cay thong do va hop chat taxol

I HC QUC GIA H CH MINH TRNG I HC BCH KHOA

KHOA K THUT HA HC B MN CNG NGH SINH HC

n chuyn ngnh

CY THNG V HP CHT TAXOL

CBHD: TS. L TH THY TIN

SVTH: NGUYN H HONG ANH

MSSV: 60700056

B MN: CNG NGH SINH HC

Tp. HCM, thng 06 nm 2011

LI CM N

Trong qu trnh thc hin n mn hc ti xin gi li cm n n:

Tin S L Th Thy Tin B mn Cng ngh Sinh Hc, i hc Bch Khoa Tp HCM hng dn tn tnh cng nh cho nhng li khuyn b ch ti c th hon thnh tt n.

Cc thy c trong b mn Cng Ngh Sinh Hc truyn t cho ti nhng kin thc hu ch gip ti c c nhng nh hng r rng trong khi thc hin n.

Cc bn sinh vin lp HC07BSH cng hc tp, trao i kinh nghim v gip ti.

Ti xin chn thnh cm n mi ngi.

i

MC LC

MC LC ....................................................................................................................... i

CC T VIT TT...................................................................................................... iii

DANH MC HNH....................................................................................................... iv

DANH MC NH ........................................................................................................ vi

DANH MC BNG .................................................................................................... vii

CHNG 1: M U .................................................................................................. 1

CHNG 2: TNG QUAN .......................................................................................... 3

2.1 Tng quan v cy Thng .............................................................................. 3

2.1.1 Gii thiu chung v h Taxaceae .................................................................. 3

2.1.2 Gii thiu chung v chi Taxus ....................................................................... 9

2.1.3 Mt s loi Thng trn th gii ............................................................. 16

2.1.3.1 Taxus baccata ........................................................................................... 16

2.1.3.2 Taxus brevifolia ........................................................................................ 18

2.1.3.3 Taxus canadensis...................................................................................... 19

2.1.3.4 Taxus cuspidata ........................................................................................ 21

2.1.3.5 Taxus floridana ........................................................................................ 23

2.1.3.6 Taxus globosa ........................................................................................... 25

2.1.3.7 Taxus chinensis ........................................................................................ 26

2.1.3.8 Taxus wallichiana .................................................................................... 28

2.1.4 Tnh trng hin ti v bo tn loi Thng Vit Nam .......................... 29

2.1.4.1 Thng Bc (Taxus chinensis Pilg.) ..................................................... 30

2.1.4.2 Thng Nam (Taxus wallichiana Zucc.).............................................. 33

2.2 Taxol .................................................................................................................. 36

2.2.1 Lch s nghin cu ...................................................................................... 36

2.2.2 Cu to Taxol ............................................................................................... 39

2.2.3 Con ng sinh tng hp Taxol .................................................................. 40

ii

2.2.4 C ch tc ng ca Taxol .......................................................................... 45

2.2.5 Mt s phng php tng hp hp cht Taxol ........................................... 49

2.2.6 ng dng hp cht Taxol trong iu tr bnh ung th ................................ 57

Chng 3: MT S KT QU VI NHN GING TAXUS ................................ 64

3.1 Vi nhn ging Taxus baccata L. ...................................................................... 64

3.1.1 Mi trng nui cy .................................................................................... 64

3.1.2 Cc giai on ca qu trnh vi nhn ging .................................................. 65

3.1.3 Kt lun ........................................................................................................ 70

3.2 Vi nhn ging Taxus wallichiana Zucc. .......................................................... 70

3.2.1 Mi trng nui cy .................................................................................... 71

3.2.2 Cc giai on ca qu trnh vi nhn ging .................................................. 73

3.2.3 Kt lun ........................................................................................................ 79

Chng 4: KT LUN ................................................................................................ 80

TI LIU THAM KHO ............................................................................................ 81

iii

CC T VIT TT

FDA U.S. Food and Drug Administration Cc qun l Thc Phm v Dc

Phm Hoa K.

CITES Convention on International Trade in Endangered Species Cng c

thng mi quc t i vi cc loi gp nguy him.

IUCN International Union for Conservation of Nature T chc bo tn thin

nhin th gii.

NCI U.S National Cancer Institute Vin ung th quc gia Hoa K.

CRADA Cooperative Research and Development Agreement Hip nh hp tc

nghin cu v pht trin.

BMS Bristol-Myers Squibb.

