancer and normal cells were examined.Results:The majority of pancreatic cancer tissues exhibited higher TFAM expression compared to the adjacent counterparts.Consistently,TFAM mRNA and protein levels were higher in pancreatic cancer cell lines than in immortalized normal pancreatic epithelial cells.There was no difference on TFAM level between gemcitabine-sensitive and resistant pancreatic cancer cells.Functional analysis demonstrated that TFAM overexpression activated pancreatic normal and tumor cells whereas TFAM inhibition effectively inhibited the growth of pancreatic cancer cells.TFAM inhibition enhanced gemcitabine’s cytotoxicity and suppressed growth,anchorage-independent colony formation and survival of gemcitabine-resistant pancreatic cancer cells.Mechanistic studies showed that TFAM inhibition resulted in remarkable mitochondrial dysfunction and energy crisis followed by oxidative stress.The basal mitochondrial biogenesis level correlated well with TFAM level in pancreatic cancer cells.Conclusions:TFAM played essential roles in pancreatic cancer via regulating mitochondrial functions which highlighted the therapeutic value of inhibiting TFAM to overcome gemcitabine resistance.

A novel synthesized prodrug of gemcitabine based on oxygen-free radical sensitivity inhibited the growth of lung cancer cells

In the present study,we introduced the H2O2-sensitive thiazolidinone moiety at the 4th amino group of gemcitabine(GEM)to synthesize a new target compound named GEM-ZZQ,and then we confirmed its chemical structure by nuclear magnetic resonance spectroscopy.We further confirmed that GEM-ZZQ had a good chemical stability in different pH solutions in vitro and that it could be activated by H2O2 to release GEM.Pharmacodynamic studies revealed that the growth inhibition of human normal epithelial cells was weaker by GEM-ZZQ than by GEM treatment and that the inhibition of various lung cancer cell lines by GEM-ZZQ was similar to that of GEM.For the lung cancer cell lines that are resistant to the epidermal growth factor receptor(EGFR)-targeting inhibitor osimertinib,GEM-ZZQ showed less growth inhibition than GEM;however,GEM-ZZQ in combination with cisplatin showed better synergistic effects than GEM in the low-dose groups.In summary,we provided a new anti-cancer compound GEM-ZZQ for treating lung cancer by modifying the GEM structure.

Gemcitabine-induced peripheral vascular disease and prolonged response in a patient with metastatic pancreatic adenocarcinoma:A case report

BACKGROUND Gemcitabine is an antimetabolite used in the treatment of pancreatic cancer.One of the side effects of gemcitabine is vascular toxicity.Here,we report the case of a patient treated with gemcitabine who had peripheral vascular disease concomi-tant with a prolonged antitumor response.CASE SUMMARY A 75-year-old man was diagnosed with locally recurrent pancreatic cancer.Partial response was achieved after 9 mo of gemcitabine.At the same time,the patient reported peripheral vascular disease without necrosis.Chemotherapy was suspended,and after one month the Positron Emission Tomography(PET)scan showed locoregional tumor recurrence.Gemcitabine was resumed and partial response was obtained,but peripheral vascular disease occurred.CONCLUSION Our results suggest that the appearance of peripheral vascular disease may be related to a prolonged response to gemcitabine.

Simultaneous Dual Selective Targeted Delivery of Two Covalent Gemcitabine Immunochemotherapeutics and Complementary Anti-Neoplastic Potency of [Se]-Methylselenocysteine

