Targeting the multidrug ABCG2 transporter with flavonoidic inhibitors: in vitro optimization and in vivo validation.

This review describes the breast cancer resistance protein ABCG2 through its structure, functional roles and involvement in cell multidrug resistance, especially in cancer cells resistance to chemotherapeutics. The different types of known inhibitors are described, some being non-selective, since they also bind to other targets, and others being quite specific such as flavonoids. The different classes of active flavonoids and other polyphenols are described, some as plant natural compounds, but most of them being prepared and derivatized through medicinal chemistry. Quantitative structure-activity relationships of the ability of flavones, chalcones, xanthones, acridones and various benzopyrane/benzofurane derivatives to inhibit ABCG2-mediated drug efflux have led to pharmacophores and molecular models allowing to optimize the available hit compounds and to design new-generation lead compounds. Interestingly, inhibitory flavonoids are quite specific for ABCG2 versus ABCB1 and ABCC1, and appear either non-competitive or partially competitive towards mitoxantrone efflux. Most compounds do not inhibit ATPase activity, and are assumed not to be transported themselves by the transporter. Some acridones, firstly optimized in vitro as potent inhibitors, are indeed efficient in vivo, against human xenografts in SCID mice, more efficiently than gefitinib taken as a control. Future developments should open the way to more efficient/targeted modulators including (i) the potential interest of bimodulation by combining two different inhibitors, (ii) computer-assisted ligand-based drug design for getting more potent and more specific inhibitors, (iii) structure-based drug design from ABCG2 molecular models allowing in silico screening and docking of new inhibitors.

The acridone derivative MBLI-87 sensitizes breast cancer resistance protein-expressing xenografts to irinotecan.

The breast cancer resistance protein ABCG2 confers cellular resistance to irinotecan (CPT-11) and its active metabolite SN-38. We utilised ABCG2-expressing xenografts as a model to evaluate the ability of a non-toxic ABCG2 inhibitor to increase intracellular drug accumulation. We assessed the activity of irinotecan in vivo in SCID mice: irinotecan completely inhibited the development of control pcDNA3.1 xenografts, whilst only delaying the growth of ABCG2-expressing xenografts. Addition of MBLI-87, an acridone derivative inhibitor, significantly increased the irinotecan effect against the growth of ABCG2-expressing xenografts. In vitro, MBLI-87 was as potent as GF120918 against ABCG2-mediated irinotecan efflux, and additionally was specific for ABCG2. A significant sensitisation to irinotecan was achieved despite the fact that doses remained well below the maximum tolerated dose (due to the rather limited solubility of MBLI-87). This suggested that MBLI-87 is an excellent candidate to prevent drug efflux by ABCG2, without altering plasma concentrations of irinotecan and SN-38 after IP (intra-peritoneal) injections. This could constitute a useful strategy to improve drug pharmacology, to facilitate drug penetration into normal tissue compartments protected by ABCG2, and potentially to reverse drug resistance in cancer cells.

Isolation and characterisation of segment 1 of the infectious salmon anaemia virus genome.

The isolation and characterisation of the largest genomic segment of infectious salmon anaemia virus (ISAV) is reported. Following identification of ISAV-specific clones from a cDNA library, a rapid amplification of cDNA ends-PCR strategy was designed to obtain the sequence of the full length mRNA transcript. The full length open reading frame (ORF) of this gene was shown to be 2169 nucleotides in length, encoding a putative protein of 722 aa. This sequence was demonstrated by RT-PCR to be specific to ISAV-infected cell cultures. The start codon of this ORF was preceded by the ISAV consensus sequence 5' GCTAAGA 3' indicating the full 5' end of the gene to have been obtained. Based on protein size and amino acid composition, this protein was shown to be similar to the PB2 protein of other orthomyxoviruses. Furthermore, a bipartite nuclear localisation signal was identified in the C-terminus of the protein as is found on all of the influenza virus P proteins. Expression of the putative PB2 as a green fluorescent marker protein-fusion protein confirmed that this protein exhibited nuclear localisation in a fish cell line. Sequences of the ISAV segment 1 gene were obtained from Scottish, Norwegian and Canadian ISAV isolates. Analyses confirmed the close genetic relationship between Norwegian and Scottish ISAV and indicated that this segment was among the most conserved of the ISAV genes identified to date. Thus, this evidence strongly suggests that the genomic segment 1 of ISAV encodes a polymerase protein which is thought to be analagous in function to the PB2 protein of influenza viruses.

