1. , -2012

2. 3. , , . , , . 2012 4. , , , , (), . . , , , , , , . , . (review) , , , . , . , , . , , , , . 2012i 5. . , , . , , . , , . , , , , . , , , , . . , , . , . , , . , . , . ii 6. , , . . , , , , , . , , , , , -. , , , , . , . , . , , , . , , C, , , . , , (stress). , , , . , , , , iii 7. , , , , . PowerPoint . www.greenchemistry.gr. iv 8. .i.iiv.....xi1. ....1 1.1 ......2 1.2 ...........2 1.3 & ..........42. , ....7 2.1 ........8 2.2 ......102.2.1 .......12 2.3 ......17 2.4 ....19 2.4.1 ...19 2.4.2 ...20 2.4.3 .......223. ..26 3.1 ...27 3.1.1 ..27 3.1.2 30 3.1.3 .....32 3.2 & ...334. N ...38 4.1 ...39 4.2 ...39v 9. 4.2.1 , ...39 4.2.2 ...41 4.2.3 .....42 4.2.4 & ...44 4.2.5 ..44 4.2.6 45 4.2.7 ....47 4.2.8 .....48 4.2.9 ....48 4.2.10 ..49 4.2.11.494.3 ........50 4.3.1 ..50 4.3.2 ...51 4.3.3 .....51 4.3.4 ....51 4.3.5 , ...52 4.3.6 ..53 4.3.7 ..53 4.3.8 .54 4.3.9 ......54 4.3.10 .54 4.3.11 ....554.4 55 4.4.1 .....55 4.4.2 ..55 4.4.3 , ..56 4.4.4 ....57 4.4.5 ..57 4.4.6 ...58 4.4.7 ...60 vi 10. 4.4.8 62 4.4.9 ..63 4.4.10 63 4.5 ..63 4.5.1 .....64 4.5.2 ....64 4.5.3 ..64 4.5.4 , 65 4.6 (Glivec GleevecTM).67 4.6.1 ....67 4.6.2 .....67 4.6.3 68 4.6.4 ......68 4.6.5 ...69 4.6.6 69 4.6.7 .71 4.6.8 ...71 4.6.9 ..72 4.7 -72 4.7.1 ....72 4.7.2 .73 4.7.3 .73 4.7.4 ..73 4.7.5 ...74 4.7.6 ..75 4.7.8 ..755. , ..76 vii 11. 6. ...81 6.1 ....82 6.2 ( C).83 6.2.1 .....83 6.2.2 ..84 6.2.3 ....85 6.2.4 C..85 6.2.5 ...86 6.2.6 C.86 6.2.7 C..87 6.2.8 ...88 6.2.9 ...88 6.2.10 88 6.2.11 Linus Pauling....89 6.3 ...91 6.3.1 .....91 6.3.2 ......92 6.3.3 ...92 6.3.4 .....92 6.3.5 .......93 6.3.6 ...94 6.3.7 , ...95 6.4 ..95 6.4.1 ...95 6.4.2 ...96 6.4.3 ....96 6.4.4 ..97 6.5 98 6.5.1 ...98 viii 12. 6.5.2 ..996.5.3 ....996.5.4 ........1016.5.5 .........1026.6 (Graviola).1036.6.1 ..1036.6.2 Graviola...1036.6.3 .....1066.7 Laetrile ( B-17) ..1066.8 714-...1086.9 Essiac..1096.10 & ....1116.10.1...1116.10.2 .....1126.10.3 ..1136.10.4 ..1156.10.5 ....1166.10.6.1176.10.7 ....1196.10.8 ...1206.10.9 ......1206.10.10 ....1216.10.11 ...1226.10.12 ......1236.10.13 ()....1246.10.14 ....1256.10.15 ....126 ix 13. 6.10.16 .....128 6.10.17 .....136 6.11 , .....137 6.11.1 ....137 6.11.2 . Budwig....139 6.11.3 . Gerson.....143 6.11.4 .....144 6.12 Lorraine Day..1467. ...149 7.1 ...150 7.2 ...1508. , .1549. ...15710. ..162 10.1 & .....163 10.2 ..169 10.3 & ......171 10.4 .....178 10.5 PowerPoint ..180x 14. , . . , , . . , . , . , , . , . , , , , (stress). , , . xi 15. 