Author: Stefan Rehnmark ; Johannes Eimer ; Matthias Löhr ; Caroline Verbeke ; Annika Wagman ; Xiaohui Jia ; Rune Toftgård ; Rainer L Heuchel ; Michael-Robin Witt ; Paola Longati

AbstractBackgroundPancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer related death. It is lethal in nearly all patients, due to an almost complete chemoresistance. Most if not all drugs that pass preclinical tests successfully, fail miserably in the patient. This raises the question whether traditional 2D cell culture is the correct tool for drug screening. The objective of this study is to develop a simple, high-throughput 3D model of human PDAC cell lines, and to explore mechanisms underlying the transition from 2D to 3D that might be responsible for chemoresistance.MethodsSeveral established human PDAC and a KPC mouse cell lines were tested, whereby Panc-1 was studied in more detail. 3D spheroid formation was facilitated with methylcellulose. Spheroids were studied morphologically, electron microscopically and by qRT-PCR for selected matrix genes, related factors and miRNA. Metabolic studies were performed, and a panel of novel drugs was tested against gemcitabine.ResultsComparing 3D to 2D cell culture, matrix proteins were significantly increased as were lumican, SNED1, DARP32, and miR-146a. Cell metabolism in 3D was shifted towards glycolysis. All drugs tested were less effective in 3D, except for allicin, MT100 and AX, which demonstrated effect.ConclusionsWe developed a high-throughput 3D cell culture drug screening system for pancreatic cancer, which displays a strongly increased chemoresistance. Features associated to the 3D cell model are increased expression of matrix proteins and miRNA as well as stromal markers such as PPP1R1B and SNED1. This is supporting the concept of cell adhesion mediated drug resistance.

01 Dec 2007·Journal of Chromatography AQ2 · CHEMISTRY

Mechanically stable porous cellulose media for affinity purification of family 9 cellulose-binding module-tagged fusion proteins

Q2 · CHEMISTRY

Article

Author: Jenny Bryan ; Mojgan Kavoosi ; Douglas G. Kilburn ; Dexter Lam ; Charles A. Haynes

A mechanically stable cellulose-based chromatography media was synthesized to permit inexpensive affinity purification of recombinant proteins containing the family 9 carbohydrate-binding module (CBM9) fused to either the N- or C-terminus of the target protein. A second-order response surface model was used to identify optimal concentrations of the primary reactants, epichlorohydrin and dimethyl sulfoxide (DMSO), required to cross-link the starting material, Perloza MT100, a compressible but inexpensive cellulose-based chromatography resin. This resulted in a mechanically stable cross-linked affinity chromatography media capable of operating at an order-of-magnitude higher linear velocity than permitted by unmodified MT100. Moments and Van Deemter analyses were used to show that rates of solute mass transfer within the column are largely unaffected by the cross-linking reaction, while the binding capacity decreased by 20% to 7.1 micromol of protein/g resin, a value superior to most commercial affinity chromatography media. In sharp contrast to MT100, the mechanical stability and purification performance of the cross-linked media are not diminished by scale-up or repeated column use.

01 Jan 2006·Drugs in R & DQ4 · MEDICINE

Metoclopramide/Naproxen-Sodium, MT??100, Naproxen-Sodium/Metoclopramide

Q4 · MEDICINE

ReviewOA

Author: &NA;

A review.Naproxen sodium/metoclopramide (MT 100), an orally-administered formulation developed by POZEN for the treatment of migraine, combines metoclopramide, a dopamine antagonist, and the NSAID naproxen, a cyclooxygenase inhibitor.Naproxen sodium/metoclopramide acts by releasing a set amount of metoclopramide followed by a set amount of naproxen.POZEN has made clear its desire to commercialize naproxen sodium/metoclopramide, following its approval, through licensing arrangements with pharmaceutical companies.In July 2003, Nycomed Danmark ApS obtained the exclusive rights to market naproxen sodium/metoclopramide in Scandinavia and Iceland.Under the terms of the agreement, Nycomed was to pay POZEN an upfront fee, as well as future milestone and royalty payments.Naproxen sodium/metoclopramide (MT 100) was approved in the UK in Nov. 2005 for use in the treatment of migraine.POZEN is now expected to seek approval in the EU through the Mutual Recognition Procedure.A rolling NDA was submitted to the US FDA in July 2003 for the marketing approval of naproxen sodium/metoclopramide for the acute treatment of migraine.In August 2005, the FDA Peripheral and Central Nervous Systems Drugs Advisory Committee voted that the potential, but unquantified, risk for tardive dyskinesia associated with the use of naproxen sodium/metoclopramide would outweigh the benefits of this combination.Based on the outcome of this meeting, POZEN announced that it would discontinue further development of the product in the US.The company explained that it would instead concentrate its development efforts on other more promising drug candidates in its pipeline.POZEN has two US patents relating to naproxen sodium/metoclopramide.The company also holds an Australian patent.Two of the patents expire in 2016.POZEN also has patent applications pending in Canada, Europe and Japan.

100 Deals associated with Naproxen Sodium/Metoclopramide Hydrochloride

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Indication	Country/Location	Organization	Date
Migraine Disorders	GB	POZEN, Inc.	24 Nov 2005

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Indication	Highest Phase	Country/Location	Organization	Date
Migraine Disorders	Discovery	US	POZEN, Inc.	-

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