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Chemo Secrets From a Breast Cancer Survivor

Breast Cancer Survivors

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ABC domains 57-58

models 61 ABC proteins 55 ABCB subfamily 20 ABCC subfamily 20 ABCG subfamily 20 ABC signature 55 ABC transporters 2-3, 20-23, 24-25 blockers 23 disease linkage 21-22 gene localization 21 monoclonal antibodies 23, 26 structure 21 substrates 22-23 absence epilepsy 6-7

action potentials, oligodendrocyte generation 202

acute lymphoblastic leukaemia 104 acute myeloid leukaemia 32, 104, 106 after-discharges (ADT) 151, 159-160 age of onset and intractability 10

AIF4 59

p-aminohippurate 42 ammons horn sclerosis 197 amygdala 150 animal models drug-resistant epilepsy 149-159 epilepsy induction 82 anthracycline resistance 23, 70 anti-epileptic drugs 43-44 ATPase assay screen 66 historical perspective 67-68 mode of action 48 monotherapy 10 site of action 48 testing model 65 when to start treatment 9 whole-tissue level 49 withdrawal, relapse risk 10 antiviral therapies 22, 75, 76

apoptosis 98,136,178

area under the concentration curve (AUC)

85-86, 87, 88 arterio-venous malformations 8 astrocytes 34,39,44,51,170-171 ataxia 109, 110,115-116, 117,215,223, 224

ATP hydrolytic cycle 58-59 ATPase assay 66 azido-ATP 59

balloon cells 170,172,176 bare lymphocyte syndrome 21 BCRP see breast cancer resistance protein BEfx 59

benign familial neonatal convulsions 14 benign syndromes 5 benzodiazepine tolerance 164,165 bepridil 23

bicarbonate permeability 193 bicuculline 190,193,195 bile salt efflux pump (BSEP) 20 biliary tract 104 biological assay 85 blockers 23

blood-brain barrier 35, 38-47, 137-139, 168 antivirals crossing 76 and drug design 39 and drug treatment 43-44 and epilepsy 43 MDR1 56,72,209 metabolism in 51

permeability and lipophilicity 39, 138 and Pgp 39-40,88,157,214-215 blood-cerebrospinal fluid barrier 42, 73, 168

antivirals crossing 76 blood-testis barrier 73 BmrR 57 brain anti-epileptic drug concentration 36

cerebrospinal fluid turnover 81 endothelium 33,34,38-39,51,72,

137-138 MDR1 expression 33-34 MRP expression 33-34 new connection formation 13 protection by MRP1 72-74 syndromes 5 breast cancer resistance protein (BCRP) 21,

23, 55,112 blockers 23

domain arrangement 56 hepatocyte expression 27 breast carcinoma, Pgp expression 215 bromide 67

C219 40

C494 169,171,177

Ca2+ channels 14, 118, 155-156, 197, 215 Caco-2 cells 229,231 callosal section 13 cAMP 76

canalicular membrane 27, 56

capillary endothelium 28, 33, 34, 38-39, 51,

72, 137-138 carbamazepine 68

daunomycin efflux inhibition 219 interictal discharges 101 kindling 160 and Pgp 34, 43 rhodamine efflux 232 therapeutic range 36 carboplatin 112 Cardiolyte® 91 cavernous angiomas 8 CD56+cells 89,209,211,212 CdCl2 resistance 22 cDNA gene array analysis 44 cell-cell adhesion 131 cerebrospinal fluid 42, 81 CFTR 22,55 CFTR/MRP subfamily 20 cGMP 76

Chinese hamster ovary (CHO) cell line 2 chloride gradient 193-195 cholesterol efflux genes 136 choroid plexus 42, 50, 56, 73 CIITA 128,130

cisplatin resistance-associated alpha protein

clinical development/trials 84-85, 108-112, 222-225

clinical resistance, definition 18 clobazam tolerance 164, 165 clonal selection 2

