References Ehf
Abolhoda A, Wilson AE, Ross H, Danenberg PV, Burt M, Scotto KW 1999 Rapid activation of MDR1 gene expression in human metastatic sarcoma after in vivo exposure to doxorubicin. Clin Cancer Res 5 3352-3356 Atadja P, Watanabe T, Xu H, Cohen D 1998 PSC-833, a frontier in modulation of P-glycoprotein mediated multidrug resistance. Cancer Metastasis Rev 17 163-168 Bates SE 1999 Drug resistance Still on the learning curve. Clin Cancer Res 5 3346-3348 Borst P, Evers R, Kool M, Wijnholds J 2000 A family...
Discussion Gql
One key finding is the depolarizing GABAa response in human epileptogenic tissue. In the rat neocortex, the reversal potential of GABAa inhibition is governed by a KCl outward transport Thompson et al 1988 originally described in crayfish stretch receptors Deisz amp Lux 1982, Aickin et al 1982 . The GABAa reversal potential, however, is about 15 mV less negative than the chloride gradient due to the partial bicarbonate permeability of GABAa channels Kaila et al 1993 . The depolarizing GABAa...
Results
Generation of epothilone A-resistant cells MDA 435 breast adenocarcinoma cells were incubated in the presence of 10 nM of epothilone A for 5 weeks. Although majority of the cells died, several clones survived the drug selection. Each clone was further expanded in media containing 10 nM epothilone A but only one clone expanded well resulting in a resistant cell line named EA10. EA10 cells served as founder cells for the selection of cells with higher epothilone A resistance that were maintained...
References Pck
Allen JD, Brinkhuis RF, van Deemter L, Wijnholds J, Schinkel AH 2000 Extensive contribution of the multidrug transporters P-glycoprotein and Mrp1 to basal drug resistance. Cancer Res 60 5761-5766 Angeletti RH, Novikoff PM, Juvvadi SR, Fritschy JM, Meier PJ, Wolkoff AW 1997 The choroid plexus epithelium is the site of the organic anion transport protein in the brain. Proc Natl Acad Sci USA 94 283-286 Belinsky MG, Bain LJ, Balsara BB, Testa JR, Kruh GD 1998 Characterization of MOAT-C and MOAT-D,...
Use of Pgp modulators in oncology
Before considering specific Pgp modulators and clinical trials in oncology, it would be useful to review the general principles that governed early studies. Some of the earliest modulators first generation were agents that were in clinical use and were found to have a general mild Pgp modulating ability. Examples are verapamil, cyclosporin and tamoxifen. The advantages with these agents were the general familiarity with longer-term use and knowledge of chronic toxicity. Limitations were the...
Drug resistance in epilepsy human epilepsy
S. M. Sisodiya , W.-R. Lin , B. N. Harding , M. V. Squier and M. Thom Epilepsy Research Group, University Department of Clinical Neurology, Department of Neuropathology, Institute of Neurology, and Department of Neuropathology, Institute of Child Health, University College London, Queen Square, London, and Department of Neuropathology, Radcliffe Infirmary, Oxford, UK Abstract. The basis of drug resistance in human epilepsy is not understood. Parallels with resistance in cancer suggest that drug...
P glycoprotein and the mechanism of multidrug resistance
Andras Varadi , Gergely Szakacsf, Eva Bakos and Balazs Sarkadif lnstitute of Enzymology, Hungarian Academy of Sciences, Karolina ut 29, Budapest H-1113, and National Institute of Hematology and Immunology, Membrane Research Group of SEB-Hungarian Academy of Science, Daroczi ut 24, Budapest H-1113, Hungary Abstract. The human P glycoprotein Pgp MDR1 is an ATP-driven transporter for hydrophobic drugs and causes multidrug resistance in cancer. Our knowledge related to the mechanistic details of...
Imaging Pgp transport in vivo with PET
Radiolabelled MDR-associated cytostatic agents can be used to study drug efflux pumps in vivo. One example is colchicine, a Pgp substrate which is a naturally occurring alkaloid Ford amp Hait 1990 . Mehta et al 1992 studied the biodistribution of 3H colchicine in mice xenografted with Pgp-negative and Pgp-positive human neuroblastoma tumours Mehta et al 1992 . The pharmacokinetics of colchicine are possibly favourable for PET studies due to their limited metabolism Hunter amp Klaassen 1975 ....
