Phase Ⅱ study of apatinib in combination with oral vinorelbine in heavily pretreated HER2-negative metastatic breast cancer and clinical implications of monitoring ctDNA

Objective:Apatinib is an oral TKI targeting VEGFR-2.Single-agent apatinib treatment has been shown to produce an objective response in patients with pretreated m BC.Oral vinorelbine also holds promise as a treatment of choice in patients with m BC.This study aimed to investigate the efficacy and safety of the oral vinorelbine-apatinib combination in patients with pretreated m BC.In addition,we detected gene variants in ct DNA to explore the therapeutic implications.Methods:This study enrolled patients with HER2-negative m BC who were pretreated with anthracycline/taxanes.Patients were treated with apatinib at 500 mg/425 mg daily plus oral vinorelbine 60 mg/m2 on days 1,8,and 15 of every cycle(3 weeks).The primary endpoint was PFS.The secondary endpoints were ORR,CBR,OS,and safety.Patients eligible for ct DNA detection were evaluated before and during treatment.Results:Forty patients were enrolled.The median PFS was 5.2 months(95%CI,3.4–7.0 months),and the median OS was 17.4 months(95%CI,8.0–27.0 months).The ORR was 17.1%(6/35),and the CBR was 45.7%(16/35).The most common AEs included gastrointestinal reaction,myelosuppression,and hypertension.In 20 patients,ct DNA was detected at baseline and during treatment.A significant difference was found in PFS for undetected vs.detected baseline ct DNA(13.9 months vs.3.6 months,P=0.018).Conclusions:All-oral therapy with apatinib plus vinorelbine displayed objective efficacy in patients with heavily pretreated HER2-negative m BC,with acceptable and manageable toxicity profiles.Patients with no gene variant detected and lower variant allele frequencies in ct DNA at baseline showed longer PFS.

Feasibility Study for Biweekly Administration of Cisplatin plus Vinorelbine as Adjuvant-Chemotherapy for Completely Resected Non-Small Cell Lung Cancer Patients in a Japanese Population

Purpose: To evaluate the feasibility of biweekly administration of cisplatin and vinorelbine as adjuvant chemotherapy for patients with completely resected non-small cell lung cancer (NSCLC). Patients and Methods: This was a single-arm, single-institutional study. Patients with completely resected NSCLC (p-Stage IB-IIIA) with no previous chemotherapy or radiotherapy were eligible. Simon’s optimal two-stage design was applied. Both cisplatin (50 mg/m2) and vinorelbine (25 mg/m2) were given on days 1 and 15, every 28 days. The primary endpoint of this study was the feasibility of this combination in the four cycles of treatment. Results: Twenty patients (19 lobectomies and 1 pneumonectomy) were enrolled in this study. 10 (50%) of patients had grade 3/4 neutropenia, and 3 (15%) had grade 3/4 anemia. Severe non-hematologic toxicities were uncommon in this series. No treatment-related death was encountered. 18 (90%) patients completed the planned 4 cycles of chemotherapy. The median intensity was 24.3 (range 18.1 to 25) mg/m2/week with an average of 23.6 (21 - 25) mg/m2/week cisplatin and 12.5 (range 10 to 12.5) mg/m2/week with an average of 12.3 (10 - 12.5) mg/m2/week vinorelbine. The median relative dose intensity of cisplatin was 97.5% (range 72.5% to 100%) with an average of 94.6% (72.5% - 100%) and that of vinorelbine was 100% (range 80% to 100%) with an average of 97.8% (80% - 100%). Conclusion: This regimen is feasible in the treatment of patients with completely resected NSCLC. A phase III trial is warranted to assess the efficacy of this regimen at promoting survival and preventing recurrence.

