PTK 787/ZK 222584, a tyrosine kinase inhibitor of all known VEGF receptors, represses tumor growth with high efficacy

The angiogenesis inhibitor PTK 787/ZK 222584 (PTK/ZK) blocks all known VEGF receptor (VEGFR) tyrosine kinases, including the lymphangiogenic VEGFR3, in the lower nanomolar range. From a panel of 100 kinases only PDGFR, c-kit, and c-fms are inhibited beyond those in the nanomolar range. PTK/ZK functions as a competitive inhibitor at the ATP-binding site of the receptor kinase as shown here in kinetic experiments. The VEGF signal blockade in microvascular endothelial cells (MVEC) results in a blockade of MVEC proliferation (IC50=30 nM), without affecting the proliferation of normal tissue cells and tumor cells. The efficacy of PTK/ZK depends on its continuous presence within the endothelial target cells. Early removal attenuates its antiproliferative activity in vitro. Growth inhibition of endothelial cells is fully reversible as demonstrated by "washout" experiments. Without inhibiting tumor cell proliferation directly, PTK/ZK results in a significant retardation of tumor growth in a number of experimental tumor models of different tissue origin. Combination of PTK/ZK with an antiandrogen revealed additive effects on tumor-growth inhibition. Treatment efficacy was monitored both by tumor weight and by the determination of serum concentrations of the surrogate marker PSA. PTK/ZK is currently being investigated in patients with different solid tumor types for its therapeutic utility. Preliminary data from phase I/II clinical trials of PTK/ZK as a monotherapy suggested a positive safety and tolerability profile, which we interpret to be a consequence of the high selectivity of the drug for a limited number of kinases. Preliminary response, time to progression, and overall survival data were promising.1 Based on these encouraging results, PTK/ZK is currently in Phase III clinical trials for metastatic colorectal cancer.     

Epothilones as lead structures for the synthesis-based discovery of new chemotypes for microtubule stabilization

Epothilones are macrocyclic bacterial natural products with potent microtubule-stabilizing and antiproliferative activity. They have served as successful lead structures for the development of several clinical candidates for anticancer therapy. However, the structural diversity of this group of clinical compounds is rather limited, as their structures show little divergence from the original natural product leads. Our own research has explored the question of whether epothilones can serve as a basis for the development of new structural scaffolds, or chemotypes, for microtubule stabilization that might serve as a basis for the discovery of new generations of anticancer drugs. We have elaborated a series of epothilone-derived macrolactones whose overall structural features significantly deviate from those of the natural epothilone scaffold and thus define new structural families of microtubule-stabilizing agents. Key elements of our hypermodification strategy are the change of the natural epoxide geometry from cis to trans, the incorporation of a conformationally constrained side chain, the removal of the C3-hydroxyl group, and the replacement of C12 with nitrogen. So far, this approach has yielded analogs 30 and 40 that are the most advanced, the most rigorously modified, structures, both of which are potent antiproliferative agents with low nanomolar activity against several human cancer cell lines in vitro. The synthesis was achieved through a macrolactone-based strategy or a high-yielding RCM reaction. The 12-aza-epothilone ("azathilone" 40) may be considered a "non-natural" natural product that still retains most of the overall structural characteristics of a true natural product but is structurally unique, because it lies outside of the general scope of Nature's biosynthetic machinery for polyketide synthesis. Like natural epothilones, both 30 and 40 promote tubulin polymerization in vitro and at the cellular level induce cell cycle arrest in mitosis. These facts indicate that cancer cell growth inhibition by these compounds is based on the same mechanistic underpinnings as those for natural epothilones. Interestingly, the 9,10-dehydro analog of 40 is significantly less active than the saturated parent compound, which is contrary to observations for natural epothilones B or D. This may point to differences in the bioactive conformations of N-acyl-12-aza-epothilones like 40 and natural epothilones. In light of their distinct structural features, combined with an epothilone-like (and taxol-like) in vitro biological profile, 30 and 40 can be considered as representative examples of new chemotypes for microtubule stabilization. As such, they may offer the same potential for pharmacological differentiation from the original epothilone leads as various newly discovered microtubule-stabilizing natural products with macrolactone structures, such as laulimalide, peloruside, or dictyostatin.     

