第一章、緒言

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1 (food additive) (nutritional supplement) cyclosporin A P-glycoprotein 2 8 (Lown et al., 1997) P-glycoprotein P-glycoprotein Paclitaxel Paclitaxel P-glycoprotein P-glycoprotein Paclitaxel Paclitaxel Paclitaxel 13

Anticancer drug Detoxification by glutathione (GSH) Rapid drug efflux via membrane Inability to enter apoptosis Modified availability or sensitivity of

2 Anticancer drug Detoxification by glutathione (GSH) Rapid drug efflux via membrane Inability to enter apoptosis Modified availability or sensitivity of drug target (eg topoisomerase II) Enhanced repair of drug induced DNA damage Failure to activate drug due to low levels of CYP (Harrison, 1995) 14

3 1-2 P-glycoprotein (Gremann, 1996) 15

4 1-3 ATP Binding Cassette (ABC) (Fricker, 2001) 16

5 H 2 N NH 2 Cl- Rhodamine 123 C 21 H 17 ClN 2 3 Mol. Wt.: Rhodamine

6 UT 1 Membrane TMD 1 TMD 2 3 IN 2 NH2 ATP NBD 1 ATP NBD 2 CH 2 (1) direction interaction with one or more of the binding sites on P-gp thus blocking transport by acting as competitive or non-competitive inhibitors. (2) Inhibition of ATP binding, ATP hydrolysis or coupling of ATP hydrolysis to translocation of the substrate. (3) Interaction with the lipid membrane of the cell thus pertubing the membeane enviroment or modifying the drug-membrane interaction. 1-5 P-glycoprotein (Stouch, 2002) 18

7 Step 1, drug substrate and ATP bind to Pgp. Step 2, binding of drug and ATP is followed by ATP hydrolysis. Step 3, following hydrolysis of ATP, both Pi and drug are released. Step 4, the ADP release (rate-limiting step) Step 5, Vanadate is provided to the system, Vi mimics Pi to trap ADP in a stable ternary conformation. Step 6, Vi nad ADP dissociate from Pgp (t 1/ min at 37 ) to initiate the next cycle. Drug ATP H 2 Pi Drug ADP Pgp Pgp Drug ATP Pgp Drug ADP Pi Pgp ADP Pgp Vi 5 Pgp ADP Vi Vi ADP Pgp P-glycoprotein ATP (Kerr, 2001) Na Na V Na Na 3 4 V Mol. Wt.: Sodium orthovanadate 19

8 Flavones ' 3' 4' 5' 6' 1' B A C Flavanones ' 3' 4' 5' 6' 1' B A C Flavonols ' 3' 4' 5' 6' 1' H B A C 6 Isoflavones ' 4' 6' 1' B A C 5' 2' Chalcones ' 2' 3' 4' 5' 6' B A α β 1-8 Flavonoids 20

9 R 2 H R 1 NH 6 H 13 H 2 C CCH 3 Paclitaxel : R 1 = - CC 6 H 5 ; R 2 = - CCH 3 C 47 H 51 N 14 Mol. Wt.: Docetaxel : R 1 = - CC(CH 3 ) 3 ; R 2 = H C 43 H 53 N 14 Mol. Wt.: Paclitaxel Docetaxel 21

10 Paclitaxel CYP 3A4 CYP 2C8 3 -p-hydroxypaclitaxel 6 - hydroxypaclitaxel CYP 2C8 CYP 3A4 6,3 -p-dihydroxypaclitaxel 1-10 Paclitaxel 22

11 1-1 (Bates, 1996) Drug transport Impaired Entry Enhanced Efflux Altered Drug Metabolism Impaired Activation Enhanced Inactivation Altered Target Increased/Decreased Expression Mutation Altered Repair Alterations in Cell Survival Pathways ncogenes Apoptosis Growth factors/receptors 23