Effects of Pachyman in Combination with Vinorelbine and Cisplatin on Tumor Growth and the Expression of EGFR and K-ras in Mice with Lung Cancer

Objective To examine the effects of pachyman in combination with vinorelbine and cisplatin on tumor growth and the expression of epidermal growth factor receptor(EGFR)and K-ras in a mouse model of lung cancer induced using the human lung cancer cell line A549,and to investigate the molecular mechanisms underlying the antitumor effects of pachyman.Methods We recorded the size of the tumor xenografts in mice after treatment with pachyman monotherapy or pachymanin combination with vinorelbine and cisplatin.We performed immunohistochemical analysis to determine the levels of expression and distribution of EGFR and K-ras in lung cancer tissues.Real-time fluorescence quantitative PCR was used to determine the relative mRNA expression levels of EGFR and K-ras in lung cancer tissues.Results Vinorelbine and cisplatin significantly decreased the rate of growth of A549 xenografts,and pachyman increased the efficacy of vinorelbine and cisplatin.EGFR and K-ras were widely expressed in A549 xenografts.Vinorelbine and cisplatin could significantly decrease the expression,distribution and mRNA expression levels of EGFR and K-ras in tumor tissues.Pachyman monotherapy significantly decreased the distribution and the mRNA expression levels of EGFR in lung cancer tissues.In addition,pachyman in combination with vinorelbine and cisplatin markedly decreased the distribution and expression levels of EGFR in lung cancer tissues.However,pachyman monotherapy or combination therapy did not significantly decrease the mRNA expression levels of K-ras.Conclusion Thus,pachyman in combination with vinorelbine can significantly inhibit the growth of A549 xenografts,and pachyman can regulate the expression of the EGFR gene to increase the efficacy of vinorelbine and cisplatin in lung cancer and decrease the side effects associated with chemotherapy.

Shenfu injection plus vinorelbine for elderly patients with non-small cell lung cancer in promoting the quality of life: a randomized controlled clinical trial

Objective： The present study aimed to investigate the efficacy of Shenfu injection plus vinorelbine on the promotion of the quality of life （QOL） in elderly non-small cell lung cancer （NSCLC） patients. Methods： A randomized single blind trial method was used. Forty-six patients with stage IIIB-IV of HSCLC were randomly divided into experimental group and control group. In the experimental group, the patients were treated with 50 mL Shenfu injection from day 1 to 14, plus vinorelbine （NVB） 25 mg/m^2 on day 1 and 8. In the control group, the patients were only treated with NVB 25 mg/m^2 on day 1 and 8. After two cycle＇s of treatment, QOL, efficacy and toxicity were observed. Results： The QOL was enhanced in both experimental group and control group. However, the difference of KPS after treatment in the experimental group was markedly higher than in the control group （14 ± 10 vs. 8 ± 10, t = 2.116, P = 0.04）, improvement rate of QOL was better than in the control group （76.2% vs. 45.0%, χ^2 = 4.188, P = 0.041）, treatment related toxicity in the experimental group was also markedly lower than in the control group （χ^2 = 3.866, P = 0.049）, but the difference of efficacy between the two groups was not significant （14.3% vs. 15.0%, χ^2 = 0.161, P = 0.688）. Conclusion： Shenfu injection plus vinorelbine can enhance QOL in elderly NSCLC patients.

The effect and side effects of Gemcitabine plus Vinorelbine in patients with triple-negative metastatic breast cancer