GGPP Geranylgeranyl pyrophosphate.

IPP Isopenthenyl diphosphate.

DMAPP Dimethylallyl diphosphate.

10-DAB 10-deacetylbaccatin III.

DAB Baccatin III.

NAA -naphthaleneacetic acid.

IAA Indole-3-acetic acid.

IBA Indole-3-butyric acid.

BA 6-benzyladenine.

iv

DANH MC HNH

Hnh 2.1: Amentotataxus argotaenia Pilger. ...................................................................... 5

Hnh 2.2: Austrotaxus spicata Compton. ............................................................................ 6

Hnh 2.3: Torreya nucifera (L.) Siebold & Zucc. ............................................................... 6

Hnh 2.4: Pseudotaxus chjenii (Cheng) Cheng. ................................................................. 7

Hnh 2.5: Taxus cuspidata Siebold & Zucc. ....................................................................... 7

Hnh 2.6: Phm vi phn b ca h Taxaceae. .................................................................... 8

Hnh 2.7: Phm vi phn b ca mt s loi thuc chi Taxus. .......................................... 11

Hnh 2.9: Phm vi phn b ca Taxus baccata khu vc Bc M. ................................. 17

Hnh 2.11: Phm vi phn b ca Taxus brevifolia khu vc Bc M. ........................... 19

Hnh 2.13: Phm vi phn b ca Taxus canadensis khu vc Bc M. ......................... 21

Hnh 2.15: Phm vi phn b ca Taxus cuspidata khu vc Bc M. ........................... 23

Hnh 2.17: Phm vi phn b ca Taxus floridana khu vc Bc M. ............................ 24

Hnh 2.19: Phm vi phn b ca Taxus globosa. ............................................................ 26

Hnh 2.21: Phm vi phn b ca Taxus chinensis. ........................................................... 27

Hnh 2.23 : Thng Bc (Taxus chinensis Pilg.). ......................................................... 30

Hnh 2.24: Phm vi phn b ca Thng Bc (Taxus chinensis Pilg.) Vit Nam. .... 31

Hnh 2.25: Thng Nam (Taxus wallichiana Zucc.). ................................................... 33

Hnh 2.26: Phm vi phn b ca Thng Nam (T. wallichiana Zucc.) Vit Nam. ... 34

Hnh 2.27: Cu trc ca Taxol. ......................................................................................... 39

Hnh 2.28 : Con ng sinh tng hp Taxol. ................................................................... 43

Hnh 2.29: Qu trnh hnh thnh vng oxetane trong sinh tng hp Taxol. ..................... 44

Hnh 2.30: Con ng sinh tng hp Taxol t tin cht gi nh c

polyhydroxyl ha. .............................................................................................................. 45

v

Hnh 2.31: C ch tc ng ca Taxol i vi t bo gy ung th. ................................. 46

Hnh 2.32: C ch phn ng ca Taxol trong h thng vi ng ca t bo. ...................... 48

Hnh 2.33: Phng php phn tch retrosynthetic ca Nicolaou. ..................................... 50

Hnh 2.34: Bn tng hp Taxol t DAB. .......................................................................... 57

Hnh 3.4: T l mu cy T. wallichiana trn cc mi trng MS khc nhau. ................. 75

Hnh 3.5: Chiu di chi trung bnh (cm) ca mu cy T. wallichiana trn mi trng

MS sa i khc nhau. ...................................................................................................... 76

vi

DANH MC NH

Hnh 2.8: Taxus baccata L. ............................................................................................... 16

Hnh 2.10: Taxus brevifolia Nutt. ..................................................................................... 18

Hnh 2.12: Taxus canadensis Marsh. ................................................................................ 20

Hnh 2.14: Taxus cuspidata Siebold & Zucc. ................................................................... 22

Hnh 2.16: Taxus floridana Nutt. ...................................................................................... 24

Hnh 2.18: Taxus globosa. ............................................................................................... 25

Hnh 2.20: Taxus chinensis Rehd. var mariei. .................................................................. 27

Hnh 2.22: Taxus wallichiana Zucc ................................................................................. .29

Hnh 3.1: Vi nhn ging T. baccata. ................................................................................. 66

Hnh 3.2: K thut gim cnh c p dng cho Taxus wallichiana. ............................. 71

Hnh 3.3: Thu thp mu cy T. wallichiana. .................................................................... 74

