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25 years after the first approval of cisplatin in the clinic against a number of cancer diseases, cisplatin and related compounds continue to be among the most efficient anticancer drugs used so far. Efforts are focused to develop novel platinum- and non-platinum-based antitumor drugs to improve clinical effectiveness, to reduce general toxicity and to broaden the spectrum of activity. In the field of non-platinum compounds exhibiting anticancer properties, ruthenium complexes are very promising, showing activity on tumors which developed resistance to cisplatin or in which cisplatin is inactive. Furthermore, general toxicity was found to be very low. The first ruthenium compound NAMI-A entered phase I clinical trials in 1999 as an antimetastatic drug, whereas the ruthenium complex KP1019 will enter phase I clinical trials in 2003 as an anticancer drug which is among others very active against colon carcinomas and their metastases. Remarkable progress is also seen in developing tumor inhibiting gallium compounds. One of them, KP46, will also enter phase I clinical trials in 2003. This article reviews briefly the achievements in the field of anticancer metal complexes focusing the discussion onto the impact of the group of Bioinorganic Chemistry at the Department of Inorganic Chemistry at the University of Vienna. The development of pH sensitive platinum prodrugs, platinum-based drug targeting strategies with low-molecular-weight carriers, kinetically inert platinum(IV) complexes, as well as tumor inhibiting non-platinum anticancer drugs based on ruthenium and gallium is covered in the following sections.

Magnetic resonance imaging (MRI) requires synthesis of contrast media bearing targeting groups and numerous gadolinium chelating groups generating high relaxivity. This paper explores the results of linking the gadolinium chelates to the targeting group, a protein molecule, via various types of linkers. Polycondensates of diethylenetriaminepentaacetic acid (DTPA) with either diols or diamines were synthesised and coupled to the targeting group, a lectin ( Lycopersicon esculentum agglutinin , tomato lectin) which binds with high affinity to specific oligosaccharide configurations in the endothelial glycocalyx. The polycondensates bear up to four carboxylic groups per constitutive unit. Gd-chelate bonds are created through dative interactions with the unshared pair of electrons on each oxygen and nitrogen atom on DTPA. This is mandatory for complexation of Gd(III) and avoidance of the severe toxicity of free gadolinium ions. The polymer–DTPA compounds were characterised by 1 H NMR and mass spectrometry. The final lectin–DTPA–polycondensate conjugates were purified by fast protein liquid chromatography (FPLC). The capacity for specific binding was assessed, and the MRI properties were examined in order to evaluate the use of these oligomers as components of selective perfusional contrast agents.

The origin of activity differences between stereoisomers of anticancer platinum(II) complexes chelated with chiral diamine ligands has been almost exclusively explained by diastereoselective interactions with DNA. Although this model has been widely accepted in vitro and in vivo experiments showed some conflicting results, leading to the conclusion that other biomolecules might be responsible for this stereoselectivity as well. These compounds, called bionucleophiles, are in most instances amino acids or proteins present in biological fluids. As these chiral molecules are very reactive towards the platinum complexes, they may contribute to stereoselectivity, but also to resistance and toxicity. This review gives a general survey of chiral platinum(II) complexes and their interactions with DNA. The bionucleophiles which have been identified and the consequences of their reaction with platinum(II) complexes are discussed. Analytical techniques used to investigate interactions between established and potential chiral platinum drugs and bionucleophiles are presented.

Purpose Non-specific extracellular contrast agents have been on the market for more than 15 years. Here, we report on the synthesis of new selective lectin–gadolinium (Gd)-loaded chitosan nanoparticles with a prolonged clearance time and a much higher relaxivity in comparison to other preparations. Procedures Chitosan nanoparticles were prepared from 85% deacetylated chitin by glutaraldehyde cross-linking of an aqueous acetic acid dispersion of chitosan in a mixture of n -hexane using sodium bis(ethylhexyl)sulfosuccinate as a surfactant. Results Several crucial parameters, namely, the Gd and protein content of the nanoparticles, their size and dispersity were determined. Magnetic resonance measurements were carried out by intravenous perfusion of mono-disperse suspensions of the nanoparticles into mice. Conclusions Chitosan nanoparticles can be used as contrast agents in magnetic resonance imaging (MRI). They are excellent candidates for controlled delivery of bioactive compounds to molecular targets and as biospecific diagnostic tools in MRI.