Objective： The aim of this study was to evaluate the anti-tumor activity and safety of Gemcitabine （GEM） combined with Vinorelbine （NVB） in patients with advanced TNABC after chemotherapy. Methods： Thirty-seven patients with immunohistochemical proved TNABC were enrolled. The patients received 21-day cycles of NVB 25mg/m^2 i.v. with GEM 1000 mg/m^2 i.v. on days 1 and 8. Results： A total of 136 cycles were given to 37 patients（median 4 cycles, ranged 2-6 cycles）. The treatment response was evaluable in all patients. Of the 37 patients, 1 received complete remission （CR）, 8 received partial remission （PR）, 20 had stable disease （SD）, 9 had progressive disease （PD）. Overall objective response （CR＋ PR） were 24.3 %. The median time to progress （TTP） was 6 months （95% CI, 4-6 months）. The median overall survival was 24 months （95% CI, 11-37 months）. The median 1-year survival rate was （66.24±8.43）%. The median 3-year survival rate was （28.77±11.96）%. The major adverse events were grade Ⅰ-Ⅱ myelosuppression, peripheral neurologic toxicities, nausea and vomiting. Some patients had rash and hepatic dysfunction. A total of 40% of patients experienced flu-like symptoms. Alopecia and diarrhea were rare. Conclusion： The combination of GEM and NVB is an effective and well tolerated regimen for the patients with TNABC.

Combined chemo-endocrine therapy as a potential new option for HR+/HER2−advanced breast cancer:a prospective study of fulvestrant plus oral vinorelbine

Objective:Endocrine therapy with fulvestrant has shown synergistic antitumor effects with some chemotherapy drugs in vitro.This study evaluated the efficacy and safety of fulvestrant with vinorelbine in patients with hormone receptor positive(HR+)/human epidermal growth factor receptor-2-negative(HER2−)recurrent or metastatic breast cancer.Methods:Patients were intramuscularly administered fulvestrant 500 mg(day 1 per cycle for 28 days)and oral vinorelbine(60 mg/m2 on days 1,8,and 15 of each cycle).The primary endpoint was progression-free survival(PFS).Secondary endpoints included overall survival,objective response rate,disease control rate,duration of response,and safety.Results:A total of 38 patients with HR+/HER2−advanced breast cancer included in the study were followed up for a median time of 25.1 months.The overall median PFS was 9.86 months[95%confidence interval(CI)7.2-23.13],and the median PFS of the first-line and the second-line treatment population was 20.73 months(95%CI 9.82 to NR)and 4.27 months(95%CI 3.68 to NR),respectively.Most adverse events reported were of grade 1/2,and none were of grade 4/5.Conclusions:This is the first exploratory study of a fulvestrant and oral vinorelbine regimen in the treatment of HR+/HER2−recurrent and metastatic breast cancer.The combination chemo-endocrine therapy was efficacious,safe,and promising for patients with HR+/HER2−advanced breast cancer.

CLINICAL EFFICACY OF VINORELBINE PLUS CISPLATIN IN ADVANCED NON-SMALL CELL LUNG CANCER

A clinical study of the efficacy of vinorelbine plus cisplatin regimen in the management of advanced NSCLC was performed in 35 patients. Five of the 35 patients failed to finish one cycle of chemotherapy with this regimen because of severe and intractable leukopenia or rapid progress of the disease. Tumor response and toxicity were evaluated in the remaining 30 cases. Results showed that, with this regimen, the objective response rate (CR+PR) was 46.7%. The most common toxicity was leukopenia; other side effects included alopecia, gastrointestinal reactions, slight and transient renal and hepatic impairment and peripheral neuropathy. It suggested that vinorelbine plus cisplatin is a safe and effective regimen in the management of advanced NSCLC.

Neoadjuvant Combination Chemotherapy with Pegylated Liposomal Doxorubicin and Vinorelbine for Locally Advanced Breast Cancer

OBJECTIVE In China, vinorelbine plus an anthracycline is a common neoadjuvant regimen for locally-advanced breast cancer （LABC）. Pegylated liposomal doxorubicin （PLD） is an alternate anthracycline formulation with a more favorable safety profile compared with conventional anthracyclines. METHODS In this open-label trial, 61 women with LABC received up to 6 cycles of PLD 30 mg/m2 on Day 1 and vinorelbine 25 mg/m2 on Days 1 and 8 every 21 days. Hormone receptor and/or HER2 status was not routinely available. RESULTS The overall clinical response rate （primary efficacy endpoint） was 80% （95% CI： 68%-89%）. Two patients achieved a pathological complete response （3%）, with 75% having their tumor down-staged, and 89% proceeding to tumor resection. The most frequent nonhematologic adverse events were stomatitis, fever, rash, and palmar-plantar erythrodysesthesia, with none considered serious. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 10% and 2% of patients, respectively. CONCLUSION PLD plus vinorelbine demonstrated comparable efficacy to conventional anthracyclines plus vinorelbine in the neoadjuvant treatment of LABC, but may offer safety advantages.