1. 1 16. 1. 1.1 . , , . . 1960 , . , . , , , , , , . , .1.2 (Green Chemistry) , . , . , . 2 17. (, , , , ,..) , . , ( 600-700 ) . (, , , , , ,, , , ..). , . , . , (), ., . . 1975, . , , , . . / 3 18. (Green and Sustainable Chemistry), .1.3 & , . , 20 21 , , . . . , . , . , , . (12) . .1. (Prevention): . , , .2. ( ), (Maximizesynthetic methods, Atom Econmy): , , .3. (Less hazardous chemical synthesis): , 4 19. .4. (Designing safer chemicals): , . .5. (Safer solvents and auxiliary substances): . , .6. (Design for energy efficiency): . .7. (Use of renewable feedstocks): (, , , ..).8. (Reduce intermediate derivatives): ( ,-, / ). , .9. . (Catalysis, catalytic reagents): , , .10. (Design products whichdegrade easily): ( ) . .5 20. 11. (Real-time analysisfor pollution prevention): , .12. (Inherently saferchemistry for accident prevention) , , , . . , , , . [1,2] 6 21. 2. 7 22. 2. 2.1 , . , , . 1600 .. , . . . . 460-370 .. (, , ). , , . 1300 .. , . , . , . 15 , . 1628 . 1761 Morgagni . 8 23. . JohnHunter (1728-1793) , . . ( ) , . 19 , Rudolf Virchow. , . , . Virchow , . . 17 18 , . , , . 1779, . 19 20 , , . . , . 1911 Peyton Rous Rockefeller , . , Rous. 9 24. 1968. 1915 , , . , , , . . , , . . [3]2.2 , . , . . 1996925.146 . , , . 400 100.000 . , . , . , , . , . , . , , . 10 25. , , , , , , . . , , , , . . , , . , . , ( -HPV, - HV, C - HCV, - HIV, ..) . , , , , . . , . , , .. . , , , , , , .. , , : ; , . ; , . ; , . 11 26. . , 20% , , 30%. 5% . , , . , . , . [4]2.2.1 . . , . (initiation) . , , . DNA, DNA, . , 12 27. DNA, DNA. , . , (promotion) , , .2.2.2 Watson Crick , DNA, . , , [5]. , DNA, . , DNA [5]. 1948 J.A.Miller , [6], 1960 p450 . 57 CYPs(Cytochrome p450 dependent monoojynases) [7]. CYP 1-3.[8] ( ), DNA, DNA ( 1). DNA , 13 28. DNA. DNA, , , [9]. DNA (excision repair) [10]. DNA DNA , - / 1: .14 29. DNA, , DNA, . ( ) DNA, DNA , , [11]. . , stress [12], , . . , (). (). , ( ) (). : 1. , . in vitro 50 ( Hayflick). 2. , , . . , 15 30. . , , . , . ; , , , , , , , . , , . , . (proto-ogogenes) (tumor suppressor) . , . . , , , . , DNA . , , . , . , . , , , , , , , , ( C ). 16 31. . , , (stress) [13].2.3 . . . : 1. 20% . , 17%. . , , , , . . 2. 40% 60% . Non-Hodgkin , . ( ), . . 3. 60% 80% . , , . ( ). , . 17 32. , . , , . . . 4. 80% : , . , , , . 24%. . CA13-5 . . . . , , . DNA, (). , . [13].18 33. 2.4 2.4.1 2007 , 20.000 . 7,6 . , , 12,3 . 6,7 .. 4,7 . , 5,4 . 2,9 . . , 10 2020 16 ! 15% Global Cancer Facts & Figures 2007. , , , , , . , , , , , . , 2000. 