OC144093 a novel P glycoprotein inhibitor for the enhancement of antiepileptic
Michael J. Newman, Ross Dixon and Barry Toyonaga Ontogen Corporation, 6451 El Camino Real, Carlsbad, CA 92009, USA Abstract. Inhibitors of P glycoprotein Pgp may be useful for the enhancement of blood-brain barrier penetration of anti-epileptic drugs AEDs . Due to polypharmacy and the need for chronic treatment, Pgp inhibitors used in epilepsy should be highly specific and non-toxic. In particular, it may be essential to use compounds that produce minimal inhibition of enzymes involved in...
Q
Rasmussen's encephalitis 8 redundancy 96 97 relapse, after anti-epileptic drug withdrawal 10 predictors 9 spontaneous 17 remote symptomatic seizures 10 rhodamine efflux 23, 232 rifampin 184 river blindness 45 RNA isolation 121 rolandic epilepsy 6 schizophrenia, seizures following ECT 162 self-sustained limbic status epilepticus model 197,202 Sestamibi 91,96-97 severe myoclonic epilepsy of childhood tolerance to 164,165 single-gene defects 13,14 So324 76 sodium channel modulation 48, 155-156...
Pgp in cancer
Drug resistance, either intrinsic or acquired, is a frequently encountered problem in the failure of antineoplastic agents. Pgp, an efflux pump that extrudes hydrophobic cytotoxic drugs from cancer cells, plays a key role in multidrug resistance MDR and may contribute to clinical drug resistance. Pgp is a 170 kDa cell-surface glycoprotein, encoded for by the MDR1 gene Riordan amp Ling 1985 . The presence of MDR has been correlated with poor outcome in acute myeloid leukaemia, non-Hodgkin's...
Drug resistance molecules lessons from oncology
George L. Scheffer and Rik J. Scheper1 Department of Pathology, Free University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands Abstract. Tumour cell insensitivity to anticancer drugs frequently appears as multidrug resistance MDR , associated with overexpression of one or more of a set of at least 10 different molecules, causing reduced drug levels at the intracellular target sites. They include transmembrane transporter proteins such as P glycoprotein, MRP1 9 and BCRP....
Gene expression profiling of epothilone Aresistant cells
Peter Atadja, Yan Yan-Neale, Harry Towbin, Frank Buxton and Dalia Cohen Functional Genomics, Novartis Corporation, Summit, NJ 07901, USA Abstract. In the current study, we isolated sublines of the human breast adenocarcinoma cell line MDA 435 that exhibited increasing resistance to epothilone A, a microtubule-stabilizing cytotoxic agent. The resistant cells did not express P glycoprotein or multidrug resistance-associated protein MRP which are known mediators of multidrug resistance MDR . Two...
References Kdi
Nitsch R, Bechmann I, Deisz RA et al 2000 Human brain-cell death induced by tumour-necrosis- factor-related apoptosis-inducing ligand TRAIL . Lancet 356 827 828 Oza AM 2002 Clinical development of P glycoprotein modulators in oncology. In Mechanisms of drug resistance in epilepsy lessons from oncology. Wiley, Chichester Novartis Found Symp 243 p 103-118 Rodin EA, Rim CS, Rennick PM 1974 The effects of carbamazepine on patients with psychomotor epilepsy results of a double-blind study. Epilepsia...
Oc144093
Pgp, with an average EC50 of 32 nM Table 1 . Full reversal of MDR is observed at doses between 0.25 and 1.0 mM Newman et al 2000 . OC144-093 is at least as potent as other third generation Pgp inhibitors currently in development, such as LY335979 Dantzig et al 1996, Starling et al 1997 and XR9576 Roe et al 1999, Mistry et al 1999 . OC144-093 is not cytotoxic by itself against 15 normal, non-transformed or tumour cell lines, regardless of Pgp status, with an average cytostatic IC50 of 460 mM,...