Sequential versus simultaneous use of vinorelbine and capecitabine at the same dosage as first-line chemotherapy for patients with metastatic breast cancer

Objective:It remains unclear whether simultaneous use of two chemotherapeutic drugs is better than sequential use.This trial was designed to explore efficacy and safety of sequential vs simultaneous use of vinorelbine and capecitabine at the same dosage as first-line therapy in metastatic breast cancer (MBC).Methods:This was a un-icenter, randomized phase II trial.Patients randomized into the simultaneous group (group A) were simultaneously administered with vinorelbine and capecitabine while those in the sequential group (group B) received vinorelbine followed by capecitabine at the same dosage.Results:Sixty-six patients were screened and 30 patients were randomized into either group.There're significant differences in the clinical benefit rate (CBR) with 80.0% for group A vs 53.3% for group B (P=0.028).With a median follow up time of 13.5 months, there were no significant differences between the two groups in PFS (median PFS:7.70 months for group A vs 7.23 months for group B, P=0.436).Grade III or IV neutropenia (83.3% vs 50.0%, P=0.006), all grades of fatigue (56.7% vs 30.0%, P=0.037) and anorexia (53.3% vs 23.3%, P=0.017) were significantly more frequent in simultaneous group.Conclusion:Simultaneous administration of vinorelbine and capecitabine can bring about improvements in CBR, but cannot translate into long-term benefits, such as progression-free survival (PFS) or overall survival (OS).These findings, combined with a relatively better tolerability in sequential group, showed that both simultaneous and sequential administrations are reasonable options for MBC patients.

Clinical study of docetaxel-vinorelbine as second-line chemotherapy in advanced non-small cell lung cancer

Objective： To evaluate the efficacy and toxicity of docetaxel and vinorelbine as second-line chemotherapy in the treatment of advanced non-small cell lung cancer （NSCLC）. Methods： 48 histologically or cytologically confirmed NSCLC patients with progressive or recurrent disease after first-line treatment were treated with docetaxel and vinoretbine. The chemotherapy included vinorelbine （25 mg/m^2） on days 1,5 and docetaxel （60 mg/m^2） on day 1. The treatment was repeated every 3 weeks. Patients receiving at least two cycles were evaluated for efficacy and toxicity. Results： Of 48 patients, 1 patient achieved complete response and 16 achieved partial response. Overall response rate for all 48 patients was 35.4% （17/48）. Main hematologic toxicities included neutropenia （60.4%） and febrile neutropenia （29.2%） and non-hematologic toxicities were mild. Conclusion： The combination of docetaxel-vinorelbine as second-line chemotherapy is an effective regimen with manageable toxicity for the treatment of advanced NSCLC. Further studies may confirm these results.

Comparison of vinorelbine plus cisplatin with vinorelbine plus capecitabine in patients with anthracyclines- and taxanes-refractory advanced breast cancer

Objective: The aim of our study was to compare the efficacy and toxicities of vinorelbine plus cisplatin(NP) regimen with that of vinorelbine plus capecitabine(NX) regimen in the treatment of anthracycline- and taxane-refractory advanced breast cancer. Methods: Forty-six patients with anthracycline- and taxane-refractory advanced breast cancer were equally randomized into a NP group(n = 23) and a NX group(n = 23). Response rates and toxicities were evaluated after 2 cycles of chemotherapy. Results: The overall response rate were 48.0% in both groups. There were no significant differences in disease control rates(78.0% vs. 83%) or 1-year survival rates(54.6% vs. 55.9%). The main adverse events were bone marrow depression and gastrointestinal reaction, and no significant difference was found in toxicities between the groups. Conclusion: For anthracycline- and taxane-refractory advanced breast cancer, NP and NX regimens exerted similar curative effects with acceptable toxicity.