[Spinal dural fistula with peri-medullar venous drainage]. / Les fistules durales rachidiennes à drainage veineux périmédullaire.

Clinical and neuroradiological findings of 8 patients with a spinal dural arteriovenous fistula are reviewed. Disturbance of micturition or defecation and weakness of the legs were always present and the most frequent initial symptom was a progressive spastic paraparesis. Duration of symptoms before diagnosis was 2 years. Lumbar puncture showed elevation of proteins and myelography demonstrated dilated perimedullar posterior veins. In every case, magnetic resonance imaging of the spinal cord (T2- weighted images) revealed intramedullary high signal intensity of the conus medullaris and selective angiography confirmed the site of the dural fistula. Each patient was treated with endovascular method consisting in liquid adhesive embolization (0.2 cc of N-butyl cyanoacrylate) with hyperselective catheterism of the dorsospinal artery. Embolization procedure was successful in 6 cases with large improvement of leg weakness and partial regression of disturbed micturition and defecation. The pathophysiological mechanisms explaining the clinical signs are discussed.

Improvement in glucose tolerance of insulin resistant rats after chronic or acute administration of benfluorex.

The effects of Benfluorex administration on glucose tolerance have been examined in young and old Sprague Dawley rats. The ageing rats were used as a model of insulin resistance. Chronic oral administration of Benfluorex decreased triglycerides levels and normalized glucose tolerance in ageing rats, independently of effects on body weight. Acute intraportal administration of 0.45 mg/kg/h of Benfluorex for 30 min resulted in a 50% increase in glucose tolerance in old rats, but did not modify that in young rats. The improved glucose tolerance brought about by Benfluorex in an animal model of insulin resistance may suggest a wider therapeutic application in man, to include insulin resistant states as type II diabetes or Syndrome X.

[Clinical aspects of receptors; from animal models to physiopathological concepts. Experience with fenfluramine]. / De la clinique aux récepteurs; des modèles animaux aux concepts physiopathologiques. L'expérience de la fenfluramine.

The fenfluramine racemate belongs to a new therapeutic class of molecules acting on food intake, without psychostimulant or addictive potential. This molecule was extensively studied in the treatment of obesity and its action was better understood by studying the dextrogyre and levogyre enantiomers. New methods allowed to show that dexfenfluramine (the dextrogyre isomer) worked through a serotoninergic activity which was responsible for the effect on food intake and disorders of eating behavior. New pharmacological concepts have emerged by using this molecule and new animal models, nearer to human pathology, were found (stress induced eating, carbohydrate selection...). Molecular Biology and Neurosciences have already led to a better knowledge of the central mechanism of action of the molecule by describing its effect on receptors and binding sites; however a lot of other concepts remain to be discovered.

[Giant intracranial aneurysm. Elective endovascular treatment using metallic coils]. / Anévrysmes géants intracrâniens. Traitement endovasculaire électif par des spires métalliques.

The authors present nine cases of giant aneurysm treated endovascularly by obliteration of the aneurysm lumen using platinum coils. Three aneurysms were located on the anterior circulation and six on the vertebrobasilar system. Presenting symptoms were mass effect in five cases and subarachnoid hemorrhage in four. Total occlusion of the aneurysms was achieved in four patients and partial occlusion in five. On follow-up (15 months), there was one repermeation and one neo-aneurysm. Both of these cases were retreated with placement of additional coils. All patients who presented with a mass effect had improvement of their symptoms (two after transient aggravation). Two patients died: one partially treated from hemorrhage, and the other from M.C.A. infarct after surgical clipping of the aneurysm. One technical complication included a lost coil which did not result in any angiographic or clinical change. One year follow-up angiographies show a permanent stable occlusion induced by coils. This technique should be considered as an option when treating giant non surgical aneurysm.

Development of macroangiopathy in sand rats (Psammomys obesus), an animal model of non-insulin-dependent diabetes mellitus: effect of gliclazide.