Interaction of cis-[Pt(NH3)2Cl2] (cisplatin) with 5′-guanosine monophosphate (5′-GMP) has been investigated for the first time by on-line coupling of high performance ion chromatography (HPIC) to inductively coupled plasma sector field mass spectrometry (ICP–SFMS). The time-dependent reaction course of the cisplatin-5′-GMP system was followed after incubation under simulated physiological conditions by monitoring the decrease in the concentration of 5′-GMP and the increase in the concentration of formed adducts, on the basis of speciation analysis. Because of the two-step mechanism an intermediate mono adduct was observed together with the major product, the bis adduct cis-[Pt(NH3)2(GMP)2]2–. The data obtained correlated well with those from earlier studies employing orthogonal techniques such as capillary electrophoresis (CE). Furthermore, HPIC–ICP–SFMS provided unambiguous stoichiometric information about the major GMP-adduct. For this purpose the platinum-to-phosphorus ratio was determined by simultaneously measuring 31P and 195Pt. To separate significant interferences from 15N16O+, 14N16O1H+, 12C18O1H+, and 13C17O1H+ on 31P, high-mass resolution (m/Δm = 4500) proved to be mandatory. The P/Pt signal ratio of 2/1 obtained corresponds to the molar ratio in the bis adduct cis-[Pt(NH3)2(GMP)2]2–.

Zielsetzung. Bei der endoluminalen Versorgung des Bauchaortenaneurysmas (BAA) stellen der kurze infrarenale Aneurysmahals, die Endoleckage und die großen steifen Einführsysteme wesentliche Problemstellen dar, die zu Komplikationen bzw. suboptimalen Ergebnissen führen. Ziel der vorliegenden Übersichtsarbeit ist es, mit Hilfe der tierexperimentellen Literaturergebnisse Vorgehensweisen bzw. Empfehlungen zur Vermeidung dieser Komplikationen vorzustellen.Material und Methode. Nach Überdeckung der Nierenarterien mit verschiedenen Stentarten wurden die Auswirkungen auf die Nierenfunktion sowie auf die Nierenmorphologie von verschiedenen Arbeitsgruppen untersucht. Um eine progressive Erweiterung des proximalen Aneurysmahalses und somit eine Endograftdislokation zu vermeiden, wurde von Sonesson ein laparoskopisches “Banding” der Aorta im Bereich des proximalen Halses bei Schweinen durchgeführt. Zur Überprüfung der Auswirkung von Endoleckagen führten Marty, Schurink und Pitton Druckmessungen in experimentellen Aneurysmen mit und ohne Endoleckagen durch. Zur Verkleinerung der Einführbesteckgrößen wurden von Sakaguchi und Pavcnik die “Twin-tube endografts” (TTEG) und die ”Bifurcated drum occluder endografts“ (BDOEG) entwickelt und deren Effektivität bei Hunden überprüft.Ergebnisse. Chavan et al. beobachteten keinen signifikanten Abfall der mittleren Inulinclearance in Verlauf von 3 Monaten nach Überdeckung der Nierenarterienabgänge (140±46 ml/min vorher, 137±58 ml/min nachher). Nasim et al. und Malina et al. beobachteten ähnliche Ergebnisse bzgl. der Nierenfunktion. Die suprarenale Verankerung führte zu vereinzelten thrombotischen Verschlüssen und Mikroinfarkten. Nach “Banding” der Aorta waren die Aortendurchmesser der Versuchsgruppe in Höhe des Bandes signifikant kleiner als die der Kontrollgruppe (8 mm Versuchsgruppe, 11 mm Kontrollgruppe, p=0,004). Das Banding sorgte für eine sichere Verankerung des Stent-grafts. Persistierende Endoleckagen führten zu signifikant hohen intraaneurysmatischen Drucken. Obwohl die TTEG- und die BDOEG-Stentgrafts kleinere Einführbestecke benötigten, wurden Schenkelverschlussraten von 8% (TTEG) und 60% (BDOEG) beobachtet.Diskussion. Die suprarenale Verankerung des Stentgrafts verursacht keine signifikante Beeinträchtigung der Nierenfunktion. Stentgraft-designabhängig können vereinzelte, thrombotische Verschlüsse der Nierenarterien oder Mikroinfarkte vorkommen. Ein Band-ing des Aneurysmahalses kann eine progressive Erweiterung im Verlauf und somit eine Stentgraftdislokation verhindern. Zur Senkung der Endoleckagenraten wäre vor der Graftimplantation eine Embolisation größerer Seitenäste, insbesondere aus Aneurysmen ohne wandständige Thrombusbildung, empfehlenswert. Zur Senkung der hohen Schenkelverschlussraten sollten die TTEG- und die BDOEG-Systeme noch verfeinert werden. Eine rationale Umsetzung der vorliegenden tierexperimentellen Ergebnisse in die klinische Praxis könnte zu einer deutlichen Verbesserung der Behandlungsergebnisse bei der endoluminalen Versorgung von Bauchaortenaneurysmen führen.