Meta-analysis of efficacy and safety of Endostar combined with vinorelbine and cisplatin in the treatment of non-small cell lung cancer

Objective:To systematically evaluate the efficacy and safety of rh-endostain(YH-16,Endostar)combined with vinorelbine and cisplatin(NP regimen)in the treatment of non-small cell lung cancer(NSCLC),and to provide evidence-based reference for clinical drug use.Methods:Retrieved from PubMed,EMBASE,the Cochrane Library,Clinical Trials,CNKI,VIP and Wan Fang database,randomized controlled trials(RCT)about YH-16 combined with NP regimen(NPY regimen,trial group)vs.NP regimen(control group)for NSCLC were collected.After screening the literature and extracting the data,the two persons evaluated the quality of the included studies,and used Rev Man 5.3 software to merge effect size.Results:A total of 18 articles were included,with a total of 2051 patients.Results of Meta-analysis showed that response rate[RR=1.66,95%CI(1.44,1.91),P<0.00001]、clinical benefit rate[RR=1.21,95%CI(1.14,1.29),P<0.00001]and quality of life improvement rate[RR=3.42,95%CI(2.45,4.79),P<0.00001]of trial group were significantly higher than those of control group.Besides,the serum CEA level[MD=-4.78,95%CI(-7.11,-2.46),P<0.0001]and CA125 level[MD=-16.44,95%CI(-20.83,-12.05),P<0.00001]of trial group were significantly lower than that of control group.There was no statistical significance in the 1-year survival rate and the incidence of myelosuppression,cardiotoxicity,gastrointestinal reaction,damage to the kidneys and liver,and alopecia(P>0.05).Conclusion:Compared with NP regimen alone,NPY regimen can improve the efficacy and quality of life of NSCLC patients,reduce the level of tumor markers,and does not increase the occurrence of adverse reactions,and has good efficacy and safety.However,the existing evidence shows that NPY regimen has the same effect as NP regimen alone in improving the 1-year survival rate of patients.The above conclusions need to be confirmed by further studies.

A retrospective clinical study of safety and efficacy of vinorelbine/epirubicin/fluorouracil(NEF) regimen as a postoperative chemotherapy for breast cancer

Objective： We aimed to investigate the safety and efficiency of vinorelbine/epirubidn/fluorouracil （NEF） regimen as adjuvant chemotherapy for breast cancer. Methods： From 2005 to 2008, 227 female breast cancer patients were treated with the NEF regimen： vinorelbine 25 mg/m^2 iv on days 1 and 8; epirubicin 60 mg/m2 iv gtt on day 1; 5-Fu 500 mg/m2 iv gtt on day 1. Chemotherapy was repeated every 21-28 days for a total of 6 cycles. Results： The major side effects were neutrope- nia and gastrointestinal syndrome, with a 5-year survival rate of 85.4%, Conclusion： NEF regimen is safe and guarantees a high survival rate which could be recommended as a adjuvant chemotherapy regimen for breast cancer,

Oral Vinorelbine as Switch Maintenance Therapy versus Best Supportive Care in Patients with Advanced Adenocarcinoma Non-Small Cell Lung Cancer EGFR Wild Type