The anti-metabolite chemotherapeutic, gemcitabine is relatively effective for a spectrum of neoplastic conditions that include various forms of leukemia and adenocarcinoma/carcinoma. Rapid systemic deamination of gemcitabine accounts for a brief plasma half-life but its sustained administration is often curtailed by sequelae and chemotherapeutic-resistance. A molecular strategy that diminishes these limitations is the molecular design and synthetic production of covalent gemcitabine immunoche-motherapeutics that possess properties of selective “targeted” delivery. The simultaneous dual selective “targeted” delivery of gemcitabine at two separate sites on the external surface membrane of a single cancer cell types represents a therapeutic approach that can increase cytosol chemotherapeutic deposition;prolong chemotherapeutic plasma half-life (reduces administration frequency);minimize innocent exposure of normal tissues and healthy organ systems;and ultimately enhance more rapid and thorough resolution of neoplastic cell populations. Materials and Methods: A light-reactive gemcitabine intermediate synthesized utilizing succinimidyl 4,4-azipentanoate was covalently bound to anti-EGFR or anti-HER2/neu IgG by exposure to UV light (354-nm) resulting in the synthesis of covalent immunoche-motherapeutics, gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu]. Cytotoxic anti-neoplastic potency of gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] between?gemcitabine-equivalent concentrations of 10-12 M and 10-6 M was determined utilizing chemotherapeutic-resistant mammary adenocarcinoma (SKRr-3). The organoselenium compound, [Se]-methylselenocysteine was evaluated to determine if it complemented the anti-neoplastic potency of the covalent gemcitabine immunoche-motherapeutics. Results: Gemcitabine-(C4-amide)-[anti-EGFR], gemcitabine-(C4-amide)-[anti-HER2/neu] and the dual simultaneous combination of gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu] all had anti-neoplastic cytotoxic potency against mammary adenocarcinoma. Gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] produced progressive increases in anti-neoplastic cytotoxicity that were greatest between gemcitabine-equivalent concentrations of 10-9 M and 10-6 M. Dual simultaneous combinations of gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu] produced levels of anti-neoplastic cytotoxicity intermediate between each of the individual covalent gemcitabine immunochemotherapeutics. Total anti-neoplastic cytotoxicity of the dual simultaneous combination of gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] against chemothe-rapeutic-resistant mammary adenocarcinoma (SKBr-3) was substantially higher when formulated with [Se]-methylsele-no-cysteine.

Gemcitabine治疗晚期非小细胞肺癌的临床研究

目的：评价Ｇｅｍｃｉｔａｂｉｎｅ（中文译名：健择）单药及其与顺氯铵铂联合化疗方案治疗ＩＩ、ＩＶ期非小细胞肺癌（ＮＳＣＬＣ）的临床疗效及其不良反应。材料与方法：１健择单药研究：从１９９７年９月至１９９８年５月入选ＩＩ、ＩＶ期ＮＳＣＬＣ病人２１例，以前未接受过任何化疗、放疗。ＩＩ期病人１１例，ＩＶ期病人１０例。健择１０００ｍｇ／ｍ２，第１，８，１５天各注一次，每２８天为一疗程。２健择与顺氯铵铂联合化疗研究：从１９９７年１０月至１９９８年７月入选ＩＩ、ＩＶ期ＮＳＣＬＣ病人４８例，以前未接受过任何化疗、放疗。ＩＩ期病人１９例，ＩＶ期病人２９例。健择１０００ｍｇ／ｍ２，第１，８，１５天各注一次；顺氯铵铂１００ｍｇ／ｍ２，第一天用，每２８天为一疗程。结果：１健择单药研究：可评价疗效的有１９例，６例获部分缓解（ＰＲ），其中２例（１０５％）经４周以上复查证实。总有效率３１５％［９５％ＣＩ，９４％～４５１５％］。全组均可评价不良反应，少数病人发生轻微胃肠道反应、白细胞下降、血红蛋白下降和血小板下降，只有４８％（各１例）患者发生ＩＩ度的恶心呕吐及白细胞下降，有１例患者发生ＩＩ度感染。全组中位生存期６１３月。２?

Treatment of Primary Liver Cancer with Postoperative After-Loading Radiotherapy and Gemcitabine

Objective： To evaluate the curative effectiveness of postoperative after-loading radiotherapy with the use of gemcitabine in 22 patients with primary liver cancer. Methods： From Oct. 1999 to Dec. 2001, 22 patients with primary liver cancer underwent postoperative after-loading radiotherapy 3-10 days after hepatectomy and chemotherapy using gemcitabine （1400 mg every week for 3 weeks, repeated after one week interval, total cycles were 6） and compared with 22 cases of sole hepatectomy. Three-six catheters were placed for irradiation after hepatectomy. The single-dose of after-loading radiotherapy was 10 Gy, 24 sessions per person. Results＇. The rate of AFP negative-reversion was 100% （17/17） in the treated group, higher than in control group （62.5%, 10/16, P〈0.05）. In the treated group, the 1-year relapse rate, metastasis rate and survival rate were 18.2% （4/22）, 0 and 100% （22/22） respectively, while in the control group they were 45.5% （10/22）, 13.6% （3/22） and 77.3% （17/22） respectively. There were significant differences between the two groups in relapse rate, metastasis rate and survival rate within a year （P〈0.05）. Conclusion： Postoperative after-loading radiotherapy with gemcitabine is an effective way for the treatment of primary liver cancer.