Hnh 3.6: Vi nhn ging in vitro T. wallichiana. .............................................................. 78

vii

DANH MC BNG

Bng 2.1: Tm tt lch s nghin cu v hp cht Taxol. ................................................ 38

Bng 2.2: Cc nghin cu gn y v kh nng thu nhn Taxol v cc hp cht c

lin quan bng phng php nui cy t bo. ................................................................... 52

Bng 3.1: Thnh phn mi trng dinh dng c s dng cho qu trnh vi nhn

ging T. baccata. ............................................................................................................... 65

Bng 3.2: Nng cc cht iu ha sinh trng v than hot tnh b sung vo mi

trng MS c s dng cho qu trnh tng trng v ko di ca chi.. ................... 72

Bng 3.3: Nng ca cht iu ha sinh trng BA v than hot tnh c b sung

vo mi trng MS cm ng s chi bt nh. ........................................................ 72

Bng 3.4: Nng cht iu ha sinh trng, vitamin B1 v than hot tnh b sung

vo mi trng MS v mi trng MS cm ng s hnh thnh r. ......................... 73

Bng 3.5: T l nhim ph thuc vo loi mu cy. ........................................................ 75

Bng 3.6: nh hng ca chi v thn c ngun gc in vitro v ex vitro trn chiu di

ca chi bn v phn trm mu cy c mang chi. ........................................................... 77

Chng 1: M U

1

CHNG 1: M U

Cc loi Taxus c bit n t thi c i, gn nh tt c cc b phn ca

n (ngoi tr o ht) u cha cht c i vi con ngi v ng vt.

Trong y hc, Thng l mt loi dc liu qu. T lu trong dn gian, cy

Thng c dng iu tr hen suyn, vin ph qun, nc, mt s bnh

tiu ha, cnh v v dng tr bnh giun a, nc sc ca cy Thng non tr

bnh au u

Nm 1963, cc hp cht c tch chit t v cy Taxus brevifolia, c hiu qu

trong cc nghin cu tin lm sng: chng li cc khi u trong c th. Nm 1971,

Taxol (Paclitaxel) - mt diterpenoid alkaloid, c xc nh l thnh phn chnh

trong hp cht ny (Wall & Wani, 1971) [32]. Taxol thc y c ch lp rp ca

cc tubulin v n nh hiu qu ca vi ng. Hiu qu ca n c kim nh

lm sng iu tr ung th v, bung trng, thc qun, bng quang, ni v c t

cung Taxol c chp thun ln u tin bi Cc qun l Thc phm v Dc

phm Hoa K (U.S. Food v Drug Administration) dng trong iu tr ung th

bung trng vo nm 1992 v ung th v di cn vo nm 1994 (Suffness v Wall,

1995) (theo Croteau, 2006) [16].

Taxol cng c tch chit thnh cng t cc loi khc trong chi Taxus,

cng nh cc b phn khc ca cy bao gm phn hoa, ht ging, l, thn v r

(Vidensek v cng s, 1990; Witherup v cng s, 1990; Fett-Neto v cng s,

1992; Wickremesinhe v Arteca, 1994) (theo D.T. Nhut, 2007) [15].

Vn kh khn nht gp phi trong sn xut Taxol chnh l ngun cung cp

hn ch vi hm lng rt thp. c tnh cn 7000 kg v cy c th sn xut

c 1kg Taxol (Cragg v cng s, 1993) [13]. Mt khc, cy tng trng chm

trong iu kin t nhin, thi gian ng ca ht ging ko di t 1.5 nm n 2 nm

(Steinfeld, 1992) (theo D.T. Nhut, 2007) [15].

Ngoi ra, t cc b phn ca nhiu loi Taxus cn thu nhn c cc hp cht

th cp khc nh lignan, flavonoid, steroid v cc dn sut ca ng. Ngi ta

tm c khong 50 lignan, bao gm neolignan v mt vi terpenolignan. C th

trong T. baccata (European yew), 5 lignan c tm thy: lariciresinol,

taxiresinol, 3-demethylisolariciresinol-9-hydroxyisopropylether, isolariciresinol

Chng 1: M U

2

v 3-demethylisosalariciresinol [27]. Cc nghin cu in vitro ch ra rng

larciresinol v isolarciresinol c hot ng c ch mnh m n nhn t gy hoi

t khi u (tumor necrosis factor- (TNF-)) v taxiresinol c cho l c hiu qu

cao trong bo v chng li cc tn thng d dy.

