The influence of 5-HT(2C) and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients

We investigated the relationships between functional genetic variants of the 5-HT(2C) receptor and multidrug-resistant protein (MDR1), coding for P-glycoprotein, and second generation antipsychotic (SDA)-induced weight gain among 108 female schizophrenic patients treated with olanzapine or risperidone for up to 4 months. No significant differences in -759C/T allelic and genotype variants of 5-HT(2C) were found between patients who gained more than 7% of their initial weight compared with those who gained less. Haplotype-based analysis of two MDR1 loci, exon 21 G2677T and exon 26 C3435T, revealed a slightly lower representation of the G2677/C3435 haplotype in the >/=7% group. In the subgroup of patients treated with risperidone, we found borderline overrepresentation of 2677T, significant overrepresentation of 3435T variant and borderline overrepresentation of 2677T/3435T haplotype the >/=7% group, whereas G2677/C3435 haplotype was found to be less represented in the >/=7% group. Our data indicate a nonsignificant role of 759C/T 5-HT(2C) in SDA-induced weight gain, and a stronger influence of the MDR1 G2677T and C3435T polymorphisms on risperidone-induced weight gain in female schizophrenic patients. 3435T and 2677T MDR1 variants, both associated with lower P-gp function, might predispose to higher risperidone accessibility to the brain that would lead to stronger effects, including weight gain

Presence of the ABCB1 (MDR1) deletion mutation causing ivermectin hypersensitivity in certain dog breeds in Belgium

Hypersensitivity to ivermectin and certain other drugs in Collies and related breeds is caused by a 4-base pair deletion mutation in the ABCB1 gene, better known as the MDR1 gene, encoding P-glycoprotein. There is no information available, however, regarding the presence of this mutation in dogs in Belgium. In this study, the ABCB1 genotype was assessed in 92 dogs of breeds suspected to possess the deletion mutation. The results indicated that the mutation was present in the Australian Shepherd, Collie, Shetland Sheepdog and Swiss White Shepherd, but was not detected in the Bearded Collies, Border Collies and German Shepherds of this study, which is in accordance with the findings in similar breed populations of other countries. In Belgium it is therefore important to take the ABCB1 genotype of the breeds involved into account, in order to use drugs in a safe and efficient manner and to improve the selection procedure in dog breeding

Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis

BACKGROUND AND AIMS: The MDR1 gene encodes P-glycoprotein 170, an efflux transporter that is highly expressed in intestinal epithelial cells. The MDR1 exonic single nucleotide polymorphisms (SNPs) C3435T and G2677T have been shown to correlate with activity/expression of P-glycoprotein 170.METHODS: This was a case-control analysis of MDR1 C3435T and G2677T SNPs in a large well-characterized Scottish white cohort (335 with ulcerative colitis [UC], 268 with Crohn's disease [CD], and 370 healthy controls). We conducted 2-locus haplotype and detailed univariate and multivariate genotypic-phenotypic analyses.RESULTS: The MDR1 3435 TT genotype (34.6% vs 26.5%; P = .04; odds ratio [OR], 1.60; 95% confidence interval [95% CI], 1.04-2.44) and T-allelic frequencies (58.2% vs 52.8%; P = .02; OR, 1.28; 95% CI, 1.03-1.58) were significantly higher in patients with UC compared with controls. No association was seen with CD. The association was strongest with extensive UC (TT genotype: 42.4% vs 26.5%; P = .003; OR, 2.64; 95% CI, 1.34-4.99; and T allele: 63.9% vs 52.8%; P = .009; OR, 1.70; 95% CI, 1.24-2.29), and this was also confirmed on multivariate analysis ( P = .007). The G2677T SNP was not associated with UC or CD. These 2 SNPs lie in linkage disequilibrium in our population (D', .8-.9; r 2 , .7-.8). Two-locus haplotypes showed both positive (3435T/G2677 haplotype: P = .03; OR, 1.44) and negative (C3435/2677T haplotype: P = .002; OR, .35) associations with UC. Homozygotes for the haplotype 3435T/G2677 were significantly increased in UC ( P = .017; OR, 8.88; 95% CI, 1.10-71.45).CONCLUSIONS: Allelic variations of the MDR1 gene determine disease extent as well as susceptibility to UC in the Scottish population. The present data strongly implicate the C3435T SNP, although the 2-locus haplotype data underline the need for further detailed haplotypic studies.</p

MDR1 siRNA loaded hyaluronic acid-based CD44 targeted nanoparticle systems circumvent paclitaxel resistance in ovarian cancer.

