Search

Background: BI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880., Methods: Two Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard therapy was not reliably effective. Two dosing schedules were investigated, 3 weeks (q3w) or once weekly (qw), starting at a dose of 40 mg. In a comprehensive biomarker approach, soluble pharmacodynamic markers (free and total plasma VEGF-A and Ang-2), as well as circulating angiogenic factors (soluble VEGF3, soluble Tie2 and placenta growth factor, amongst others) were analyzed to assess target engagement in peripheral blood for q3w doses. A Population based pharmacokinetics/pharmacodynamics (PopPK/PD) model was built using the limited Phase I dataset to support dose finding by simulations. In order to demonstrate drug activity in the tumor, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was applied., Results: DCE-MRI scans supported target engagement in the tumor. Free VEGF-A was depleted at all doses, whereas free Ang-2 decreased dose-dependently, reaching depletion in most patients from 360 mg q3w onwards. While total VEGF-A levels increased in a dose-dependent manner, reaching saturation at 360 mg q3w, total Ang-2 levels increased, but did not plateau. Angiogenic biomarkers showed changes from doses ≥ 360 mg q3w. PopPK/PD modeling showed that doses ≥ 360 mg q3w led to > 90% inhibition of free Ang-2 at steady-state in most patients. By increasing the dose to ≥ 500 mg q3w, > 90% of patients are expected to achieve this level., Conclusions: The comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule., Trial Registration: NCT02674152 and NCT02689505., (© 2024. The Author(s).)

Background: Clinical studies of antivascular endothelial growth factor (anti-VEGF) agents have demonstrated that angiogenesis is critical to colorectal cancer (CRC) tumor growth and metastasis. Nintedanib is a triple angiokinase inhibitor of VEGF, platelet-derived growth factor, and fibroblast growth factor signaling. Nintedanib, combined with docetaxel, has been approved in the European Union for the treatment of patients with non-small-cell lung cancer with adenocarcinoma tumor histologic type after first-line chemotherapy. The objective of the present study (1199.52; clinicaltrials.gov identifier NCT02149108; LUME-Colon 1) is to evaluate the efficacy and safety of nintedanib plus best supportive care (BSC) in patients with advanced colorectal cancer refractory to standard chemotherapy regimens and biologic agents., Patients and Methods: A total of 764 patients worldwide will be randomized 1:1 to receive either nintedanib 200 mg twice daily plus BSC or placebo plus BSC in 21-day courses until disease progression, undue toxicity, or withdrawal of informed consent. The primary endpoints are progression-free survival (PFS) and overall survival (OS). The secondary endpoints are the objective tumor response and disease control. PFS and OS will be evaluated using a log-rank test to determine the effect of nintedanib independently at the 2-sided α-level of 0.05. Other assessments will include the frequency and severity of adverse events and changes in laboratory parameters to measure the safety, health-related quality of life, and pharmacogenomic analyses, focusing on exploring the predictive biomarkers and drug-resistance mechanisms. The results are expected in 2016., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Osteogenic properties of bone cells are a key parameter governing osseointegration of implant devices. In this context, osteoblasts have a central role via extracellular matrix synthesis and remodeling that they regulate through different protease activity. In this study, we have analyzed the expression of two matrix metalloproteinases (MMPs): MMP-2 (72 kDa) and MMP-9 (92 kDa) and their specific tissue inhibitors TIMP-1 and TIMP-2 in primary human osteoblastic cells. The effect of titanium, zirconia, and alumina ceramics on the synthesis of these proteases was assessed using reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and zymographic analysis. Our results showed that osteoblasts express MMP-2 and -9 mRNA. Furthermore, MMP-2 mRNA expression was decreased by titanium and increased by alumina whereas zirconia did not have any significant effect. Conversely, MMP-9 mRNA expression was stimulated by titanium but decreased with zirconia, whereas alumina induced no significant changes. Zymographic analysis has evidenced pro-MMP-2 gelatinolytic activity in all cell populations with time-dependent increase profile; pro-MMP-9, however, was not detected. Enzyme-linked immunosorbent assay data confirmed the production of MMP-2 and very low levels of MMP-9. In addition, TIMP-1 was secreted in 24-h-cultured cells and increased to maximal level at 48-72 h whereas TIMP-2 levels were very low. The interactions between human osteoblasts and the studied biomaterials altered both MMP-2, -9 and TIMP-1expression indicating that biomaterials may influence osseointegration and bone remodeling., (Copyright 2003 Wiley Periodicals, Inc. J Biomed Mater Res 68A: 114-122, 2004)

The effects of Verapamil and S9788 (triazineaminopiperidine), a new modulator of multidrug resistance, on mdr-1 mRNA expression were determined using in situ hybridization. S9788 appeared to be a better reversal drug by strongly decreasing drug efflux. However, Verapamil only decreased mdr-1 mRNA expression in Human erythroleukemic resistant cells (ADM/k562) and in Human lymphoblastic resistant cells (VLB/CEM). This effect occurred in all Verapamil-treated resistant cells with no difference between cell subpopulations. These results were confirmed by slot-blot experiments. In conclusion, S9788 and verapamil effects are comparable overall although the mechanisms responsible for this resistance modulation are not strictly identical.

