PubMed Health⌕ Search

Biomedical subjects

W Skuballa

Publications and source records attributed to W Skuballa.

15 recordsLinked to original sources
PubMed2001

Subcellular distribution of epothilones in human tumor cells.

Epothilones are a new class of natural and potent antineoplastic agents that stabilize microtubules. Although 12,13-epoxide derivatives are potent antiproliferative agents, the activities of the corresponding 12,13-olefin analogs are significantly decreased. These data were confirmed for two new analogs, 6-propyl-EpoB (pEB) and 6-propyl-EpoD (pED), in comparison with the natural compounds EpoB/EpoD, by using human A431, MCF7, and MDR1-overexpressing NCI/Adr cells. By using tritiated pEB/pED, compound uptake, release, and nuclear accumulation were investigated in A431 and NCI/Adr cells. In these cells, epothilones can principally be recognized and exported by Verapamil-sensitive efflux pumps, which are not identical to MDR1. The degree of export depends on the structure, olefin vs. epoxide-analog, and also on the intracellular drug concentration. The accumulation of pED used at 3.5 or 70 nM, respectively, was increased in the presence of 10 microM Verapamil in both cell lines 2- to 8-fold. In contrast, the intracellular levels of pEB were affected by Verapamil only at 3.5 nM pEB in NCI/Adr (2-fold) and not in A431 cells. In addition, strong nuclear accumulation was observed for pEB (40-50%) but not paclitaxel or pED (5-15%) in both cell lines. Our study suggests that differences in growth inhibitory efficacy between epoxide and olefin analogs may be based on different mechanisms of drug accumulation and subcellular distribution.

Antineoplastic Agents, Phytogenic↗
PubMed1995

Novel prostanoid thromboxane A2 agonists.

The chemistry and biology of novel TXA2(TP)-receptor agonists based on the prostanoid skeleton is described and structure-activity-relationships are discussed. One compound,(5Z,13E), (9R,15R)-9-fluoro-15-hydroxy-16-phenoxy-17,18,19,20-tetranor- 5,13-prostadienoic acid (33), was identified which is 10 times more potent than the standard TP-receptor against U 46619.

Blood Platelets↗
PubMed1991

Effects of prostacyclin analogues in in vivo tumor models.

Much attention has recently focused on the role of tumor cell-platelet interaction in the metastatic cascade. Prostacyclin and stable prostacyclin analogues have been shown to inhibit specifically the formation of metastases in experimental tumor models. This action is based on their ability to reduce the attachment of tumor cells to platelets and to inhibit adhesion of tumor cells-platelet aggregates to the endothelial lining. To investigate the antimetastatic potential of two prostacyclin analogues (Iloprost and Eptaloprost, Schering AG), we have tested these compounds in the spontaneously metastasizing R 3327 MAT Lu prostate carcinoma of the Cop rat in two types of experiments. Treatment was performed for 33 days, starting one day before s.c. implantation of the tumor. The primary s.c.-implanted tumor remained in situ throughout the experiment. In the first test, Iloprost (0.3 micrograms/kg/min) and Eptaloprost (0.1 micrograms/kg/min) were administered via Alzet mini pumps s.c.. There was a considerable reduction of the number of visible lung metastases by Eptaloprost. In the second test, Eptaloprost was administered p.o. in doses of 0.1 and 0.5 mg/kg daily. The number of lung metastases was significantly reduced. Both compounds had no effect on the growth of the primary tumor in the first as well as in the second test. These data show that the prostacyclin analogue Eptaloprost has a significant antimetastatic activity in a spontaneously metastasizing tumor model and thus merits further investigation.

Animals↗
PubMed1988

Stable 9 beta- or 11 alpha-halogen-15-cyclohexyl-prostaglandins with high affinity to the PGD2-receptor.

Various chemically stable prostaglandin analogues were studied for their affinity towards the PGD2-receptor in human platelet membranes in order to define the requirements for specific ligand binding to this receptor. On replacing the 11- or 9-hydroxyl groups of PGF2 alpha by an 11 alpha- or 9 beta-chloro- or fluoro atom, stable prostaglandin analogues were obtained, which showed high affinity towards the PGD2-receptor. The lower side chain consisted of a 15-cyclohexyl group or of the natural 15-n-pentyl group, other substitutents decreased the affinity substantially. The highest PGD2-mimetic activity with a relative affinity of 0.5 to the PGD2-receptor was found in 9-deoxy-9 beta-chloro-16,17,18,19,20-pentanor-15-cyclohexyl-PGF2 alpha (ZK 110 841, compound 16 in Table 1). ZK 110 841 is a chemically stable crystalline substance, which is orally active and which might thus turn out to be an interesting tool for the study of PGD2-receptor interactions. Some other prostaglandin as well as prostacyclin analogues with a 15-cyclohexyl or 15-n-pentyl group exhibited in addition to their known high affinity to the PGE2-receptor of human uterine membranes or the PGI2-receptor of human platelets also affinities to the PGD2-receptor. Generally, the receptor affinities correlate with the activities as stimulators of adenylate cyclase and inhibitors of thrombin induced elevation of cytoplasmic free calcium as well as their ability to inhibit ADP-induced platelet aggregation. The PGI2-character regarding the effector systems prevails in compounds with affinity to both the PGI2- and PGD2-receptor. Compounds which bind to the PGE2- and PGD2-receptor show a flat dose response curve regarding platelet activation suggesting a mixture of pro- and antiaggregatory properties within these molecules.

