The formation of DNA interstrand cross-links by a novel bis-[Pt2Cl4(diminazene aceturate)2]Cl4.4H2O complex inhibits the B to Z transition

We present data demonstrating that the cytotoxic compound [Pt2Cl4(diminazene aceturate)2]Cl4.4H2O (Pt-berenil) circumvents cisplatin resistance in ovarian carcinoma cells. The analysis of the interaction of Pt-berenil with linear and supercoiled DNA indicates that this compound induces the formation of a large number of covalent interstrand cross-links on DNA and that this number is significantly higher than that produced by cis-diamminedichloroplatinum(II) (cis-DDP). Renaturation experiments, interstrand cross-link assays, and electron microscopy indicate that the kinetics of DNA interstrand cross-link formation caused by Pt-berenil binding is faster than that caused by cis-DDP at similar levels of platinum bound to DNA. Furthermore, the number of DNA interstrand cross-links in Pt-berenil-DNA complexes is influenced by supercoiling. Circular dichroism experiments show that Pt-berenil strongly inhibits the B-DNA-to-Z-DNA transition of poly(dG-m5 dC). poly(dG-m5dC) at salt concentrations (3 mM MgCl2) at which the native methylated polynucleotide readily adopts the Z-DNA conformation, which suggests that the induction of interstrand cross-links by Pt-berenil inhibits the Z-DNA transition. On the basis of these results, we propose that bis(platinum) compounds with structure similar to Pt-berenil may act as blockers of DNA conformational changes and may also display activity in cisplatin-resistant cells.     

In vitro study of the interaction between quinolones and polyvalent cations

The aim of the present study was to evaluate the influence of aluminium and iron on the in vitro dissolution kinetics of ciprofloxacin and ofloxacin as well as the usefulness of this type of in vitro data to predict modifications in in vivo absorption processes as a consequence of different factors, such as the widely documented in vivo interaction between quinolones and cations. Fitting of experimental data to different theoretical in vitro dissolution profiles was performed by non-linear regression methods and the statistical moments were calculated from raw experimental data. Analysis of residuals applied to dissolution curves as well as statistical comparison of the estimated parameters were carried out to evaluate the in vitro interaction. The results reveal significative modifications of the dissolution profiles of these quinolones as a consequence of the presence of cations, especially for Fe2+ which decreases 34.7% the maximum amount dissolved for ciprofloxacin and 29.1% for ofloxacin. Al3+ also produces a decrease of the total amount of quinolone dissolved although less relevant than Fe2+. Analysis of residuals proved to be the best statistical method to evaluate differences between whole dissolution profiles, at least under the experimental conditions used.     

Inhibition of fibrinolysis by a synthetic urokinase inhibitor enhances lung colonization of metastatic murine mammary tumor cells

We have investigated the role of coagulation and fibrinolysis during the metastatic lung colonization of F3II mouse mammary carcinoma cells. The selective synthetic urokinase inhibitor B623 significantly enhanced lung colonization and blocked the antimetastatic effect of heparin when administered i.p. during the first stages of metastasis formation. In B623-treated mice the overall activity of the fibrinolytic system was reduced and circulating urokinase was specifically inhibited by this agent. In vitro studies demonstrated that B623 induces the aggregation of F3II cells in the presence of mouse plasma and facilitates the entrapment of tumor cells in a fibrin gel matrix. Our data suggest that imbalances of fibrin deposition and removal may dramatically influence metastatic lung colonization.     

Clivus ependymoma

Summary An 8-month-old girl had an ependymoma in the clivus, 2x6 cm in size, connected with the fourth ventricle by a cord of tissue 0.5 cm thick. There were no indications to make us suspect the origin of the tumour in the fourth ventricle, or that it was a case of ependymoma.     

Occlusion of the cerebral arteries in Recklinghausen's disease

Summary Two children, aged 18 months and 6 years, who had Recklinghausen's disease, had occlusion of cerebral arteries. One child had no motor deficit but the other had right hemiparesis and partial occlusion of the left posterior cerebral artery, a fact not found in the literature.     

Regulation of insulin receptor substrate-1 in the liver, skeletal muscle and adipose tissue of rats throughout pregnancy.