Here, we describe a 20-yr-old woman with COACH syndome (hypoplasia of Cerebellar vermis, Oligophrenia, congenital Ataxia, Coloboma, and Hepatic fibrosis) developing multiple liver lesions. Epigastric and right upper abdominal pain and lack of appetite led to clinical evaluation. Liver function tests showed an increase in transaminases and cholestatic parameters; α-fetoprotein was in the normal range. Ultrasound and magnetic resonance imaging examinations revealed multiple liver lesions. Histological examinations of ultrasonographically guided biopsies were consistent with regenerative hepatic nodules without features of malignant or dysplastic cells. The sizes of these tumors did not change over a period of 12 months. Our report presents the 10th case of COACH syndrome with a hitherto undescribed association with hepatic tumors.

Research in the field of bioinorganic chemistry has been stimulated by the worldwide success of the anticancer drug cisplatin. 40 years after the first report about its biological activity, carboplatin and oxaliplatin are in routine clinical use today, whereas nedaplatin, lobaplatin, and heptaplatin (SKI2053R) are only approved in Japan, China, and South Korea, respectively. Up to now, about 35 platinum complexes entered clinical trials in order to circumvent the side-effects and the problem of tumor resistance to cisplatin. Additionally, improvement of tumor selectivity as well as the need for a broader spectrum of indications are the motivations for tremendous efforts in the development of novel anticancer platinum-based drugs. New synthetic strategies and innovative analytical approaches provide a basis for a deeper understanding of the pharmacological profile of cisplatin and analogues (biodistribution, clearance, detoxification, sideeffects, tumor specificity, cellular uptake, acquired or intrinsic resistance, platinum-DNA adduct removal by the cellular machinery) and give rise to a rational design of promising anticancer platinum coordination compounds. This article reviews the recent development of preclinical platinum complexes with interesting in vitro and in vivo tumor inhibiting properties. It focuses also on innovative synthetic strategies leading to novel classes of platinum complexes. A small part of the review is dedicated to new analytical approaches which have been supplied to or emerged in this field of research.

AbstractPlatinum(IV) complexes are promising candidates as prodrugs for oral application in anticancer chemotherapy. However, only a few Pt(IV) compounds entered (pre)clinical trials, e.g. satraplatin, while most of the others were only tested in vitro. Aim of the study was investigation of the in vivo pharmacological behavior as well as the anticancer activity of two novel platinum(IV) complexes vs. satraplatin. The drugs were selected due to significantly different in vitro cytotoxicity while sharing some physicochemical properties (e.g. lipophilicity). Initial experiments indicated that the highly in vitro cytotoxic compound 1 ((OC-6-33)-dichloridobis((4-ethoxy)-4-oxobutanoato)-bis(ethylamine)platinum(IV)) was also characterized by high drug absorption and tissue platinum levels after oral application. Interestingly, analysis of serum samples using SEC-ICP-MS revealed that the administered drugs have completely been metabolized and/or bound to proteins in serum within 2 h after treatment. With regard to the activity in vivo, the outcomes were rather unexpected: although potent anticancer effect of 1 was observed in cell culture, the effects in vivo were rather minor. Nevertheless, 1 was superior to 2 ((OC-6-33)-diammine(cyclobutane-1,1-dicarboxylato)-bis((4-cyclopentylamino)-4-oxobutanoato)platinum(IV)) after i.p. administration, which was, at least to some extent, in accordance to the cell culture experiments. After oral gavage, both compounds exhibited comparable activity. This is remarkable considering the distinctly lower activity of 2 in cell culture as well as the low platinum levels detected both in serum and tissues after oral application. Consequently, our data indicate that the prediction of in vivo anticancer activity by cell culture experiments is not trivial, especially for orally applied drugs.Graphical Abstract

Forty years after the discovery of the anticancer effects of cisplatin, scientists are still pursuing the development of platinum complexes with improved properties regarding side effects and resistance, which are two main problems in cisplatin treatment. Among these compounds, trans-configured platinum complexes with oxime ligands emerged as a new class with features distinct from those of established anticancer agents, including different DNA binding behavior, increased cellular accumulation, and a different pattern of protein interaction. We report herein on the reactivity with biomolecules of three novel pairs of cis- and trans-configured acetone oxime platinum(II) complexes and one pair of 3-pentanone oxime platinum(II) complexes. Cellular accumulation experiments and in vitro DNA platination studies were performed and platinum contents were determined by inductively coupled plasma mass spectrometry. The trans-configured complexes were accumulated in SW480 cells in up to 100 times higher amounts than cisplatin and up to 50 times higher amounts than their cis-configured counterparts; rb values (number of platinum atoms per nucleotide) were more than tenfold increased in cells treated with trans complexes compared with cells treated with cisplatin. The interaction of the complexes with DNA was studied in cell-free experiments with plasmid DNA (pUC19), in capillary zone electrophoresis with the DNA model 2-deoxyguanosine 5′-monophosphate, and in in vitro experiments showing the degree of DNA damage in the comet assay. Whereas incubation with cis compounds did not induce degradation of DNA, the trans complexes led to pronounced strand cleavage.