Background: This study was performed to evaluate the efficacy and safety of switch maintenance therapy with oral vinorelbine in advanced non-small cell lung cancer (NSCLC) with adenocarcinoma limited to epidermal growth factor receptor (EGFR) wild type. Materials and Methods: In this single randomized trial, patients with advanced stage (IIIB and IV) NSCLC with adenocarcinoma EGFR wild-type status, treated with 6 cycles of platinum based chemotherapy. Patients did not show progression after first-line chemotherapy were randomly assigned to receive switch maintenance with vinorelbine (80 mg/m2, day 1, 8) (group I) or the best supportive care until disease progression (group II). Results: The median progression free survival (PFS) was 9.7 months for group I versus 5.7 months for group II with statistically significant difference between both groups [HR = 1.15;95% CI 1.19 to 1.49;P value = 0.002], while the median overall survival (OS) was 13.2 months for group I versus 11.9 months for group II with no statistically significant differences between both groups [HR = 1.24;95% CI 1.05 to 1.46;P value = 0. 3]. The patients who received oral vinorelbine had tolerable toxicity profile. Conclusion: Switch maintenance therapy with oral vinorelbine, though improve PFS, did not improve OS in patients with NSCLC with adenocarcinoma EGFR wild type.

Clinical Efficacy and Safety of Oxaliplatin-tegafur,Gimeracil and Oteracil Potassium and Vinorelbine-Pt in the Treatment of Advanced Triple Negative Breast Cancer

The purpose of this study was to investigate the efficacy and safety of oxaliplatin combined with tegafur,gimeracil and oteracil potassium(SOX regimen)and vinorelbine combined with Pt(NP regimen)in the treatment of advanced triple negative breast cancer(TNBC).First of all,88 patients with advanced breast cancer were selected and divided into observation group and control group with 44 cases each by random number method.Both groups received conventional supportive therapy.On this basis,SOX regimen was adopted in the observation group and NP regimen in the control group,and the efficacy,occurrence of toxic and side effects in the two groups were compared.The results showed that the objective effective rates and clinical benefit rates of the two groups were statistically significant(P<0.05).In addition,both groups had hand foot syndrome,diarrhea,liver function damage,decreased platelet(PLT)and other toxic side effects,but the incidence of rash,oral ulcer and pigmentation in the observation group was significantly lower than that in the control group(P<0.05).Therefore,both SOX regimen and NP regimen can effectively treat advanced TNBC adverse reactions,but SOX regimen was more effective.

Inetetamab combined with pyrotinib and oral vinorelbine for patients with human epidermal growth factor receptor 2 positive advanced breast cancer:A single-arm phase 2 clinical trial

Background Human epidermal growth factor receptor 2(HER2)-targeted agents have significantly improved the outcomes of patients with HER2-positive breast cancer;however,a large proportion of patients still develop resistance to trastuzumab.In this study,we investigated the efficacy and safety of inetetamab,another anti-HER2 antibody,combined with pyrotinib and oral vinorelbine in patients with HER2-positive advanced breast cancer so as to provide new ideas for the treatment.Methods In this prospective,single-arm,phase 2 trial,patients with HER2-positive advanced breast cancer with disease progression after trastuzumab were recruited.Patients received a combination of inetetamab(loading dose of 8 mg/kg and subsequent doses of 6 mg/kg intravenously once every 3 weeks),pyrotinib(400 mg orally once daily),and vinorelbine(60 mg/m^(2)orally once weekly)until disease progression or intolerable toxicity.The primary endpoint was progression-free survival(PFS).The secondary endpoints included objective response rate(ORR),overall survival(OS),disease control rate(DCR),and safety.Results Between February 13,2022 and December 25,2022,30 patients were screened and enrolled in this study.The median age of the patients at enrollment was 54 years,12 patients(40.0%)had hormone-receptor-positive disease and 23 patients(76.7%)had visceral metastasis.The median PFS was 8.63 months(95%confidence interval[CI]4.15-13.12 months).The median OS was not reached.The ORR was 53.3%(16/30)and the DCR was 96.7%(29/30).The most common Grade III/IV adverse events were leukopenia(n=5,16.7%),neutropenia(n=4,13.3%),and diarrhea(n=3,10%).No treatment-related serious adverse events or deaths occurred.Conclusions The combination regimen of inetetamab,pyrotinib,and oral vinorelbine showed encouraging efficacy and favorable safety in patients with HER2-positive advanced breast cancer and could be considered as an alternative treatment option for the patients.