1/3 100 20 . 21 ! 70% . 13% 58 2005. , , .19 34. : 1,3 . . 1 . . 662.000 . 665.000 . 502.000 . , : , , , , , . : , , , , . , . , , , .[14]2.4.2 3,2 2006, 300.000 20 35. 2004, 53% 47% (Ferlay et al, 2007). 429.900 (13.5%). 412.900 (12.9%). 386.300 (12.1%). 1,7. (56% 44% ) 2006. 334.800 , 1/5 , , 2020, . 334.800 . 207.400 . 131.900 . 118.200 , . , , . H 20 1980 2006, , , 1980 (Levi at al, 2002). , , 2004, 161,9 100.000 , 182,43 .. , , 20 , (161,14 1985 161,9 100.000, 2004). [14]21 36. 2.4.3 , , , , , . , , . , . , ; , (, , , , ,..) , . , , ( 600-700 ), . (, , , , , ,, , , ..). , . , , . , 22 37. (), , . . , . . , , , . . , . , , . , . . . , . , , , , . . , , , - .23 38. , . , " , , . , . , . ... . , (research & development) , , CO2, , . , , . , , (hazardous) , . . (risk) ( ) = (Risk = Hazard X Exposure) . ( , , ,, , ..), 24 39. ( ). . , , . . , , , ( ). , , , , , , , . [2,15]25 40. 3. 26 41. 3. 3.1 3.1.1 , , . . . , . . . ( -) , . , . , , . , . , . , . , , . . . , , , , . , 27 42. , [13,16]. , . . , . , . ( , ). : : . : DNA . : DNA . : . . : DNA . : . : Gleevec . : . 28 43. . : . . , . Burkitt, Wills, . , . , , , , , . , . , 99% . , 42% . . , , , . , , , . I , . III IV , . , . 29 44. [13]. Der Spigel, . , , , , . , 95%, 1,8 . , , , 25 . , . , . , , . , , . . . , . , Mayo-Clinic , , , .3.1.2 . 30 45. . (MajorHistocombatibility Complex MHC) . MHC - . - - . - . - -. . . . . . 7 . DNA . . 1892 Memorial . William B. Colley . : ( (Tumor Necrosis Factor- TNF)) (IL2-IL12) GM-CSF. 31 46. . . . . , , . . . . . . , -, TNP-470, . .3.1.3 , , . , , . 32 47. , .[13]3.2 & . 15 , 802 . in vitro . ( NCI) . 40 . 400.000 . [17] , . . . () ( ) . . in vitro . in vitro, . 33 48. . , . (NCI) 1960 1982 L1210 P-388. , , , , , , , . , ( ), , . in vivo , , . , in vitro 1985 1990. NCI 60 , . , . 60 NCI , . , .34 49. in vitro , . . . : . . . . . (NCI,2001). . . . . . . : , , , . 20 80 . 35 50. . . . . . . . . 100 300 . . . . 1000 3000 . . . V FDA (). . . , , . , . , . , . :36 51. [13]. 37 52. 4. 38 53. 5. 4.1 , , 250.000 , , , , . . 5.000 , , . , , , . , , , , , , , . , 15 ( ), ., (Campotheca,podophyllum,Taxus ) , . , : , Vinca Taxus. [18]4.2 4.2.1 , (vinca alkaloids), , 39 54. . Catharanthus roseus, . , Vinca rosea, . Robert Noble Charles Beer. 1959, . , (vincristine) (vinblastine) . , , (vindesine) (vinorelbine) . , , , : () (). ( , ), . (-) , , , . (5--) , [19,20]. O ( 2) : .:C46H56N4O10 .:C46H58N4O9 .:C43H55N5O7. .:C45H54N4O840 55. 