The risk of developing macroangiopathy associated with diabetes led us to study in sand rats the long-term consequences of non-insulin-dependent diabetes on the development of arterial lesions promoted by feeding a high-cholesterol diet. Gliclazide, an agent whose preventive effect has previously been suggested in other experimental models of atheroma, was also investigated in these diabetic and hypercholesterolemic animals. Sand rats were fed a natural diet (ND group), a standard laboratory feed (StD group), or a high-cholesterol feed (HCD group) for 15 months. Biologic parameters were monitored throughout the period of the study, and histologic and histochemical examinations were conducted when the animals were killed (month 15). One StD group and one HCD group were treated with gliclazide from month 3 to month 15. The StD group developed a syndrome of obesity, hyperglycemia, hyperinsulinemia, and triglyceridemia. The high cholesterol feed further increased hypercholesterolemia. These biologic abnormalities were accompanied by arterial lesions (thickening of the intima, deposition of glycosaminoglycans). Foam cells were seen in the intima, and microthrombi were present in the lumen of the arteries of animals in the HCD group. Long-term gliclazide medication at doses that normalized serum glucose levels also reduced the obesity, hyperinsulinemia, lipid disorders, and it prevented or retarded the appearance of arterial lesions.

[Emergency preoperative embolization using coils of ruptured sylvian aneurysm. Apropos of a case]. / Embolisation pré-opératoire en urgence par coils d'un anévrysme sylvien rompu. A propos d'un cas.

The authors report a case of a 73 year old patient who presented with a right temporal lobe hematoma secondary to rupture of a right middle cerebral artery bifurcation aneurysm. Treatment consisted of partial thrombosis of the aneurysm by the endovascular introduction of metallic coils followed by surgical hematoma evacuation and aneurysm clipping. Thrombus of the aneurysm done probably diminished the risk of intraoperative rupture. Partial endovascular treatment has a very small risk and may be done on a emergency basis at the same time as the diagnostic arteriogram. It can also be suggested for patients in poor condition to diminish the risk of recurrent hemorrhage until the patient is well enough to undergo definitive surgical clipping.

The liver metabolite S-422 of the hypolipidaemic drug benfluorex decreases cholesterol esterification in fibroblasts and monocyte-like cells.

The effects of S-422 (1-(3-trifluoromethylphenyl)-2-[N-(2-hydroxyethyl) amino] propane), an hepatic metabolite of the hypolipidaemic drug Benfluorex, on lipid metabolism have been investigated in two experimental models: in human fetal lung fibroblasts, for study of the apo B/E receptor-mediated regulation of cholesterol metabolism, and in murine J 774 monocyte-like cells, for study of the scavenger receptor-mediated induction of cholesteryl ester accumulation. In human fibroblasts S-422 increased low density lipoprotein (LDL) catabolism by about 20%, whereas it decreased oleic acid incorporation into triacylglycerols and cholesteryl esters by 25 and 35%, respectively. In J 774 cells, S-422 decreased acetylated LDL degradation and cholesteryl ester formation by about 35%. In both cell types, ACAT activity was significantly reduced by the drug, either after a 24 h pretreatment of the cultured cells, or after an in vitro 30 min preincubation of cell homogenates. The results suggest that S-422, and thus Benfluorex, might prevent the development of atherosclerotic plaques.

Astrocytic tumours.

Astrocytic tumours are frequent, accounting for nearly 50% of all brain tumours. They are divided into three groups: benign astrocytomas, anaplastic astrocytomas and malignant glioblastomas. The usual clinical manifestations of benign astrocytic tumours are epileptic seizures, whereas those of glioblastomas are rapidly progressing neurological deficits. These lesions show fairly characteristic neuroradiological features which have been largely studied. Injections of iodine-based or paramagnetic contrast media are important since they help in tumour grading: low-grade tumours are not enhanced, while glioblastomas are almost invariably enhanced. MRI seems to be indispensable for the study of astrocytic tumours: it provides an excellent anatomical analysis of the lesion during preoperative or pretherapeutic evaluation, and it is the only available method to confirm low-grade lesions that have passed unnoticed or have merely been suspected at CT. To avoid missing these tumours, every adult presenting with recent onset epileptic seizures should be explored by MRI using T2-weighted spin-echo sequences.