Development of multidrug resistance (MDR) is an almost universal phenomenon in patients with ovarian cancer, and this severely limits the ultimate success of chemotherapy in the clinic. Overexpression of the MDR1 gene and corresponding P-glycoprotein (Pgp) is one of the best known MDR mechanisms. MDR1 siRNA based strategies were proposed to circumvent MDR, however, systemic, safe, and effective targeted delivery is still a major challenge. Cluster of differentiation 44 (CD44) targeted hyaluronic acid (HA) based nanoparticle has been shown to successfully deliver chemotherapy agents or siRNAs into tumor cells. The goal of this study is to evaluate the ability of HA-PEI/HA-PEG to deliver MDR1 siRNA and the efficacy of the combination of HA-PEI/HA-PEG/MDR1 siRNA with paclitaxel to suppress growth of ovarian cancer. We observed that HA-PEI/HA-PEG nanoparticles can efficiently deliver MDR1 siRNA into MDR ovarian cancer cells, resulting in down-regulation of MDR1 and Pgp expression. Administration of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles followed by paclitaxel treatment induced a significant inhibitory effect on the tumor growth, decreased Pgp expression and increased apoptosis in MDR ovarian cancer mice model. Our findings suggest that CD44 targeted HA-PEI/HA-PEG/MDR1 siRNA nanoparticles can serve as a therapeutic tool with great potentials to circumvent MDR in ovarian cancer

Consequences of cell-to-cell P-glycoprotein transfer on acquired multidrug resistance in breast cancer: a cell population dynamics model

Cancer is a proliferation disease affecting a genetically unstable cell population, in which molecular alterations can be somatically inherited by genetic, epigenetic or extragenetic transmission processes, leading to a cooperation of neoplastic cells within tumoral tissue. The efflux protein P-glycoprotein (P gp) is overexpressed in many cancer cells and has known capacity to confer multidrug resistance to cytotoxic therapies. Recently, cell-to-cell P-gp transfers have been shown. Herein, we combine experimental evidence and a mathematical model to examine the consequences of an intercellular P-gp trafficking in the extragenetic transfer of multidrug resistance from resistant to sensitive cell subpopulations. We report cell-to-cell transfers of functional P-gp in co-cultures of a P-gp overexpressing human breast cancer MCF-7 cell variant, selected for its resistance towards doxorubicin, with the parental sensitive cell line. We found that P-gp as well as efflux activity distribution are progressively reorganized over time in co-cultures analyzed by flow cytometry. A mathematical model based on a Boltzmann type integro-partial differential equation structured by a continuum variable corresponding to P-gp activity describes the cell populations in co-culture. The mathematical model elucidates the population elements in the experimental data, specifically, the initial proportions, the proliferative growth rates, and the transfer rates of P-gp in the sensitive and resistant subpopulations. We confirmed cell-to-cell transfer of functional P-gp. The transfer process depends on the gradient of P-gp expression in the donor-recipient cell interactions, as they evolve over time. Extragenetically acquired drug resistance is an additional aptitude of neoplastic cells which has implications in the diagnostic value of P-gp expression and in the design of chemotherapy regimensComment: 13 pages, 8 figures, 1 tabl

Frequency estimation of disease-causing mutations in the Belgian population of some dog breeds, part 1 : shepherds

In light of improving breeding advice, the frequency was estimated for all the disease-causing mutations that were known at the start of the study and that are potentially relevant for a group of dog breeds, which are relatively popular or in which the genetic diversity in Belgium is low to moderately low. In this study, the results for the German shepherd dog, Malinois, Lakenois, Groenendael, Tervuren, Australian shepherd and Border collie are presented. Disorders with a frequency high enough to warrant routine genotyping for breeding programs are (1) multidrug resistance 1 and hereditary cataract for the Australian shepherd, (2) degenerative myelopathy for the German shepherd dog, Malinois and Groenendael and (3) collie eye anomaly for the Border collie. In addition, the hyperuricosuria mutation described in the German shepherd dog was not found in its Belgian population, but was, to the authors' knowledge discovered for the first time in the Malinois