Reductive lipid nanoparticles loaded with vinorelbine inhibit chemotherapy-induced invasion of cancer cells by modulating ENPP2

Cancer is a predominant culprit behind worldwide death and accounts for up to 10 million deaths every year.Chemotherapy is the primary therapeutic method employed for cancer in clinical settings and is essential in controlling tumor progression.Despite the advances in this field,tumor invasion and metastasis during treatment remain a significant cause of treatment failure.Nevertheless,the underlying mechanisms involving such a disappointing phenomenon are still not fully elucidated.Vinorelbine(VNB)extends the lifespan of many cancer patients in the clinic as an emerging chemotherapy drug approved by Food and Drug Administration(FDA).However,VNB-induced tumor metastasis is still an intractable problem,which may be closely related to the abnormal oxidative stress generated during VNB-mediated treatment.Hence,the study aims to construct a reductive nanosystem loaded with VNB,called VNB-VNP,to improve cancer cure rates and reduce tumor metastasis.With the reductive component vitamin E,VNB-VNP can effectively reduce oxidative stress and significantly outperform free VNB in preventing tumor progression.The transcriptome analysis shows that VNB-VNP can alleviate the over-expression of ectonucleotide pyrophosphatase/phosphodiesterase 2(ENPP2),which may be the main reason why VNB-VNP can inhibit tumor invasion and metastasis.Overall,the research designs a new platform for VNB treatment,which demonstrates promising efficacy in inhibiting neoplastic progression and identifies a new mechanism associated with VNB-induced tumor metastasis,which may offer several valuable references for enhancing chemotherapy efficacy in clinical anti-tumor therapy.

Efficacy of Aidi Injection(艾迪注射液)on Overexpression of P-Glycoprotein Induced by Vinorelbine and Cisplatin Regimen in Patients with Non-Small Cell Lung Cancer

Objective：To investigate the efficacy of Aidi Injection（艾迪注射液） on overexpression of P-glycoprotein（P-gp） induced by vinorelbine and cisplatin（NP） regimen in patients with non-small cell lung cancer（NSCLC）, and study the difference between intravenous administration and targeting intratumor administration of Aidi Injection with thoracoscope. Methods：Totally 150 patients with NSCLC were randomly assigned to the control group, the intravenous group and the intratumor group by the random envelope method, 50 cases in each group. The patients were treated with NP regimen（2 cycles）, NP regimen（2 cycles） plus Aidi intravenous injection, or NP regimen（2 cycles） plus Aidi intratumor injection with thoracoscope, respectively for 6 weeks. The clinical efficacy was observed based on Response Evaluation Criteria in Solid Tumors（RECIST） rules, the expression of P-gp in the tumor tissue was tested before, 3 and 6 weeks after treatment, the safety was evaluated by monitoring the toxicity in the process of treatment, and the progressionfree survival（PFS） was measured. Results：Fifteen cases dropped out because of the irreconcilable conditions which had no relationship with the treatment, 4 in the control group, 5 in the intravenous group, and 6 in the intratumor group, respectively. Compared with the control group, the response rates（complete remission ＋ partial response） and the disease control rates（complete remission ＋ partial response ＋ stable disease） were significantly higher, the P-gp expressions were significantly decreased after 3 and 6 weeks of treatment, and the Kaplan-Meier survival curves of PFS were significantly longer in the intravenous and intratumor groups（P〈0.05 or P〈0.01）, and the intratumor group showed better effects than the intravenous group（P〈0.05 or P〈0.01）. Compared with the control group, the occurrences of rash, nausea and leukocytopenia were significantly decreased in the intravenous and intratumor groups（P〈0.05）, but without significant difference between the intravenous and intratumor groups（P〉0.05）. Conclusion：Aidi Injection not only improves the efficacy of NP regime, but also has the function of reducing adverse events and preventing against overexpression of P-gp induced by chemotherapy of NP regimen.

