Addition of bevacizumab enhances antitumor activity of erlotinib against non-small cell lung cancer xenografts depending on VEGF expression

Li, Heyan; Takayama, K.; Wang, Shuo; Shiraishi, Yuji; Gotanda, Keisuke; Harada, Taishi; Furuyama, Kazuto; Iwama, Eiji; Ieiri, Ichiro; Okamoto, Isamu; Nakanishi, Yoichi

doi:10.1007/s00280-014-2610-x

Cited by 62 publications

(59 citation statements)

References 40 publications

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“…EGFR-mutated tumors display higher VEGF expression levels than wild-type EGFR tumors (16). EGFR-TKI-resistant tumors also produce greater levels of VEGF, and the amount of VEGF production varies according to the mutation type (17,18). These data may explain the favorable efficacy of Bev-containing chemotherapy in patients with EGFR exon 19 deletions.…”

Section: Discussionmentioning

confidence: 62%

A prospective cohort study of patients with non-squamous non-small cell lung cancer treated with bevacizumab

Naoki

Takeda²,

Soejima

et al. 2017

Oncology Letters

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Abstract. First-line chemotherapy regimens that include bevacizumab (Bev) have been hypothesized to improve outcomes in patients with advanced non-squamous non-small cell lung cancer (non-sq NSCLC). Although approved to treat NSCLC in 2009, insufficient data exist on the clinical uses of Bev in Japan. The present study prospectively evaluated the efficacy and safety of Bev-containing combination chemotherapy. Eligible patients exhibited histologically or cytologically documented advanced or recurrent non-sq NSCLC. Patients were administered 15 mg/kg Bev with standard chemotherapy followed by maintenance Bev. The primary endpoints were progression-free survival (PFS) and safety. A total of 102 patients with non-sq NSCLC were enrolled, 44.1% of whose tumor carried epidermal growth factor receptor (EGFR) mutations. The overall response rate to the intervention was 44.1%, and the median PFS was 8.3 months [95% confidence interval (CI)=6.4-10.2 months]. The median overall survival was 26.3 months (95% CI=22.2-30.4 months). The incidence of Bev-associated severe adverse events was similar to those in previous trials, excluding a grade 3-4 hypertension rate of 30.4% in the present study. Multivariate analysis revealed that a higher TNM classification of malignant tumor staging-T factor, adjusted hazard ratio (HR)=1.33 (95% CI=1.10-1.61), and poor performance status [adjusted HR=1.63 (1.02-2.60)] were associated with significantly shorter PFS, whilst the EGFR exon 19 deletion was significantly associated with prolonged PFS [adjusted HR=0.47 (0.25-0.87)]. Bev-containing chemotherapy was safe and effective for patients with non-sq NSCLC in clinical settings in Japan. The EGFR exon 19 deletion was suggested as a positive predictive factor for the efficacy of Bev-containing chemotherapy. IntroductionIn several clinical trials, first-line combination chemotherapies containing bevacizumab (Bev) were revealed to improve clinical outcomes in patients with advanced non-squamous non-small cell lung cancer (non-sq NSCLC) (1-3). Sandler et al (3) reported significant survival benefits, such as overall survival (OS) of >1 year (12.3 months), with addition of Bev to paclitaxel plus carboplatin in the treatment of non-sq NSCLC. Although Bev was approved for NSCLC in 2009 in Japan, there are insufficient data regarding the efficacy, toxicity and predictive markers for Bev treatment. The present study evaluated the efficacy and safety of Bev-containing combination chemotherapy in patients with non-sq NSCLC in clinical settings in Japan. Landmark survival analysis, or disease control at 8 weeks, was reported to be a more powerful predictor of subsequent survival compared with the traditional tumor response rate in advanced NSCLC (4). This may provide an early assessment of subsequent outcome. Since treatment with bevacizumab occasionally results in cavitary lesion without tumor shrinkage (5), stable disease may also be important for understanding drug efficacy. Therefore, landmark analysis was utilized in the present study. In addition, ...