A P-glikoprotein membrán mikrokörnyezete és működésének gátolhatósága modulátor és antitest együttes alkalmazásával = P-glycoprotein membrane microenviroment and inhibition of pumping by the combined application of modulators and specific antibody

A multidrog rezisztencia hátterében gyakran a P-glikoprotein (Pgp) pumpa működése áll, melynek gátlására jelentős erőfeszítések történnek világszerte. Az UIC2 antitest a fehérjét katalitikus ciklusa egy fázisában ismeri fel, és ott blokkolja. Az így elért gátlás azonban általában kisfokú, mert az antitest a sejtfelszíni Pgp-knek csak egy hányadához kötődik - vizsgálataink utóbbi jelenség megértésére és befolyásolására irányultak. Megállapítottuk, hogy egy korábbi munkáinkban leírt teszt segítségével azonosítható szubsztrát/modulátor (S/M) csoport bármelyik tagja jelenlétében az antitest az összes sejtfelszíni Pgp-hez kötődik és azt inaktív állapotba hozza. Ez a S/M-ok önmagukban hatástalan koncentrációja mellett valósul meg, és in vivo is megtörténik, mint azt xenotranszplantációs kísérletekben demonstráltuk. Megállapítottuk, hogy az UIC2 által mindig felismert Pgp-k hányada (pool I) lipid tutaj- (raft)- asszociált, klasztereket alkot és az UIC2 kötés nyomán fokozottan internalizálódik. Számos olyan fehérjét azonosítottunk, melyek a Pgp molekuláris környezetében vannak: ezek nagy része az aktomiozin-kapcsolt trafficking apparátus része. Az antitest által csak egyes S/M-ok jelenlétében felismert Pgp-k szoliter molekulák. Mindkét pool funkcionális Pgp molekulákat tartalmaz, a pool I valamilyen endogén szubsztrát által indukált ATPáz aktivitás során csapdázódik az UIC2 jelenlétében. A kétféle lipid környezet az eltérő oldékonyságú S-ok optimális transzportját szolgálhatja. | P-glycoprotein (Pgp), an ABC transporter often responsible for the multidrug resistance of cancer cells, is recognized and inhibited by the UIC2 mAb that freezes the transporter in a particular phase of its catalytic state. However, the degree of this inhibition is mitigated by the lack of its binding to all cell surface Pgps, a phenomenon poorly understood. We have demonstrated that Pgp is present in two distinct subpopulations on the cell surface: Both pools contain functional Pgp molecules, but only pool I is recognized in the absence of exogeneous substrates/modulators (S/M-s), while pool II Pgps bind UIC2 only upon addition of certain S/M-s, identified by a test introduced by us earlier. In the presence of any of this group of S/M-s administered at such a low concentration which is insufficient to cause Pgp inhibition when used alone, the mAb can completely inhibit the pump also in vivo, as demonstrated in xenotransplantation experiments. Pgp molecules of the two pools could be distinguished in terms of membrane microdomain localization, clustering propensity, cytoskeletal anchorage, intracellular molecular neighbours, and trafficking characteristics. Endocytosis of Pgp involves the actin microfilament system, and primarily targets the raft associated pool I, when an ATP- conformational state is stabilized. The presence of the pump in two different lipid environment may be optimal for the transport of S-s with different solubilities

The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers.

Encapsulation of drugs within nanocarriers that selectively target malignant cells promises to mitigate side effects of conventional chemotherapy and to enable delivery of the unique drug combinations needed for personalized medicine. To realize this potential, however, targeted nanocarriers must simultaneously overcome multiple challenges, including specificity, stability and a high capacity for disparate cargos. Here we report porous nanoparticle-supported lipid bilayers (protocells) that synergistically combine properties of liposomes and nanoporous particles. Protocells modified with a targeting peptide that binds to human hepatocellular carcinoma exhibit a 10,000-fold greater affinity for human hepatocellular carcinoma than for hepatocytes, endothelial cells or immune cells. Furthermore, protocells can be loaded with combinations of therapeutic (drugs, small interfering RNA and toxins) and diagnostic (quantum dots) agents and modified to promote endosomal escape and nuclear accumulation of selected cargos. The enormous capacity of the high-surface-area nanoporous core combined with the enhanced targeting efficacy enabled by the fluid supported lipid bilayer enable a single protocell loaded with a drug cocktail to kill a drug-resistant human hepatocellular carcinoma cell, representing a 10(6)-fold improvement over comparable liposomes