过表达Plk-1对gemcitabine诱导的胰腺癌细胞化疗敏感性的影响

目的观察Plk-1基因过表达对gemcitabine诱导胰腺癌细胞AsPC-1化疗敏感性的影响。方法①将携带有人外源性Plk-1基因的真核表达质粒转染AsPC-1细胞系设为处理组,转染空载体设为对照组,无处理组设为空白组,转染24 h后,提取细胞总RNA和总蛋白,利用RT-PCR法及Western blot鉴定AsPC-1细胞内Plk-1基因和蛋白表达水平。②采用流式细胞术检测转染组细胞凋亡的改变。③不同浓度gemcitabine作用于转染细胞,MTT法测定转染48 h后细胞增殖能力。结果①测序结果表明成功的从AsPC-1细胞总RNA中扩增Plk-1基因。RT-PCR结果表明:未转染组AsPC-1细胞组、转染空载体pcDNA3.1组及pcDNA3.1/Plk-1组24 h各组细胞内Plk-1 mRNA相对量分别为(2.14±0.16)、(2.18±0.15)、(2.58±0.18),转染pcDNA3.1/Plk-1组与其他各组相比,差异有高度统计学意义(P<0.01)。Western blot结果显示:未转染组AsPC-1细胞组、转染空载体pcDNA3.1及pcDNA3.1/Plk-1组24 h各组细胞内Plk-1基因的蛋白表达水平为(0.989±0.018)、(1.022±0.021)、(1.243±0.143),转染pcDNA3.1/Plk-1组与其他各组相比,差异有高度统计学意义(P<0.01)。②在gemcitabine作用下,pcDNA3.1/Plk-1转染组细胞凋亡率明显低于未转染组及空载体转染组,差异有高度统计学意义(P<0.01)。③AsPC-1/Plk-1转染组细胞的生长抑制率亦明显高于未转染组及空载体转染组,差异有高度统计学意义(P<0.01)。结论胞浆过表达Plk-1活性分子可明显降低gemcitabine诱导的AsPC-1细胞凋亡,增强其对化疗药物的耐受性。

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.

Efficacy and safety of gemcitabine-oxaliplatin combined with huachansu in patients with advanced gallbladder carcinoma

AIM: To evaluate the efficacy and safety of gemcitabine-oxaliplatin (GEMOX) combined with huachansu (cinobufagin) injection treatment in patients with locally advanced or metastatic gallbladder carcinoma (GBC), and to assess the quality of life (QOL) of such patients. METHODS: Twenty-fi ve patients with locally advanced or metastatic GBC were treated with intravenous gemcitabine (1000 mg/m2) over 30 min on days 1 and 8, 2 h infusion of oxaliplatin (120 mg/m2) on day 1, and 2-3 h infusion of huachansu (20 mL/m2) on days -3-11, every 3-4 wk. Treatment was continued until occurrence of unacceptable toxicity or disease progression. QOL of patients was assessed by the EORTC QLQ-C30 at baseline, at the end of the fi rst, third and sixth chemotherapy cycles, and 1 mo after the treatment. RESULTS: Among the 25 patients with a median age of 64 years (range 42-78 years), 23 were evaluable in the study. A total of 137 cycles of therapy were performed and the median cycle was 5 (range 1-8) per patient. Out of the 23 patients whose response couldbe evaluated, 8 partial responses (PR) were observed (34.8%), while 7 patients (30.4%) demonstrated a stable disease (SD). The disease control rate was 65.2%. Progression of cancer was observed in 8 (34.8%) patients. The median progression-free and overall survival time was 5.8 mo (95% CI: 4.5-7.1 mo) and 10.5 mo, respectively. The therapy was well tolerated, with moderate myelosuppression as the main toxicity. Anemia grade 2 was seen in 16.0%, neutropenia grade 3 in 8.0% and thrombocytopenia grade 3 in 24.0% of patients, respectively. Non-hematologic toxicity ranged from mild to moderate. No death occurred due to toxicity. The QOL of patients was improved after chemotherapy, and the scores of QOL were increased by 10 to 20 points. CONCLUSION: GEMOX combined with huachansu (cinobufagin) injection is well tolerated, effective, thus improving the QOL of patients with advanced GBC.

Does gemcitabine-based combination therapy improve the prognosis of unresectable pancreatic cancer?