CNQX 190 colchicine 141-142 colon cancer 104 complex partial seizures 10 contraceptives, male 73 cortical malformations and intractability 7,10 Pgp and MRP1 expression 169-170, 172 cortical slices 186-199 neuronal properties 188 preparation 187-188 synapatic responses 188-191

frequency dependence 191-193 tissue viability 199-200 CPG55845A 193,195 crossover design 85 cyclosporin 85, 88, 108 cyclosporin A 23,65,143,215 cystic fibrosis 22

cystic fibrosis transmembrane conductance regulator 55 cytochrome P450 92, 112 CYP2C8 216 CYP3A4 51,116,178,216

D-APV 187,188-190 daunomycin efflux 219 daunorubicin, radiolabelled 142 dendritic cell migration/maturation 28 depolarization shifts (DS) 188-190,

191-193,195,197 developmental arrest/regression 7 dexamethasone 143

diabetes insipidus, etoposide-induced 73 dideoxyinosine, radiolabelled 76 dinitrophenyl glutathione 72 dogs, epileptic 150 dose escalation 116 dose-limiting toxicity 97 doxorubicin 22, 49-50, 85, 104, 110, 148 drug excretion, MDR1 role 88 drug tolerance 163-165

drug resistance acquired/intrinsic 16 history 1-2 mechanisms 74 proportion of cases 167 see also multidrug resistance drug-resistant clones 2 drug-resistant syndromes 7-9 drug-stimulated ATPase activity 58 Dubin-Johnson syndrome 21,70,234 dynamins 130-131

dysembryoplastic neuroepithelial tumours, Pgp and MRP1 expression 170-171, 172

dysmetria 110

dysplastic neurons 170,171,172 E

electroconvulsive therapy, seizures following 162

electroencephalogram, abnormal pattern 10 electron microscopy 43, 57 endothelium 28, 33, 34, 38-39, 51, 72, 137-138

epidemiology, developing countries 17 epilepsy heterogeneity 12 molecular basis 14-15 mortality 4, 9 prognosis 4-12, 15 epilepsy surgery, slices from 186-199 neuronal properties 188 preparation 187-188 synapatic responses 188-191

frequency dependence 191-193 tissue viability 199-200 epilepsy treatment history 9-10, 177 when to start 9 epipodophyllotoxin resistance 23, 70 epothiloneA 119-120 resistance 131

cell generation 121 cell selection 120 gene expression profiling 124-128 Pgp or MRP mediation 123-124 potential mechanisms 121-122 reversal 132-133 epothiloneB 119-120 epoxide hydrolase 128, 131,133-134

etoposide 22, 234

diabetes insipidus and 73 exon 2 polymorphism 44 exon 26 genotype 232 exon 26 polymorphism 44 expression profiling 124-128,180

febrile convulsions 6, 195 fexofenadine 184 focal cortical dysplasia 169, 179 follistatin 128 fumitremorgin C 23

GABAa receptors 14, 186-187,190, 191,

193,195,197, 200,201-202 GABAB receptors 186, 187, 191, 193, 195,

197,201,202 GABAergic inhibition 68 gabapentin 44, 234

mode of action 48 gene expression 124-128,180 GF120918 23,88,89 GLC4-Adr 50 glia 32, 33-34, 202 GLUT1 43 glutamate efflux 39 glutamatergic terminals 195,197 glutathione 22, 51, 70, 72 glutathione transferases 133 glycine 23 GTP binding 131

head injury 15 hepatocytes 27-28, 49, 56 hierarchical clustering 124 hippocampal sclerosis 11, 156

Pgp and MRP1 expression 170, 172, 175 hippocampus 161

therapy-refractory temporal lobe epilepsy 155-156 HisP dimer 61

HIV protease inhibitors 118, 143 HLA class I molecules 32 home-run trials 84-85 HPLC assay 231 hydrogen bonding 39

hyperbilirubinaemia 107, 109, 110, 116, 215,

225 hypoxia 172

imaging 90-92, 139-143, 145-146 immune response 32 Imodium 52, 118 indinavir 231 indomethacin 23 infantile spasms 7

inhibitory postsynaptic potentials, GABAA

receptor mediation 191 integrin b3 128

interferon-inducible genes 124, 130, 133 interferon-inducible GTPases 126, 134 interictal discharges, carbamazepine treatment 101 interleukins 32