2: .4.2.2 . , , , , , , . , (tubulin ) (tubulin ). 450 55.000 kDa. . 13 . 41 56. . , , . , . , . , , , () cAMP, () , () t-RNA DNA-, () , () .4.2.3 in vitro . (multidrug resistance, MDR), . MDR mdr-1 1.280 , - 170, 170 kDa. 170, , , , , , . 170 , . 170 , . , , , 42 57. , , , D, C, . 1994 , 1(multidrug resistance associated protein 1, MRP1), 190 kDa, 15% 170. MRP1 16p13.1 170 7q21.1. MRP1, , . 170, MRP1 , . MDR . in vitro MDR , , ,, , . , , . - , . , , , - . , . , . , , , . , , . 43 58. 4.2.4 & , , . , . , . , . , , . . , CYP3A P-450 . . , , 50% 1,5-3mg% 75% 3mg%. . , .4.2.5 in vitro , . in vitro , , . , , , . L- , , .44 59. 12 24 L-. C , . CYP3A -450 (,, , , , , , , , , , ) . . 10 [19,20].4.2.6 , . , . , . , . , . , , . , , . . , , , , , . , (),, , , . , . , , , , 45 60. , , , . . , , , , . , , . 2mg, , . 25mg. (, CharotMarieTooth), . , , . , , , , 15 -20mg., . , , . . , . 1, 6 12, . , ., , . . 46 61. , . , , , . [19, 20, 21].4.2.7 , . . , 5-10 . , , . . , . , . , , . , , , , . . 2-3 . , , , , , , , , , , , . . . . 47 62. . , . , 5%. , , , , , , Raynaud, , , ( ), , , .[19,20]4.2.8 1,4mg/m2, 0,4mol. 4875%. . 2385 . . 12% 72 ( ). , , , Hodgkin, nonHodgkins, , Ewing . . , 0,050 0,065 mg/Kg/ 1,4mg/m2/ . 2mg. , 96 , 0,2mg/m2/ ( VAD)[19,20].4.2.9 6mg/m2, 0,4moL. 2024 . P450 CYP3A 4deacetylvinblastine ( ). 48 63. , , . 6 mg/m 2, 1,52mg/m2 , 5 C. Hodgkins, non -Hodgkins, Kaposi, , , , . .[19, 20 ,22]4.2.10 , 3mg/m2 , 0,11,0mol, 2024 . , 4mg/m 2 3mg/m2 , . , 1,3mg/m2 5 21 . ( ), . , , , , . [19, 20]4.2.11 , , . 1849 . . , , , , . , , CYP3A P450. , 1625%. 2530mg/m2 . 49 64. 43%. 6080mg/m2 . 12 . o , , . , , (Herceptin)., , Hodgkin, Hodgkin , [21, 20].4.3..: C20H16N2O4Mr=348.3524.3.1 , . 1966, Wall Wani, . Camptotheca acuminata, , (Xi Shu ). , . , . , . (Hycamtin) (Camptosar) , 1996 FDA () Pharmacia Glaxo Smithkline. 50 65. 4.3.2 , ( ), (C), ( D) - ( ) S 20 (C-20). R- C-20 . , . 3: 4.3.3 () . , , . , . , ( ), . , . ( ), (, ), .4.3.4 DNA. DNA . , 51 66. DNA . (), :) C-20 533 (sp 533) ) C-21 364 (Arg 364). D DNA C-17. 4: - -DNA.4.3.5 , 7,9,10 11 , 12 14 . :1) 7 , . 52 67. 2) C D .3) C-20 C-21. (hCPT). H , . 5: 4.3.6 . , DNA. DNA. , DNA- , . S . . , , , ,, ..4.3.7 . SN-38 ( ). 53 68. , . .4.3.8. . Wall Wani, (1966). , , (,,) . Lopez-Avila Benedicto Janet. , Camptotheca Acuminata . , CO2 ( ).4.3.9 , , , , ( , ). , ( ) CO2 200 atm ( 400 atm) 400C ( 50-600C). CO2 . ( ), . , . , , 350atm, ( 20% ). ( 5 ), . , CO2 . . .4.3.10 1. CO2. 54 69. 