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products whichdegrade easily): ( ) . .5 20. 11. (Real-time
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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
( ): .