Nuclear morphological alterations associated with multidrug resistance (MDR) were evaluated by image cytometry in various human leukemic cell sub-lines: 3 cell lines with P-gp-mediated resistance (CEM-VLB, HL60/Vinc, K562-Dox), the non-Pgp-mediated MDR HL60/AR leukemic cell line with over-expression of MRP, and the at-MDR CEM-VMI leukemic cell line with alteration of topoisomerase II. All these MDR cell sub-lines were obtained by drug selection and were compared with their sensitive counterparts and with the hamster LR73-R cell line obtained by transfection of mouse mdrl cDNA. All MDR cell sub-lines obtained by drug selection displayed decreased DNA Feulgen stainability as compared with their respective sensitive parental cell line, a phenomenon not observed in the transfected LR73-R cells. Nuclear texture analysis on G0/G1-selected cell nuclei revealed 2 types of textural phenotype. The first phenotype was characterized by chromatin decondensation with small but compact chromatin clumps, and was observed in drug-selected P-gp-mediated MDR cells (CEM-VLB, HL60-Vinc, K562-Dox) and in the non-P-gp-mediated MDR HL60/AR cell line. The second phenotype was characterized by a condensed and homogeneous chromatin pattern, and was observed in the at-MDR CEM-VMI cell line. LR73-R cells transfected with mdrl cDNA did not display any significant changes in textural phenotype as compared with sensitive LR73 cells, suggesting that P-gp over-expression alone cannot account for the cytological modifications observed in MDR cells. These data suggest that multidrug resistance could be associated with specific nuclear morphological changes which appeared to be a consequence of alterations occurring during selection by cytotoxic drugs rather than of P-gp over-expression.

The triazinoaminopiperidine derivative S 9788 is a new multidrug resistance modulator. The modulating activity of S 9788, comparatively to those of verapamil and the combination of S 9788 and verapamil, was demonstrated on the human leukemic T cell line CCRF-CEM resistant (about 6000 fold) to vinblastine using Microculture Tetrazolium Assay. S 9788 at 5 microM, strongly potentialized the cytotoxic activity of vinblastine but the reversion of resistance remained partial. Verapamil and the combination S 9788-verapamil, tested at equimolar concentrations, were respectively 1000 and two times less active than S 9788 alone. The impact of S 9788, verapamil and their combination on the cytological modifications bound to vinblastine resistance of CEM cells was evaluated by multiparametric quantitative cytological analysis (21 nuclear parameters measured) using a SAMBA 2005 cell image processor. Treatments with the different modulators, in absence or in presence of vinblastine, had no significant effects on the morphology of sensitive CEM cells. On vinblastine resistant CEM cells, S 9788 and the combination S 9788-verapamil induced significant cytological modifications. These modifications were characterized by a partial reversion of some parameters (more specifically nuclear texture parameters) to values close to those observed in parental sensitive cells and permitted an automatic classification of these treated resistant cells in cells of "sensitive" type with a percentage superior to 50%. In conclusion, the reversion of resistance induced by S 9788 on CEM cells resistant to vinblastine does not fit only with a biological phenomenon like the efflux of cytotoxic agents but is associated with a set of cellular alterations involved in multidrug resistance.

The induction of differentiation is at present one of the most promising pathway used in the field of cancer chemotherapy. As part of this research, the study of the human K562 erythroleukemic cells differentiation has shown that these cells are potent to synthesize hemoglobin when treated by 40 nmoles/l of adriamycin, 30 nmoles/l of aclacinomycin or 3.10(4) nmoles/l of hemin. This functional differentiation is accompanied by some changes in three membrane antigens expression: GPA, CD15 antigen and TfR. To complete these result, we have studied the differentiation of resistant K562 cells to adriamycin by these three inducers. Our results suggest that this cell population is able to synthesize hemoglobin after its exposition to 2.10(3) nmoles/l of adriamycin, 100 nmoles/l of aclacinomycin or 7, 5.10(4) nmoles/l of hemin. In contrary to aclacinomycin and adriamycin, hemin did not affect the three markers expression. On the other hand, only the induction by adriamycin causes membrane phenotypical changes which are erythroid differentiation specific.