Primary and secondary lymphomas of the brain: an MRI study.

Three types of lymphoma of the central nervous system are known: primary non-Hodgkin's malignant lymphoma (NHML), secondary NHML and neurological lesions of Hodgkin's disease. NHML's are rare tumours, often associated with immunodeficiency and presenting predominantly as neuropsychological disorders. In this study 8 patients were explored by CT and MRI, with pathological confirmation. None of our patients had AIDS. The most typical neuroradiological image of this type of tumour is that of a large and intensely contrast-enhanced tumoral mass which is often multifocal and periventricular with infiltration of the subarachnoidal spaces and leptomeninges. Mass effect and perifocal oedema are less pronounced than expected with tumours of that size. NHML's may totally regress under corticosteroid therapy. This tumour of obscure aetiology must be recognized as it is now increasingly frequent.

[Digital arteriography using an intra-arterial route in vertebrobasilar insufficiency. Comparison of iopromide 300 and ioxaglate 320 mgI/ml]. / Artériographie numérisée par voie intra-artérielle dans l'insuffisance vertébro-basilaire. Comparaison de l'iopromide 300 et de l'ioxaglate 320 mgI/ml.

During intra-arterial digital subtraction angiography of the vertebral and basilar arteries, 24 patients were included in a prospective double-blind randomized trial comparing a new non-ionic contrast medium, iopromide 300 and an ionic low osmolar medium, ioxaglate 320 mgI/ml. There was a statistically significant reduction in the number of adverse effects observed with Iopromide 300, particularly in terms of unwanted movements, source of image quality degradation.

Embryonal rhabdomyosarcoma of the biliary tree in children: a case report.

Embryonal rhabdomyosarcoma (ERS) in children is a very rare tumor. Jaundice is the capital symptom. Diagnosis can be made by echography, which shows echogenic formations without posterior conic shadows in a dilated biliary duct. The prognosis is bleak in spite of the combination of surgery, radiotherapy and chemotherapy.

[Value of ultrasonics in the diagnosis of acute intestinal invagination in infants and children. Apropos of a series of 60 cases]. / Intérêt de l'échographie dans le diagnostic de l'invagination intestinale aiguë du nourrisson et de l'enfant. A propos d'une série de 60 cas.

Sixty cases hospitalized between May and October 1985 for suspicion of acute intestinal intussusception in whom emergency ultrasonography was performed are reported. The diagnostic reliability of this non-invasive technique reduces the indication for performing barium enemas to treatment only.

[Acute intestinal intussusception in infants and children and abdominal ultrasonography]. / Invagination intestinale aiguë du nourrisson et de l'enfant et échographie abdominale.

Ultrasound imaging findings of the invaginated bud are described in 60 young children referred with a suspected acute intestinal intussusception over a period of 5 months. An initial group of 28 children were examined by ultrasonography and a barium enema for diagnostic and possible therapeutic purposes. The second series of 32 children were a therapeutic enema only when ultrasound images provided a positive diagnosis. The method is considered to be a reliable one requiring less medication, and has the principal advantage of suppression of the need for diagnostic barium enema.

[Lymphomatous polyposis of the digestive tract]. / Poliposis linfomatosa del tubo digestivo.

A case of multiple lymphomatous polyposis of the gastrointestinal tract is presented. The recent literature on this type of lymphoma is reviewed. Also summarized are the clinical findings, diagnostic procedures, current methods of treatment and prognosis of these patients. Diarrhea upon admission, lead us to a complete work up finally to the correct diagnosis. The lack of symptoms of this patient was in contrast with most of the cases reviewed, so the diagnosis was mainly based on the endoscopic findings (colonoscopy and esofago-gastro-duodenoscopy). It is emphasized the importance of repeated biopsies in case of negative ones, as it occurs in this patient, in which an endoscopic "polypectomy" from the recto-sigmoid area, provided enough material to the pathologist, for the diagnosis, after several "non-diagnostic" biopsies taken previously. Finally the therapy for this entity is updated, with special reference to quemotherapy and a list of drugs combination is given.