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Section: Discussionmentioning

confidence: 62%

A prospective cohort study of patients with non-squamous non-small cell lung cancer treated with bevacizumab

Naoki

Takeda²,

Soejima

et al. 2017

Oncology Letters

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“…[17][18][19] VEGF and its receptors are frequently overexpressed in human tumors and inhibition of angiogenesis with bevacizumab, a monoclonal antibody that selectively binds to VEGF has shown promising clinical efficacy. [20][21][22][23][24] Multiple studies have shown that high VEGF expression in tumor or in serum is an indicator of prognosis of non-small cell lung cancer and response to anti-angiogenesis. 25,26 As such, VEGF SNP has been extensively investigated for its role in predicting cancer susceptibility, progression and anti-VEGF therapeutic response in subjects with tumors.…”

Section: Discussionmentioning

confidence: 99%

Correlation of genetic polymorphism of vascular endothelial growth factor gene with susceptibility to lung cancer

et al. 2015

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The aim of the study is to study the correlation of genetic polymorphism of vascular endothelial growth factor (VEGF) gene with susceptibility to primary lung cancer. A total of 414 patients with primary lung cancer and 338 healthy volunteers were enrolled in this case-control study from September 2008 to October 2011. Gene identification with PCR-RFLP (polymerase chain reaction-based restriction fragment length polymorphism) was used to detect in white blood cells from the subjects the single-nucleotide polymorphisms (SNP) of VEGF gene, including +405G/C, -460 T/C, -1154G/A, -2578C/A sites. Association of genotypes or haplotypes with susceptibility of lung cancer was analyzed with unconditional logistic regression adjusted by gender and age. Smoking was significantly associated with increased risk of lung cancer. Gene phenotypic analysis demonstrated that C allele of +405G/C in VEGF gene was significantly associated increased risk of lung cancer in males (P=0.0094, odds ratio=1.634.3), as that with carrying GCTC haplotype (odds ratio=1.349), whereas carrying GACG had decreased risk for lung cancer (odds ratio=0.044). No relationship existed between 460 T/C, -1154G/A, -2578C/A alleles of VEGF gene and risk of lung cancer. VEGF gene polymorphism may have a role in the development of lung cancer.

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“…The concentration of DNR in each tissue was calculated using high-performance liquid chromatography (HPLC) for subsequent determination of its distribution in tissues from the different groups. 23 …”

Section: Determination Of Dnr Concentration By High-performance Liquimentioning

confidence: 99%

Targeted multidrug-resistance reversal in tumor based on PEG-PLL-PLGA polymer nano drug delivery system

Guo

Zhang

Wang

et al. 2015

IJN

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The study investigated the reversal of multidrug resistance (MDR) and the biodistribution of nanoparticles (NPs) that target leukemia cells in a nude mice model via a surface-bound transferrin (Tf). The cytotoxic cargo of daunorubicin (DNR) and tetrandrine (Tet) was protected in the NPs by an outer coat composed of polyethylene glycol (PEG)-poly- l -lysine (PLL)-poly(lactic- co -glycolic acid) (PLGA) NPs. Injection of DNR-Tet-Tf-PEG-PLL-PLGA NPs into nude mice bearing MDR leukemia cell K562/A02 xenografts was shown to inhibit tumor growth, and contemporaneous immunohistochemical analysis of tumor tissue showed the targeted NPs induced apoptosis in tumor cells. Targeted tumor cells exhibited a marked increase in Tf receptor expression, with noticeable decreases in P-glycoprotein, MDR protein, and nuclear factor κB, as assessed by quantitative real-time polymerase chain reaction and Western blot analysis. Moreover, the concentration of DNR was shown to increase in plasma, tumor tissue, and major organs. Flow cytometry analysis with a near-infrared fluorescent (NIRF) dye, NIR797, was used to study the effectiveness of Tf as a targeting group for leukemia cells, a finding that was supported by NIRF imaging in tumor-bearing nude mice. In summary, our studies show that DNR-Tet-Tf-PEG-PLL-PLGA NPs provide a specific and effective means to target cytotoxic drugs to MDR tumor cells.

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Addition of bevacizumab enhances antitumor activity of erlotinib against non-small cell lung cancer xenografts depending on VEGF expression

Cited by 62 publications

References 40 publications

A prospective cohort study of patients with non-squamous non-small cell lung cancer treated with bevacizumab

A prospective cohort study of patients with non-squamous non-small cell lung cancer treated with bevacizumab

Correlation of genetic polymorphism of vascular endothelial growth factor gene with susceptibility to lung cancer

Targeted multidrug-resistance reversal in tumor based on PEG-PLL-PLGA polymer nano drug delivery system

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