2. To CO2 , , , , , , , .3. 50% 85%.4. .4.3.11 . , , , . , . , , . , . , . CO2 31,10C 72,9atm. [23, 24, 25, 26]4.4 ()4.4.1 .. : C47H51O14Mr=853,906 ..=214,50C: ( ): , , , (DMSO).4.4.2 1962 Arthur Barclay, 200 . , (Pasific yew tree), Taxus brevifolia ( ), Packwood Washington.55 70. 1964 , Taxus . , , . 1967 () American ChemicalSoseity (Miami Beach). To (CI) . 1969 28Kg 1200Kg , ( ) 10g . 1971 Journal of American Chemical Sosiety(JACS), , 1977, 600g 3,5 . 1978 .4.4.3 , 1982 NCI . 1984 . . , , . . ( 1988), . , NCI . 1992 Bristiol-Myers Squibb(BMS) NCI, FDA . 5 . 1993 BMS , , 2000, 1592 ., 4,3 .. 56 71. 4.4.4 Susan Horwitz (Albert Einstein College of Medicine). , : (hyperstabilization of microtubules). (25nm), 0,2-25m, - - . . , (GTP), . -. ( ). . , -, , . () .4.4.5 , (0,01-0,03%). 1Kg 10 3000 . 360000 . , , , . . Robert Holton , . 10- (10-DAB), 57 72. Taxus baccata. 10-DAB (9 C 11 ). (0,1% ) 10-DAB. 10-DAB, . C-13 (--2R,3S-3--), - ( Ojima). , 10-DAB, . , -, : 6: 10-DAB.4.4.6 , , , . . , , , . 90 , 30 . . Holton . 58 73. Holton ( ) 1994 Holton, (linear) , . (-) , 13 , (1). -(2), (3), (4), . C Robinson-Stock. 7: ( Holton). . ( ,San Diego) o 1994, (convergent) . C , Shapiro ( , ). McMurray( , ) . D ( Ojima) 13.E 8: ( ). 59 74. 9: Holton--Danishefsky : , .4.4.7 ( BMS) , ., , , - ( ), ( , ), . , , , , , . (PCF) . Phyton Biotech GmbH, , , Taxus chinensis. , 1 , ( 60 75. ), . , ( ) , , . ( ), , . , , , . , ., . , , . . BMS 2004 . 1993 , . 61 76. 10: .4.4.8 - , . Kaposi. . , . (1/1) , Cremophor L ( BASF). Cremophor L . , (/ NaCl 0,9%) / 5%, . Abraxane - . , . 62 77. (99,5%) 235 1g( 2009).4.4.9 ( ): 6,5% : 89-98%: : 5,8 : ,.4.4.10 , . : , , , , , ,, . . [27, 28] 11: 11 . , (,C) (). D () C4.5..: C22H22O8Mr=414,4163 78. 4.5.1 Podophyllumhexandrum Berberidaceae. O . .hexandrum, , , .peltatum, , . Podophyllum. H , .4.5.2 250. . , . Catesby to 1731 Carolina,Florida and Bahama Islands. 19 . 1942 (,) . , , , , .. , , . .hexandrum .4.5.3 , .64 79. . . .4.5.4 , , . 7 4. , . , Hodgkins, . , , .n vitro . , , . , , in vitro ( ) , . (Kadkade,1981-1982) P.peltatum. .hexandrum . 1989 Van Uden .hexandrum . Van Uden : 5 2% , 4% 4mg/L .65 80. 150prm. . . 0,3% . , 15, . Woerdenbag(1990) .hexandrum, , -, , 0,012%. , in vitro, , , .: : : : 50 .: 3 / : ( 12,5%, 20-25%, 5-15%) ( 20-25%). : WARTEC/Gambriel Health: cr.ext. us 0,15% tub x 5gsol.ext. us 0,5% fl x 3ml. [29] 66 81. 12: 4.6 (Glivec GleevecTM)4.6.1 ..: C29H31N7O ( ) r=493,6M.T.: C30H35N7O4S ( ): .