Medizin‐Nobelpreis 2008: Papillomviren und Krebs

Unser Titelbild zeigt einen Schnitt durch ein mit HPV infiziertes Epithel. Mit verschiedenen Immunfluoreszenz‐ Farbstoffen werden die Replikation der HPV‐DNA (rot) und eines dafür wichtigen viralen Proteins (grün) sichtbar gemacht. Die Gegenfärbung mit DAPI (blau) zeigt die nicht infizierten Zellen. Mehr über Papillomviren, Gebärmutterhalskrebs und die Entwicklung von Impfstoffen gegen HPV lesen Sie in unserer Titelgeschichte, die auf Seite 22 beginnt. Die Abbildung wurde freundlicherweise von Dr. John Doorbar vom National Institute for Medical Research in London zur Verfügung gestellt.     

Papillomviren und Krebs. Wie aus einem Anfangsverdacht ein Impfstoff wurde

Since a long time epidemiologic studies suggested a sexually transmitted infectious agent as cause of cervical cancer. Human papillomaviruses (HPV) were considered as causative agents since members of the papillomavirus family can induce tumors in animals, and genital infections with papillomaviruses in man are common. Several discoveries ranging from the identification of the plurality of HPVs, the regular finding of genomes of certain, so called high‐risk HPV types within tumor biopsies, insights into the transforming mechanism and informative epidemiological surveys finally led to the conclusion within the scientific community of a causative link between these viruses and cervical cancer as well as other human malignancies. This awareness triggered the development of HPV‐specific vaccines as means of cancer prevention.     

Bernard Krebs

Ohne Zusammenfassung     

Krebs durch Chemikalien

Aristolochia as human carcinogen Aristolochic acid (AA), the active principle of the old drug Aristolochia ssp. has recently been classified as human carcinogen. The elucidation of the molecular mechanism of carcinogenesis of AA in animals led to the establishment of two specific biomarkers which were used to prove a causative role of AA in human cancers. These are AA‐DNA adducts, biomarkers of exposure to AA and AT→TA transversion mutations induced by these DNA adducts, biomarkers of effect. By detecting both biomarkers in individuals who ingested Aristolochia herbs during a weight‐reduction regimen in Belgium and in farmers in the Balkans where Aristolochia ssp are growing as weeds in cereal fields AA was identified as the cause for urothelial cancer and a disease of the kidney (AAN).     

Krebs,ein instabiler Regelkreis

Summary A uniform block diagram has been designed describing the normal cell increase as well as that of goodnatured and malignant tumours. It was shown that the various cancer diseases have their origin in changements of the structure data of the controller.Frequency and transition responses, locus diagrams, and stability conditions of the above mentioned cases were studied. The stability determination has shown that the instability of the automatic control loop for the cell increase in malignant tumours can be made stable by a chemotherapeuticum to be developed influencing the molecular structure of the regulator genes so that the frequency response of the controller regains its positive component in the portional band, which was lost in the course of the disease.Zusammenfassung Es wurde für die normale Zellvermehrung sowie für die gutartigen und malignen Tumoren ein gemeinsames Blockschaltbild entwoffen und das Entstehen der verschiedenen Krebserkrankungen auf Veränderungen der Strukturdaten des Reglers in den Regulatorgenen zurückgeführt.Die oben aufgeführten Fälle wurden hinsichtlich ihrer Frequenzgänge, Ortskurven, Übergangsfunktionen und Stabilität untersucht.Die Stabilitätsprüfung hat gezeigt, daß die Beseitigung der Instabilität des Zellvermehrungs-Regelkreises bei einem malignen Tumor denkbar ist, wenn es gelingt, z.B. ein Chemotherapeuticum zu entwickeln, welches den molekularen Aufbau der Regulator-Gene dahingehend beeinflußt, daß deren Reglerfrequenzgang im P-Glied den während des Krankheitsvorganges verlorengegangenen positiven Anteil wiedererlangt.

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Herrn Prof. Dr.-Ing. habil. Werner Krämer zum 65. Geburtstag.     

Krebs and his trinity of cycles

Everyone who has ever taken biology at school has heard of the Krebs cycle, but few realize that Hans Krebs also discovered two other cycles. It is appropriate, at the centenary of his birth, to consider the circumstances and experiments that led Krebs to establish these metabolic pathways.     

Ein Krebs für die Krebsforschung

A crayfish for cancer research Marmorkrebs (or marbled crayfish) is a triploid crayfish known since the mid‐1990s, which reproduces parthenogenetically. It originated from the North American decapod species Procambarus fallax and was distributed as a popular aquarium pet. Subsequent anthropogenic releases have resulted in the establishment of several stable populations in the wild that constitute a serious invasive threat. Interestingly, marbled crayfish use a parthenogenetic mode of reproduction that results in the generation of clones with minimal genetic variation. In addition, the animals can be easily bred and manipulated in the laboratory. These features establish marbled crayfish as a novel and innovative model organism for tumor biology, particularly for the analysis of clonal evolution and epigenetic adaptation of tumor genomes.     

Organization of Krebs tricarboxylic acid cycle enzymes

Binding of enzymes of the Krebs TCA cycle to biological membranes was characterized with respect to intracellular location, susceptibility to various chemical and physical treatments, and extractability as a macromolecular component of the mitochondrial inner membrane. It was shown that citrate synthase and malate dehydrogenase bind to the inner membrane in an ionic strength-sensitive, saturable, and specific manner to a relatively thermostabile component manifested on the inner (matrix) surface of the inner membrane of the mitochondrion. From these data several arguments in support of the physiological applicability of these processes were deduced, and the question of whether these two enzymes bind to the same or different membrane components was considered. Also, experiments preliminary to purification of the citrate synthase binding component were presented.     

Noninvasive tracing of Krebs cycle metabolism in liver

To quantify intrahepatic Krebs cycle metabolism, phenyl acetate, excreted in urine as a glutamine conjugate, was given to healthy subjects infused with [3-14C]lactate. They were studied after 60 h of fasting and when given glucose after an overnight fast. Distributions of 14C in glutamate from urinary phenylacetylglutamine and blood glucose were determined. Corrections to the distributions because of the fixation of 14CO2 formed from the [3-14C]lactate were determined by administering [14C]bicarbonate. Comparisons of distributions in glucose and glutamate support the assumption that the glutamate distributions reflect those in hepatic alpha-ketoglutarate. From the distributions in glutamate, the extent of exchange of labeled with unlabeled carbons and relative flow rates in the cycle in liver were estimated. Dilution of 14C by 12C in the cycle was found in the fasted but not the fed state. In the fasted state, pyruvate carboxylation was estimated to be at least twice the rate of Krebs cycle flux and the rate of pyruvate's decarboxylation less than 1/25 the rate of its carboxylation. In the fed state, the rate of decarboxylation was estimated to be between one-sixth and one-half the rate of carboxylation. The rate of conversion of oxalacetate to fumarate in both states appeared to be greater than 6 times the rate of Krebs cycle flux.     

The Krebs Cycle Enzyme System of Pea Seedlings

A particulate fraction, showing catalytic activity towards intermediatesof the Krebs cycle, has been isolated from pea seedlings bythe method of differential centrifugation. The particulate material,possibly consisting of mitochondria, appears homogeneous underthe microscope and is stained by Janus Green B. The enzyme system necessary for the integrated and single stepreactions of the Krebs tricarboxylic acid cycle is described,and the requirenients for cofactors, discussed.