The mechanism responsible for insulin resistance during pregnancy remains unclear. Considerable evidence indicates that insulin receptor substrate-1 could play an important role in insulin sensitivity. It seems possible that the gestational hormonal milieu could affect insulin receptor substrate-1. In the present study, measurements of tyrosine phosphorylation and protein content of insulin receptor substrate-1 and gene expression in the liver, skeletal muscle and adipose tissue in the rat indicated that, during pregnancy, significant changes occurred in these parameters. We found in early gestation that muscle and adipose tissue were highly sensitive to insulin action, because the phosphorylation of insulin receptor substrate-1 is greater than in late gestation. However, in late gestation the tissue most sensitive to insulin action, reflecting insulin receptor substrate-1 phosphorylation, was the liver. Our hypothesis was that these results are connected with the changes in concentrations of estradiol and progesterone observed during pregnancy. It was concluded that the present findings demonstrate that different concentrations of gestational hormones play an important role in insulin sensitivity in this period, and that each tissue responds in the most appropriate manner to guarantee the gestation in its entirety, controlling the phosphorylation of insulin receptor substrate-1 in response to insulin receptor activation.     

SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile.

SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.     

Preoperative uracil, tegafur, and concomitant radiotherapy in operable rectal cancer: a phase II multicenter study with 3 years' follow-Up.

PURPOSE: To assess tolerance and efficacy of preoperative treatment with uracil/tegafur and radiotherapy (RT) followed by surgery and postoperative flurouracil (FU)/leucovorin (LV) in patients with rectal cancer. PATIENTS AND METHODS: Patients (n = 94) with potentially resectable tumors, ultrasound at stages T2N+ (n = 4), T3 (n = 77), T4 (n = 13) were treated with UFT (400 mg/m2/d, 5 days a week for 5 weeks) and concomitant RT to the pelvis (45 Gy; 1.8 Gy/d over 5 weeks). Patients underwent surgery 5 to 6 weeks later followed by four cycles of FU/LV. Primary end points included downstaging, pathologic responses, and sphincter-preserving surgery. Secondary end points were recurrence-free survival and overall survival. RESULTS: All patients received the full RT dose. Fifteen patients (16%) needed UFT dose reduction. Preoperative G3+ toxicities included diarrhea (14%), leukopenia (1%), thrombocytopenia (1%), and nausea (4%). The downstaging rate was 54%, pathologic complete response (pCR) was 9% and, in an additional 23%, there were only residual microscopic foci. When cellular viability criteria were taken into account, the pCR was 15%. From 43 patients with abdominoperineal resection indication, 11 (25%) had sphincter-preserving surgery performed. Postoperative scheduled chemotherapy dose was not administered to 24% of patients because of G3+ toxicity (diarrhea, 8%; mucositis, 9%; and leukopenia, 7%). Patients with downstaging had significantly higher survival and recurrence-free survival rates than those without. At 3 years, actuarial patterns of failure were pelvic, 5% and distant, 11%. OS was 75%. CONCLUSION: UFT combined with RT is safe and effective. In resectable rectal cancer, if preoperative treatment is considered, this approach can be an option.     

The importance of angiogenesis in ovarian cancer

Advanced stage ovarian cancer has a high rate of recurrence even after surgery followed by chemotherapy combining carboplatin and a taxane. New strategies are currently under way to combat this situation and one of the most promising ones is based on the knowledge that angiogenesis, the mechanism of formation of new blood vessels coupled with the degradation of the extracellular matrix for metalloproteinases, could be crucial in the development of this tumor. The principal molecule implicated in angiogenesis process of ovarian cancer is the vascular endothelial growth factor (VEGF). Several studies are now in progress to clarify its role as a diagnostic tool or its therapeutic implication. Presently, there is no indication for the use of VEGF in a preliminary diagnosis seeing that an increase in levels can be seen in both benign and malignant ovarian conditions. VEGF is also responsible for an increase in vascular permeability and is directly related to symptoms such as ascites and pleural effusion, both of which are frequent in ovarian cancer. Several papers have analised the role of VEGF as a prognostic factor and some of them do confirm VEGF as an independent prognostic factor in ovarian cancer. VEGF and the metalloproteinase system coupled with angiogenesis are currently being evaluated as therapeutic targets but no positive results have yet to be seen in this field.