Development of targeted sunitinib plus vinorelbine liposomes modified with DSPE-PEG_(2000)-pemetrexed conjugate and the inhibitory effect toresistant breast cancer in vitro

Multidrug resistance （MDR） of breast cancer is a major cause of failure in chemotherapy. In the present study, a distearoylphosphatidyl ethanolamine-polyethylene glycol-pemetrexed （DSPE-PEG2000-PMT） conjugate was synthesized from DSPE-PEG2000-NH2 and pemetrexed, and targeted sunitinib plus vinorelbine liposomes were developed by modifying DSPE-PEG20o0-PMT onto the surface of liposomes to overcome the MDR of breast cancer. The synthesized DSPE-PEG2000-PMT was confirmed to be consistent with the target product by matrix-assisted laser desorption/ionization time of flight mass spectrometry （MALDI-TOF-MS）. The concentrations of sunitinib and vinorelbine were measured simultaneously by high performance liquid chromatography （HPLC）. The analysis was performed on an ODS column at 30℃ at a wavelength of 215 nm with the mobile phase consisting of acetonitrile, 0.05 M KH2PO4 （pH 3.5） and triethylamine （35：65：0.3, v/v/v）. The limits of detection for sunitinib and vinorelbine were 25 ng/mL and 5 ng/mL, respectively, and the limits of quantification for both drugs were 0.25μg/mL. Two drugs were linearly correlated in the range of 0.5-25.0 μg/mL. For varying types of liposomes, the encapsulation efficiencies were 〉90%; the particle sizes were approximately 90 nm, and zeta potentials were slightly negative. The inhibitory effects were evaluated in the resistant breast cancer MCF-7/Adr cells. The results revealed that targeted sunitinib plus vinorelbine liposomes exhibited the strongest inhibitory effect to the resistant MCF-7/Adr cells among the varying formulations. Targeted coumarin liposomes were used as a fluorescent probe to evaluate the targeting effect to resistant breast cancer MCF-7/Adr cells. The results demonstrated that the targeted coumarin liposomes displayed the highest cellular uptake compared to non-targeted formulations. In conclusion, the targeted sunitinib plus vinorelbine liposomes represented a novel type of nano-formulations, which could accumulate in the resistant breast cancer cells, thereby inhibiting proliferation of the resistant cancer cells. Accordingly, the targeted sunitinib plus vinorelbine liposomes may provide a new strategy for circumventing the drug resistance in the resistant breast cancer.

Inhibition effects of using sequential microtubule depolymerization drug and polymerization drug on tumor cells

Objective: To investigate the different inhibition effects of different sequential usages of microtubule depolymerization drug and polymerization drug on tumor cells. Methods: Three tumor cell lines including MCF-7, SK-OV3, A549 were incubated with paclitaxel (PTX) and/or vinorelbine (NVB) of different concentrations. The cyto-toxicity was exam- ined by MTT test after incubating 72 h. According to different drugs and different sequences added to 96-well tissue culture plates, 5 groups were divided: PTX group (Group 1), NVB group (Group 2), PTX plus NVB group (Group 3), PTX first and NVB 4-h-later group (Group 4), and NVB first and PTX 4-h-later group (Group 5). Drug concentrations were 100% peak plasma concentration (PPC), 50% PPC, 25% PPC, 12.5% PPC, and 6. 25% PPC. Results: The inhibition effects on the three tumor cell lines in Group 5 were stronger than those in the other four groups (P < 0.01). And the inhibition effects in Group 4 were not stronger than those in Groups 1, 2 or 3 (P > 0.1). Conclusion: Using microtubule depolymerization drug first and then using microtubule polymerization drug has synergic inhibition effect on tumor cells.