Hin ti, vic tch chit, kim tra hat tnh sinh hc ca diterpenoid alkaloid

mi cng nh tng hp hay bin i cu trc ca cc taxane c cp trong

nhiu nghin cu. Hng trm cu trc khc nhau ca taxoid c bit n v mt

s c kh nng lm tin cht sn xut Taxol, mt s khc c tc dng tng t

thm ch vt tri hn so vi Taxol. iu ny cho thy tim nng ca nhiu loi

Taxus vn cha c khai thc ht, n ha hn s l ngun cung cp dc liu

quan trng cho iu tr ung th v nhiu loi bnh khc trong hin ti v tng lai.

Vic nghin cu trn cy Thng Vit Nam cn rt khim tn, ch mi

din ra trong khong 10 nm tr li y v tng bc t c mt s thnh cng

bc u ch yu trn lnh vc nhn ging in vitro. Hin nay xc nh c 2

loi Thng l Thng Bc (Taxus chinensis Pilg.), phn b ch yu cc

tnh vng cao nh Sn La, H Giang, Tuyn Quang v Thng Nam (Taxus

wallichiana Zucc.) phn b ri rc mt s tnh Khnh Ha, Lm ng ( Lt,

n Dng) [1]. Tuy nhin, qun th Thng ny trong t nhin rt t, nu dng

chit xut Taxol th s liu thuc cha tr ung th cng ch l mt con s rt

nh (D.T Nhut, 2007). T thc trng ny, cho thy vic nhn ging cy Thng

bng cc phng php in vitro v a ra trng i tr l cn thit cung ng cho

nhu cu iu tr trong nc.

n ny c thc hin vi mc ch a ra mt ci nhn tng quan v cy

Thng trn th gii v Vit Nam, phn loi, c im, phm vi phn b

cng nh v hp cht Taxol, tnh cht l ha, con ng sinh tng hp, c ch v

ng dng ca Taxol trong iu tr ung th. Cui cng, trnh by mt s kt qu

nghin cu nhn ging in vitro trn mt s loi Thng nh Taxus baccata L. v

Taxus wallichiana Zucc.

Chng 2: TNG QUAN

3

CHNG 2: TNG QUAN

2.1 Tng quan v cy Thng

2.1.1 Gii thiu chung v h Taxaceae

Taxaceae mt h nh chim khong 2% trong ngnh thc vt ht trn, bao gm

5 chi v 25 loi c phn b ch yu Bc bn cu [16].

2.1.1.1 Tn thng gp

Yew (Hils, 1993) [26], Taxaces [French], Eibengewchse [German], taxceas

[Spanish], [Russian], hong dou shan ke [Chinese],

[Japanese] [31].

2.1.1.2 M t c im chung

Cy thng xanh, n tnh khc gc (i khi n tnh cng gc nh loi

Torreya v Taxus canadensis), cy thn g hoc cy bi, v mng v d bong hoc

v th, dy v b cht, mu nu hoc nu m, i khi xut hin tinh th calci

oxalate kt tinh, g khng c nha, vi cu trc xon c trn vch th cp ca

trc t bo dng ng (thng khng c trong Austrotaxus), cnh lan rng n

thng ng v tng dn chiu cao, cnh i xng hoc xen k, khng c lng, mu

nu hoc mu xanh l, mang l gn nh khng c cung l [16].

L tn ti t 2, 3 hoc 4 nm, thng thng l 2 nm, thng c nh, ni bt

vi decurrent di, xen k (ngoi tr Amentotaxus), thng ti thng mi mc, mng,

nhn mi hoc nhn u, khng c lng, i khi c nh trn gn gia hoc mp l,

cung l di 1 - 2 mm hoc khng c cung l, mp l lin, cun ngoi (revolute),

mt trn l mu xanh m, mt di mu xanh m, xn vng hoc vng xanh, c

kh khng, dc theo 2 bn, mu lc lam hoc mu xanh nht ti mu hung, l n ,

gn gia ni, to thnh rnh hoc khng r rng mt trn, hin r hn mt

di, nha c trong cc ng n (Amentotaxus), nm ri rc trong nhu m hoc

khng c [16].

