(A) Relative changes and (B) normalized histograms of ADC for each group in PC9 xenografts

(A) Relative changes and (B) normalized histograms of ADC for each group in PC9 xenografts. (PDF) Click here for additional data file.(194K, pdf) S4 FigHistological staining of tumor vessels in PC9 mice tissues. Representative immunohistochemical images of CD31-immunostaining for each group (100X). (B) MVD in tumor tissue was counted in three randomly chosen. Columns, mean; Bars, SD.(PDF) pone.0187824.s004.pdf (261K) GUID:?7440A9A6-69ED-42BD-99DC-C142B11C9817 Data Availability StatementAll relevant data are within the paper and its Supporting Information files. Abstract This study aimed to investigate the therapeutic responses of lung cancer mice models with adenocarcinoma HCC827 (gefitinib sensitive) and HCC827R (gefitinib resistant) to the epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib alone and in combination with the anti-angiogenesis agent bevacizumab using dynamic contrast enhanced (DCE) and diffusion-weighted MRI. In the HCC827 model, temporal changes in DCE-MRI derived parameters (and significantly decreased at week 2 in the groups receiving erlotinib alone and in combination with bevacizumab, whereas decreased at week 1 and 2 in both treatment groups. In addition, there was a significant difference in between the treatment groups at week 1. Compared to the control group of HCC827, there was a significant reduction in microvessel density and increased tumor apoptosis in the two treatment group. ADC value increased in the erlotinib alone group at week 1 and week 2, and in the erlotinib combined with bevacizumab group at week 2. Enlarged areas of central tumor necrosis were associated with a higher ADC value. However, progressive enlargement of the tumors but no significant differences in DCE parameters or ADC were noted in the HCC827R model. These results showed that both erlotinib alone and in combination with bevacizumab could effectively inhibit tumor growth in the gefitinib-sensitive lung cancer mice model, and that this was associated with decreased vascular perfusion, increased ADC percentage, decreased microvessel density, and increased tumor apoptosis with a two-week treatment cycle. Introduction Lung cancer is the most common cause of cancer-related death worldwide, and it is a significant public health problem associated with a poor prognosis under current therapeutic options [1]. Recent advances in cancer therapeutics have FG-4592 (Roxadustat) shown that identifying molecular targets for lung cancer treatment FG-4592 (Roxadustat) such as vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) is important to improve patient survival. VEGF is a pro-angiogenic factor which binds membrane receptors, and its intra-cytoplasm domain presents tyrosine kinase activity. Angiogenesis is considered to be important for tumor growth, metastasis and patient prognosis [2C4]. Targeted therapy against angiogenesis can lead to regression or normalization of neovascular structures, and the inhibition of new blood vessel growth. Bevacizumab (Avastin, Genentech/Roche) is a monoclonal antibody that selectively binds to VEGF and prevents interactions with its receptor. It was shown to significantly prolong progression-free survival (PFS) and overall survival when added to doublet chemotherapy in Eastern Cooperative Oncology Group (ECOG) study E4599, and to prolong PFS in the Avastin in Lung (AVAiL) study. Bevacizumab is approved for patients with advanced non-squamous non-small cell lung cancer (NSCLC) [5C7]. However, responses to bevacizumab alone have been reported to be transient and susceptible to resistance, so that other targets for the treatment of patients with NSCLC are needed [8]. Somatic mutations in the EGFR gene have been identified in patients who respond to EGFR-tyrosine kinase inhibitors (TKIs) [9C11]. The two most common EGFR mutations are deletions of exon 19 that eliminate a leucine-arginine-glutamate-alanine motif in the tyrosine kinase domain of EGFR, and L858R point mutations in exon 21 that result in substitution of arginine for leucine at amino acid 858 [12]. Gefitinib and erlotinib target the EGFR tyrosine kinase detectable in most cases of NSCLC. Phase II and III trials have shown partial responses in 8% to 12% of patients with progressive NSCLC after chemotherapy [13C16]. In addition, a phase II study suggested synergistic activity in first-line treatment with a combination of bevacizumab and erlotinib in stage IIIb/IV NSCLC [17], and the addition of bevacizumab to erlotinib has been reported to Rabbit polyclonal to Icam1 prolong PFS in patients with NSCLC with activating EGFR mutations compared with erlotinib alone [18]. The phase FG-4592 (Roxadustat) II trial (BELIEF) also provided evidence of benefit for the combination of erlotinib and bevacizumab in patients with EGFR-mutant NSCLC [19]. Research into the mechanism and therapeutic response of lung cancer to variable treatment strategies and the development of new.