AIM:To assess whether gemcitabine-based combination therapy improves the prognosis of unresectable pancreatic cancer compared with gemcitabine treatment alone.METHODS:A quantitative up-to-date meta-analysis was undertaken to investigate the efficacy of gemcitabine-based combination treatment compared with gemcitabine monotherapy in locally advanced or metastatic pancreatic cancer.Inclusion was limited to highquality randomized clinical trials.RESULTS:Twenty-six studies were included in the present analysis,with a total of 8808 patients recruited.The studies were divided into four subgroups based on the different kinds of cytotoxic agents,including platinum,fluoropyrimidine,camptothecin and targeted agents.Patients treated with gemcitabine monotherapy had significantly lower objective response rate [risk ratio(RR),0.72;95% confidence interval(CI):0.63-0.83;P < 0.001],and lower 1-year overall survival(RR,0.90;95%CI:0.82-0.99;P = 0.04).Gemcitabine monotherapy caused fewer complications,including fewer grade 3-4 toxicities:including vomiting(RR,0.75;95%CI:0.62-0.89;P = 0.001),diarrhea(RR,0.66;95%CI:0.49-0.89;P = 0.006),neutropenia(RR,0.88;95%CI:0.72-1.06;P = 0.18),anemia(RR,0.96;95%CI:0.82-1.12;P = 0.60),and thrombocytopenia(RR,0.76;95%CI:0.60-0.97;P = 0.03) compared with gemcitabine combination therapies.CONCLUSION:Gemcitabine combination therapy provides a modest improvement of survival,but is associated with more toxicity compared with gemcitabine monotherapy.

Nedaplatin/Gemcitabine Versus Carboplatin/Gemcitabine in Treatment of Advanced Non-small Cell Lung Cancer: A Randomized Clinical Trial

Objective： To evaluate the efficacy and safety of nedaplatin/gemcitabine （NG） and carboplatin/gemcitabine （CG） in the management of untreated advanced non-small cell lung cancer （NSCLC）. Methods： Sixty-two patients with previously untreated advanced NSCLC were recruited between June 2006 and November 2007. Subjects were randomly assigned to the NG arm （n=30） and the CG arm （n=32）. Only patients （24 and 25 in the NG and CG arms, respectively） who completed 〉2 chemotherapy cycles were included in the data analysis. The primary outcome measure was the objective response rate （ORR）. The secondary outcome measures included progression-free survival （PFS）, overall survival （OS） and adverse events. Results： There were no statistically significant differences in the efficacy measures （ORR, P=0.305; median PFS, P=0.298, median OS, P=0.961） or in the major adverse events （grade 3/4 neutropenia, P=0.666; grade 3/4 anemia, P=0.263; grade 3/4 thrombocytopenia, P=0.222） between the two treatment arms. However, there was a trend towards higher ORR （37.5% vs. 24.0%）, longer PFS （6.0 vs. 5.0 months）, and less adverse events in the NG arm. Conclusion： NG regimen seems to be superior over CG regimen for advance NSCLS, but further investigation is needed to validate this superiority.

Meta-analysis on inoperable pancreatic cancer: A comparison between gemcitabine-based combination therapy and gemcitabine alone

AIM: To compare gemcitabine-based combination therapy and gemcitabine (GEM) alone in patients with advanced pancreatic cancer (APCa) through meta- analysis. METHODS: MEDLINE and EMBASE searches were supplemented by information from trial registers of randomized controlled trials (RCTs) for GEM-based combination therapy and GEM alone for APCa. A quantitative meta-analysis was carried out by two reviewers based on the inclusion criteria from all available RCTs. The meta-analysis involved overall survival (OS), objective remission rate (ORR), clinical benefit rate (CBR), time to progress/progress free survival (TTP/PFS) and toxicity. RESULTS: The meta-analysis included 22 RCTs. There was significant improvement in the GEM combination group with regard to the 6-mo survival rate (RD = 0.04, 95% CI 0.01-0.06, P = 0.008), 1-year survival rate (RD = 0.03, 95% CI 0.01-0.05, P = 0.01), ORR (RD = 0.04, 95% CI 0.01-0.07, P = 0.02), CBR (RD = 0.10, 95% CI 0.02-0.17, P = 0.01) and 6-mo TTP/PFS (RD = 0.07, 95% CI 0.04-0.10, P < 0.00001). However, the Grade 3-4 toxicity set by WHO was higher for the GEM combination group for neutropenia (RD = 0.05, 95% CI 0.01-0.10, P = 0.02), thrombocytopenia (RD = 0.05, 95% CI 0.02-0.08, P = 0.002) and vomiting/nausea (RD = 0.03, 95% CI 0.00-0.05, P = 0.02). CONCLUSION: GEM-based combination therapy may improve the overall survival and palliation in optimalpatients with APCa as compared with GEM alone.