12 1-2 P-glycoprotein (Germann, 1996) rganism Drug transporters Phospholipid transporters Human MDR1 MDR2 Mouse mdr1a, mdr1b mdr2 Rat mdr1a, mdr1b mdr2 Hamster P-gp 1, P-gp 2 P-gp 3 MDR = multidrug resistance; P-gp = P-glycoprotein 24

13 1-3 ABC transporter (Borst, 2002) Name Sub-family Members ABCA ATP-binding cassette, sub-family A (ABC1) 12 ABCB ATP-binding cassette, sub-family B (MDR/TAP) 11 ABCC ATP-binding cassette, sub-family C (CFTR/MRP) 12 ABCD ATP-binding cassette, sub-family D (ALD) 4 ABCE ATP-binding cassette, sub-family E (ABP) 1 ABCF ATP-binding cassette, sub-family F (GCN20) 3 ABCG ATP-binding cassette, sub-family G (WHITE) 5(1?) 25

14 Tissue Small intestine and colon Liver Kidney CNS Testis Placenta 1-4 P-glycoprotein (Fromm, 2002) Localization Function Apical (luminal) membrane of epithelial cells Secretion of drugs into gut lumen Canalicular membrane of hepatocytes Secretion of drugs into bile Apical membrane of epithelial cells of proximal tubules Secretion of drugs into tubules lumen Luminal membrane of endothelial cells forming the blood-brain barrier Protection of CNS from xenobiotics Endothelial cells of capillary blood vessels Blood-testis barrier Trophoblasts Protection of fetus from xenobiotics 26

15 1-5 P-glycoprotein (Lum, 1993) High Moderate Low Adrenal cortex Adrenal medulla Skin Kidney Trachea vary Colon Lung (major bronchi) Heart Liver Placenta Small bowel Brain Testis Pancreas Spleen Esophagus Stomach Skeletal muscle Spinal cord Bone marrow Macrophages 27

16 1-6 (mouse) (rat) multidrug resistance (MDR) genes (Silverman,1997) Tissue Human Mouse Rat Liver Small intestine Colon Kidney Lung Spleen MDR1 MDR2 mdr1a mdr1b mdr2 mdr1a mdr1b mdr2 Uterus Uterus when pregnan Brain Heart Skeletal muscle to indicate increasing levels of expression; indicates not found; = not determined 28

17 1-7 P-glycoprotein (Fromm, 2002) Drug Anticancer agents Antibiotics actinomycin D erythromycin etoposide levofloxacin docetaxel sparfloxacin doxorubicin Steroids daunorubicin dexamethasone irinotecan Lipid-lowering agents mitomycin C simvastatin paclitaxel lovastatine teniposide Calcium channel blocker metabolites topotecan ditiazem vinblastine mibefradil vincristine verapamil Cardiac drugs D-617 β-acetyldigoxin D-620 α-methyldigoxin β-adrenoceptor antagonists digitoxin bunitrolol digoxin celiprolol quinidine talinolol HIV protease inhibitors H 1 -antihistamines amprenavir fexofenadine indinavir terfenadine nelfinavir H 2 -antihistamines saquinavir cimetidine ritonavir ranitidine Immunosuppressants thers cyclosporine A colchicine tacrolimus debrisoquine Antiemetic drugs losartan domperidon morphine ondansetron phenytoin Antidiarrheal agents rifampin loperamide 29

18 1-8 MDR ( ) (Silverman, 2000) First generation Amiodarone Cremophor EL Cyclosporin A FK506 Trans-flupenthixol Ketoconazole Progesterone Quercetin Quinidine Rapamycin Rapamycin Reserpine Staurosporine Tamoxifen Trifluoroperizine Verapamil Second generation BIBW22 GG918(GF120918) LY PAK200 PSC 833(Valspodar) SDZ VX-710(Biricodar) SCH66336 MS-209 XR