interpatient variability 92, 117, 150 interstitial fluid 81

intracerebroventricular injection 81-82 intractability anti-epileptic drug treatment and 9-11 genetic predisposition 11 medication change 13 predictors 10 intractable syndromes 7-9 intravenous therapy 116-117 ion channels 14 ivermectin 45, 88, 148

juvenile myoclonic epilepsy 10 K

K+ channels 14 kainate model 44, 47, 183 KCC2 194,195,200-201 kindled rats 150-152, 159-160

anti-epileptic drug evaluation tool 152 drug resistance mechanisms 152-155 kindling 150

brain uptake of anti-epileptic drugs 156-157

changing cellular targets of anti-epileptic drugs 155-156 drug-induced delay or protection 160 humans 162 kinesin 131

Lafora's disease 7 Landau—Kleffner syndrome 8—9 Lennox—Gastaut syndrome 8 lesional partial epilepsy 8 leukotriene LTC4 28 levetiracetam 152, 162 lipophilicity 39,50—51,138,172 liver disease 21, 70 MDR transporters 27—28 stress, Pgp induction 174 loperamide (Imodium) 52, 118 lung mucosa 27

transplantation, verapamil scan 146—147 lung resistant protein 112 LY335979 217

major vault protein 28 male contraceptives 73 MalK 62

maximal electroshock seizure test 151, 229 maximum concentration (Cmax) 86, 87, 88, 92 maximum tolerated dose (MTD) 92, 110-111, 116 MDR/TAP subfamily 20 MDR1 3, 20,44, 55-57, 84, 93-94,104,139, 178,214 ATP-binding site mutations 60 ATP hydrolytic cycle 58-59 blockers 23

blood-brain barrier 56, 72, 209 brain expression 33-34 deletions 45

dendritic cell migration/maturation 28

domain arrangement 56

drug excretion 88

functions 28, 56

g-binding site 57

hepatocyte expression 27, 56

induction 184

induction following trauma 183 intramolecular interactions regulating activity 59-62 kidney expression 56 localization 56 MgATP binding 59

monoclonal antibodies 23, 26 polymorphisms 44-45, 207-210 action 210

functional consequences 211 tissue variation 210-211 structure 57

up-regulation and phenytoin 32 Walker A mutants 60-61 MDR1a 72,139,142,180,182, 214 MDRIb 180,181,214 MDR2 44

MDR3 20,21,27,55,139

membrane-embedded/transmembrane domains (TMDs) 55 mesial temporal epilepsy with hippocampal sclerosis 11 metabolic disorders 7 0-Mg model 193-195,200 MgATP binding 59 mibefridil withdrawal 52 microdialysis 163, 181-182 mitochondrial disorder 7 mitochondrial volume fraction 39 mitoxantrone 23, 85 MK571 23

molecular basis of epilepsy 14-15 monoclonal antibodies 23, 26, 168-169 C219 40

C494 169,171,177 MRK16 40,66 monotherapy, first line drug of choice 10 mortality 4, 9 MRK16 40,66 mRNA 194-195,200-201 MRP1 3,20,22,41,42,44,55,69,70, 167-168 blockers 23 choroid plexus 42, 73 dendritic cell maturation 28 domain arrangement 56 drug resistance 74-75 functions 28 hepatocyte expression 27 histological study 168-172 monoclonal antibodies 168-169 overexpression 171-172, 175 protection of brain and testis tissue by 72-74

Mrp 1 knockout mice 72-73, 80 MRP2 20,21,22,55,69,70 hepatocyte expression 27

valproate as substrate 44, 233—234 MRP3 20,22,55,69,70 MRP4 22, 42, 69, 70, 72, 75—76 MRP5 22,42,55,69,70,72 drug resistance 75—77 white cell expression 80 Mrp5 mutant mice 76—77 MRP6 21, 22—23, 27, 42, 69, 70, 72 MRP7 69, 70 MRP8 22 MRP9 22 MRPrl 168—169