Weekly albumin-bound paclitaxel/cisplatin versus gemcitabine/cisplatin as first-line therapy for patients with advanced non-small-cell lung cancer:A phase II open-label clinical study

Objective: The aim of this trial was to compare both the efficacy and the safety of a weekly nanoparticle albumin-bound paclitaxel(nab-paclitaxel) plus cisplatin vs. gemcitabine plus cisplatin in patients with advanced non-small-cell lung cancer(NSCLC).Methods: A total of 84 participants received either 100 mg/m^2 nab-paclitaxel each week on d 1, 8 and 15 of a 28 day cycle, as well as cisplatin 75 mg/m^2 on d 1 every three weeks(nab-TP arm); or gemcitabine 1,000 mg/m^2 on d 1 and 8, plus cisplatin 75 mg/m^2 on d 1 every three weeks(GP arm). The primary end point was progression-free survival(PFS). The secondary end points were overall response rate(ORR) and overall survival(OS).Results: According to our analysis, the median PFS was 4.8 months for the nab-TP arm vs. 5.2 months for the GP arm(P=0.55). Analysis showed the median OS was 14.6 months for participants who were in the nab-TP arm vs. 15.1 months for those in the GP arm(P=0.94). Besides, nab-TP showed OS advantages over GP in patients harboring epidermal growth factor receptor(EGFR) mutation(26.7 vs. 15.3 months, P=0.046) and patients with a performance status of 0(23.5 vs. 14.7 months, P=0.020). It was found that incidences of drug-related grade 3 or 4 toxicities were comparable between the two treatment arms.Conclusions: Therefore, it can be seen that weekly nab-TP treatment has a similar efficacy and tolerability to GP treatment for patients who are undergoing their first-line treatment for NSCLC. It could be that survival differences among platinum doublets in the context of both EGFR mutation and performance status have the potential to be the basis for our further clinical trials.

Synergetic anticancer effect of combined gemcitabine and photodynamic therapy on pancreatic cancer in vivo

AIM： To investigate the anti-tumor effects of combined cytotoxic drug （gemcitabine） and photodynamic therapy （PDT） on human pancreatic cancer xenograft in nude mice.METHODS： Human pancreatic cancer cell line SW1990 was used in the investigation of the in vivo effect of combined gemcitabine and PDT on human pancreatic cancer xenograft in mice. Sixty mice were randomly allocated into a control group （without treatment）, photosensitizer treatment group （2 mg/kg photosan, without illumination）, chemotherapy group （50 mg/kg gemcitabine i.p.）, PDT group （2 mg/kg photosan ＋ laser irradiation） and combined treatment group （photosan ＋ chemotherapy）, with 12 mice in each group. Tumor size was measured twice every week. Anti-tumor activity in different groups was evaluated by tumor growth inhibition （TGI）RESULTS： No significant anti-tumor effect was observed either in photosensitizer treatment group or in chemotherapy group. PDT led to necrosis in cancer lesions and significantly reduced tumor volume compared with photosensitizer on day 6 and at the following time points after initialization of therapy （0.24 ± 0.15-0.49 ± 0.08 vs 0.43 ± 0.18-1.25± 0.09, P 〈 0.05）. PDT significantly reduced tumor volume in combined treatment group compared with photosensitizer treatment group （0.12 ± 0.07-0.28 ± 0.22 vs 0.39 ± 0.15-2.20 ± 0.12, P 〈 0.05）, small dose chemotherapy group （0.12 ± 0.07-0.28 ± 0.12 vs 0.32 ± 0.14-1.16 ± 0.08, P 〈 0.05） and control group （0.12 ± 0.07-0.28 ± 0.12 vs 0.43 ± 0.18-1.25 ± 0.09, P 〈 0.05）. TGI was higher in the combined treatment group （82.42%） than in the PDT group （58.18%）.CONCLUSION： PDT has a significant anti-tumor effect, which is maintained for a short time and can be significantly enhanced by small doses of gemcitabine.