19 1-9 HUCHE 01 Artemisiae Capillaris Herba Flavonoids HUCHE 02 Chamomillae Flos Flavonoids HUCHE 03 Digitalis Folium Flavonoids HUCHE 04 Digitalis Folium Flavonoids HUCHE 05 Swertiae Herba Flavonoids HUCHE 06 Swertiae Herba Flavonoids HUCHE 07 Aurantii Fructus Immaturus Flavonoids HUCHE 08 Astragali Radix Flavonoids HUCHE 09 Astragali Radix Flavonoids HUCHE 10 Sennae Folium Flavonoids HUCHE 11 Sennae Folium Flavonoids HUCHE 12 Hydrangeae Dulcis Folium Flavonoids HUCHE 13 Gambir Tannin HUCHE 14 Ergota Sterol HUCHE 15 Paeoniae Radix Tannin HUCHE 16 Zingiberis Rhizoma Flavonoids HUCHE 17 Glycyrrhizae Radix Flavonoids HUCHE 18 Cinnamoni Cortex HUCHE 19 Gambir Tannin HUCHE 20 Aurantii Fructus Immaturus Flavonoids HUCHE 21 Aurantii Fructus Immaturus Flavonoids HUCHE 22 Sophorae Flos Flavonoids HUCHE 23 Aurantii Fructus Immaturus Flavonoids HUCHE 24 Flavonoids HUCHE 25 Citri Reticulate Flavonoids HUCHE 26 Scutellariae Radix Flavonoids HUCHE 27 Scutellariae Radix Flavonoids HUCHE 28 Scutellariae Radix Flavonoids HUCHE 29 Puerariae Radix Flavonoids HUCHE 30 Puerariae Radix Flavonoids HUCHE 31 Puerariae Radix Flavonoids HUCHE 32 Viscum Coloratum Flavonoids HUCHE 33 Viscum Coloratum Flavonoids 31

20 1-9 ( ) HUCHE 34 HUCHE 35 Artemisiae Capillaris Herba Flavonoids HUCHE 36 Swertiae Herba HUCHE 37 Paeoniae Radix Flavonoids HUCHE 38 Cinnamoni Cortex HUCHE 39 Cinnamoni Cortex HUCHE 40 HUCHE 41 Paeoniae Radix Tannin HUCHE 42 Pyracantha fortuneana Flavonoids HUCHE 43 Aurantii Fructus Immaturus Flavonoids HUCHE 44 Flavonoids HUCHE 45 Amomi Cardamomi Fructus HUCHE 46 Cinae Flos(Santonica) HUCHE 47 Cardamomi Fructus HUCHE 48 HUCHE 49 Cardamomi Fructus HUCHE 50 Cinae Flos(Santonica) HUCHE 51 Glycyrrhizae Radix Saponin HUCHE 52 Zizyphi Fructus Triterpenoid HUCHE 53 Zizyphi Fructus Triterpenoid HUCHE 54 Aurantii Fructus Immaturus Flavonoids HUCHE 55 Flavonoids HUCHE 56 Cinnamoni Cortex HUCHE 61 Mori Radix Cortex Flavonoids HUCHE 62 Paeoniae Radix Flavonoids HUCHE 63 Propolis Flavonoids HUCHE 64 Zingiberis Rhizoma Flavonoids HUCHE 65 Paeoniae Radix Flavonoids HUCHE 66 Hibiscus Abelmoschus Flavonoids HUCHE 67 Vernonia Cinerea Flavonoids HUCHE 68 Apple Flavonoids HUCHE 69 Ardisia squamulosa HUCHE 70 Tamarix Aphyiia Flavonoids HUCHE 71 Ginko Biloba Flavonoids 32

第38章抗肿瘤药.ppt

第38章抗肿瘤药.ppt 1. 2. DNA RNA 3. cell cycle nonspecific agents CCNSA cell cycle specific agents, CCSA growth fraction GF GF CCNSA CCSA DNA DNA RNA DNA natural resistance acquired resistance multidrug resistance MDR