Adenylyl Cyclases↗
PubMed1986

Pharmacological profile of a novel carbacyclin derivative with high metabolic stability and oral activity in the rat.

A novel carbacyclin derivative (16S)-13,14-dehydro-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro- 6a- carbaprostaglandin-I2 (3-oxa-analogue) has been synthesized in order to find chemically and metabolically stable prostacyclin-mimetics with a potency equal or even superior to PGI2. The 3-oxa-analogue was found to be stabilized against beta-oxidation, a main metabolic degradation step also for chemically stable PGI2-analogues. The compound is orally available and displays a long duration of 4.5-48 h of antiaggregatory and hypotensive action. The 3-oxa-analogue inhibits ADP-induced platelet aggregation with an IC50 of 3.0 nM. Following intravenous application the 3-oxa-analogue lowers diastolic blood pressure in a dose dependent manner, the ED20 being 0.1-0.2 micrograms/kg after injection and less than or equal to 0.05 micrograms/kg/min after infusion respectively. In vivo platelet aggregation is inhibited after i.v. infusion of the 3-oxa-analogue with an IC50 of 0.037 micrograms/kg/min. As compared to Iloprost, the 3-oxa-analogue is 5-12 fold more potent with respect to in vivo hypotensive and anti-aggregatory effects. The results of the present studies indicate that the 3-oxa-analogue has a pharmacological profile comparable to prostacyclin (PGI2) and Iloprost. Due to the fact that the 3-oxa-analogue is chemically and metabolically stable, long term oral treatment can be achieved in clinical conditions in which PGI2 and Iloprost have already been shown to be therapeutically useful principles.

Administration, Oral↗
PubMed1984

In vitro effects of PGF2 alpha and a metabolically stable derivative on 20 alpha-hydroxysteroid-dehydrogenase activity in corpora lutea isolated from pseudopregnant rat ovaries.

Single intact corpora lutea were isolated from pseudopregnant rat ovaries stimulated with PMSG and HCG. The activity of 20 alpha-hydroxysteroid-dehydrogenase (20 alpha-OH-SDH) was measured at various stages of pseudopregnancy. The influence of PGF2 alpha or a metabolically stable PGF2 alpha-derivative on this enzyme in vitro was assessed. 20 alpha-OH-SDH activity was low from day 6 to 8, started to rise on day 10 and reached a maximum on day 14 after administration of HCG. The enzyme could be stimulated by the PGF2 alpha-derivative on day 10 and 11 but not on day 6, 8, when basal enzyme activity was still very low or on 12 and 14 of pseudopregnancy when the enzyme had already reached maximal levels. PGF2 alpha or its derivative had no effect on enzyme activity in a cytosolic fraction indicating that particulate cell constituents were required for this process. PGE2 as well as cycloheximide (an inhibitor of protein biosynthesis) were without influence on enzyme stimulation. dB-cAMP but not dB-cGMP decreased enzyme activity. Ca2+ -ions were required for the stimulation of 20 alpha-OH-SDH activity. It is concluded that PGF2 alpha or its stable derivative may modulate ovarian steroid metabolism by acute stimulation of luteal 20 alpha-OH-SDH.

20-Hydroxysteroid Dehydrogenases↗
PubMed1984

Antifibrillatory action of the stable orally active prostacyclin analogues iloprost and ZK 96 480 in rats after coronary artery ligation.

Iloprost (ILO) and ZK 96 480 (96 480) are stable prostacyclin (PGI2) analogues with platelet aggregation-inhibiting and hypotensive activities equal or superior to PGI2 which in contrast to PGI2 show longlasting pharmacological effects also after oral application. PGI2 as well as ILO and 96 480 with i.v. infusion at equihypotensive doses in rats after coronary artery ligation reduce ventricular ectopic beats, markedly reduce or abolish the periods of ventricular tachycardia and entirely prevent ventricular fibrilloflutter. Even nonhypotensive doses of the prostanoids attenuate postligation arrhythmias. Catecholamine depletion by reserpine pretreatment also markedly reduced the incidence of arrhythmias. As PGI2 and ILO have previously been shown by others to preserve noradrenaline content of sympathetic nerve terminals in ischemic myocardium, prevention of excessive catecholamine loss from hypoxically compromised sympathetic nerve terminals might be involved in the antiarrhythmic action of PGI2, ILO and 96 480.

Adenosine Diphosphate↗