Monitoring and Improving the Reliability of Plasma Spray Processes

Monitoring and improving of process reliability are prevalent issues in thermal spray technology. They are intended to accomplish specific quality characteristics by controlling the process. For this, implicit approaches are in demand to rapidly conclude on relevant coating properties, i.e., they are not directly measured, but it is assumed that the monitored variables are in fact suggestive for them. Such monitoring can be performed in situ (during the running process) instead of measuring coating characteristics explicitly (directly) and ex situ (after the process). Implicit approaches can be based on extrinsic variables (set from outside) as well as on intrinsic parameters (internal, not directly adjustable) having specific advantages and disadvantages, each. In this work, the effects of atmospheric plasma spray process variables are systemized in process schemes. On this basis, different approaches to contribute to improved process reliability are described and assessed paying particular attention to in-flight particle diagnostics. Finally, a new test applying spray bead analysis is introduced and first results are presented.     

Solving constrained combinatorial optimization problems via importance sampling in the grand canonical ensemble

Combinatorial optimization problems are usually NP-hard. These problems are generally tackled by heuristic or branch-and-bound methods. The aim of this paper is to tackle constrained combinatorial optimization problems by importance Monte Carlo sampling. For this, we show that every constrained combinatorial optimization problem can be represented by a thermodynamical system in a suitable grand canonical ensemble given by the quantities of temperature, volume, and chemical potential. In order to find optimum solutions of the optimization problem, the grand canonical Monte Carlo method can be applied to the corresponding thermodynamical system. This method will amount to importance sampling, i.e. good feasible solutions of the optimization problem will be preferably sampled, provided that the intensive quantities of temperature and chemical potential are appropriately chosen. Our approach extends the standard importance sampling approach in the canonical ensemble to tackle unconstrained combinatorial optimization problems. The knapsack problem is considered as a prototype example.     

Die Bestimmung von Schwefelanteilen im Stahl unter 10 μg/g

Analytische Möglichkeiten einer neuen Gerätegeneration. Weiterentwicklung des Verfahrens mit synthetischer Eichung bis zur Bestimmungsgrenze 2 μg/g.     

Festlegung der physikalischen Wirkzusammenhänge,Unterprogramm PHYWIZ,beim rechnerunterstützten systematischen Projektieren und Konstruieren

Aufgabe des Unterprogrammes PHYWIZ. Ermittlung physikalischer Funktionen zur Erfüllung der Funktionen der festgelegten logischen Funktionskette. Variante physikalische Funktionen und Mehrfachzuordnungen. Programmstruktur zur Berechnung physikalischer Wirkzusammenhänge. Behandlung der unmittelbar schnittstellenabhängigen Zusammenhänge. Vorgehen bei Überschreitung der Schnittstellenbedingungen. Bearbeitung der physikalischen Wirkzusammenhänge, die keinen Einfluß auf die Schnittstellenbedingungen haben können. Bewertung varianter Funktionsketten und endgültige Festlegung auf eine physikalische Funktionskette.     

Optimierung spektrometrischer Verfahren durch ein Datenverarbeitungssystem

Einsatz von Prozeßrechnern in Laboratorien. Aufbau eines Systems zur Produktionsüberwachung eines Sauerstoffaufblasstahlwerkes. Beschreibung des Rechners und der Programmgestaltung. Ablauf der emissionsspektrometrischen und röntgenfluoreszenzspektrometrischen Roheisen-, Stahl- und Schlackenanalysen. Erste Ergebnisse und Erfahrungen.     

Integral Antireflective Surface Production on Optical Glass

Integral antireflective surfaces with extremely high laser-damage thresholds were prepared on optical glasses by controlled corrosion in neutral solution. Properties of such surfaces are discussed and compared with gradient antireflective surfaces produced on phase-separated borositicate glasses.