MTS growth inhibition assays 120—121 multidrug resistance 19—20, 119,214 mechanisms 104, 105 reversal 83—96

home-run trials 84—85 imaging studies 90—92 interpatient variability 92 pharmacokinetic interactions 85—88 surrogate studies 88—90 transporters in 20—23, 24—25, 54—55 functions 28 history 83—84

monoclonal antibodies 23, 26 normal tissue localization 26—28 treatment-induced 104—105 multidrug-resistant proteins 11, 40—42, 69—79

disease associations 70 epithilone A-resistance 123—124 functions 70, 71 see also specific MRPs multiple myeloma 104 Mx protein 126,130,131

neocortical slices see cortical slices network phenomenon 13, 15, 161, 204-205 neuronal membrane 14, 48 neurons 48

dysplastic 170,171,172 properties 188 nifedipine 118

Pgp inhibition 51-52 nimodipine 52, 118 nipecotic acid 204 NMDA antagonists 44,160

NMDA-receptor mediated currents 187, 188-190, 193

non-competitive inhibition 66 non-Hodgkin's lymphoma 104 northern blotting 121

OAT 42,49 OATP-A 42 OATP family 42,49 Oatp1 42 Oatp2 42

OC144-093 116,214

clinical development 222-225 discovery and characterization 216-222 toxicity 226-227 occipital epilepsy 6

oligodendrocytes, action potential generation 202

onchocerciasis 45

OntoBLOCK® System 213

OntoCHROM™ 214

Ontogen 213,216

oral therapy 116-117

organic acid transporters (OAT) 42, 49

organic anion-transporting polypeptide

(OATP) family 42, 49 ovarian cancer 117

p44 126,130,131

P glycoprotein (Pgp) 22, 55, 83-84,137,139, 167-168,214 antagonists 84

anti-epileptic drug effects on expression 48

apoptosis 98, 178

at blood-brain barrier 39-40, 88, 157,

214-215 cancer 104-107 choroid plexus 42, 50 drug binding sites 43 drug interaction 50-51 electron microscopy 43 epothilone A-resistance 123-124 functional diversity 107 gain-of-function 66 in glia 33

histological study 168-172

history of development 2 induction following insult 175 inhibition 51-52,217 inverse correlation with response to therapy 105-106 lipophilicity and 50-51,172 monoclonal antibodies 169 normal tissue expression 107 overestimated relevance 97-98 overexpression 117, 168, 171-172, 175, 180

pharmacokinetic reactions 88 rifampin induction 184 St John's wort induction 184 stress response 47,174 transport, PET imaging 141-143 variability of human function 44-45 paclitaxel maximum tolerated dose 92 OC144-093 and 220-222 PSC 833 and 87-88, 89,110,111-112, 216 pain, periodic electrical stimulation 162 paired-pulse depression 191,195 paroxysmal depolarization shifts (PDS) 188, 193

paroxysmal kinesigenic choreoathetosis 22 partial seizures, lesional origin 8 penicillin 81

pharmacokinetics 85-88,110 interpatient variability 92 Phase 1 and 2 enzymes 51 phenobarbitone 172 history 67 kindling 160 Pgp substrate 43 phenytoin 172

brain entry, Pgp independence 34 daunomycin efflux inhibition 219 GABAergic inhibition 68 genetic differences in susceptibility to

153-155 history 67-68 kindling 160 MDR1 up-regulation 32 mode of action 48 and Pgp 43, 143, 168, 215, 234 susceptibility to 153-155 therapeutic range 36 phosphodiesterase inhibitors 76 placebo-controlled trials 9 placebo treatment 17-18

platelet-activating factor 178 PMEA (9-(2-phosphonylmethoxyethyl)-

adenine) 75—76 polymorphisms 15,23,92 MDR1 44—45,207—210 action 210

functional consequences 211 tissue variation 210—211 positron emission tomography (PET)

139—143, 145—146 postmortem tissue 176 postsynaptic potentials 188 potassium antimonyl tartrate resistance 22 pre-epileptic tissue 169, 177—179 probenecid 23, 233 prognosis 4—12, 15

progressive familial intrahepatic cholestasis 21,22

progressive myoclonic epilepsies 7 proinflammatory cytokines 32 PSC833 23,86,157,215,227,231 ataxia 115—116 clinical development 109—112 imaging 91

maximum tolerated dose 110—111 paclitaxel and 87—88, 89, 110, 111—112, 216

pseudoxanthoma elasticum 21, 22, 70 Pjrococcusfuriosus 62 pyruvate carboxylase 171

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