Nn c c cui l hoc nch l, n l hoc thnh tng cm t 2 4 nn,

khng cung hoc c cung, hnh cu hoc hnh tr thun di khi cy cn non,

hnh tr hoc hnh nn khi cy trng thnh, di 2 - 10 mm, vy khng sinh sn (

8) di cc l bo t nh (vi 2 vy khng sinh sn xen gia cc l bo t nh

Chng 2: TNG QUAN

4

trong Pseudotaxus), l bo t nh t 3 - 14 (rt nhiu trong Torreya), ti bo t

thp v i xng ta trn (trong Taxus Pseudotaxus, v Austrotaxus) hoc ti bo

t cao (ch c ti bo t dc theo trc pht trin y ) v sp xp mt lng

bng (trong Amentotaxus v Torreya), di 1 - 3 mm, c cung (tr Austrotaxus),

hnh khin hoc c nh dy, ti bo t sn xut giao t c t (2 -) 3 - 9, phn hoa

khng c bng hoc cnh (ngoi tr trong Amentotaxus argotaenia), c cung

hoc khng c cung, ht (granular) mng hoc sn si, mng ngoi ca bo t

trong 2 lp c dy bng nhau [16].

Nn ci bao gm mt nn nm n c tn cng, khng cung hoc c

cung di khong 1.5 cm, vy khng c kh nng sinh sn, 6 - 14, vng xon sp

xp i xng hoc dng ch thp, non trng thnh hay ht c bao quanh bi

v o (mt phn tht ca cc l bo t ln (c quan sinh sn ci) c pht trin t

trc hoc nh ca nch chi mang non), v o c dng hnh cu, hnh trng hoc

thun di, 5 - 30 10 - 15mm, c mi thm, mm, c mu , trng, xanh hoc

tm, ht kh v nutlike (ging ht), vi 2 l mm [16].

S lng nhim sc th, n = 12, c trng hp n = 11 (trong Torreya

californica v T. nucifera, c th c Amentotaxus formosana), hoc trng hp

him gp n = 7 ( A. argotaenia) hoc khng m c (Austrotaxus,

Pseudotaxus) [16].

2.1.1.3 Phn loi:

H Taxaceae bao gm 5 chi v 25 loi (bao gm c 2 loi lai nhn to)[16].

Chng 2: TNG QUAN

5

Kha phn loi cc chi trong h Taxaceae [16]:

1. Nn c to thnh chm, l rng 5 - 9 mm.

2. L i xng, nn c nm tn cng hoc gn tn cng, qun bo xon

dy . ....................................................................................... Amentotaxus

2. L sp xp hnh xon c, nn c nch l, t bo ng khng xon

dy

................................................................................................ Austrotaxus

1. Nn c nm n c, l rng < 5mm.

3. o ht ng li nh, che ch cc ht ging, cnh i xng, gn

gia khng ni mt trn ca l ................................................. Torreya

3. o ht m nh, l ra cc ht bn trong, gn gia ni ln b mt

trn ca l.

4. o ht mu trng, nn c c vy khng sinh sn, nh ch c

mp l

....................................................................................... Pseudotaxus

4. o ht mu , nn c khng c vy khng sinh sn, nh dc theo

trc gn l ................................................................................. Taxus

Hnh 2.1: Amentotataxus argotaenia Pilger [16].

A. Cnh, nn ci trng thnh rng,v nn ci cha trng thnh cn li.

B. Nn c. C. Nn ci v o ht. D. B mt l (tri) v (phi) dc theo trc.

Chng 2: TNG QUAN

6

Hnh 2.2: Austrotaxus spicata Compton [16].

A. Cnh vi nn ci v o ht. B. Cnh vi nn c. C. Nn c.

D. B mt l (tri) v (phi) dc theo trc.

Hnh 2.3: Torreya nucifera (L.) Siebold & Zucc [16].

A. Cnh mang nn c. B. Nn c. C. Cnh mang nn ci cha trng thnh,

trng thnh v o ht . D. B mt l (tri) v (phi) dc theo trc.

Chng 2: TNG QUAN

7

Hnh 2.4: Pseudotaxus chJenii (Cheng) Cheng [16].

A. Cnh. B. Nn c. C. Nn ci v o ht.

D. B mt l (tri) v (phi) dc theo trc.

Hnh 2.5: Taxus cuspidata Siebold & Zucc [16].

A. Cnh mang nn c. B. Nn c khng m.

C. Cnh mang nn ci. D. Nn ci v o ht.

E. B mt l (tri) v (phi) dc theo trc.

Chng 2: TNG QUAN

8

2.1.1.4 Phn b :

H Taxaceae c phn b Bc bn cu. Chu u: t Anh ti Bc Iran. Chu

: Nga, Hn Quc, Nht Bn, Trung Quc, i Loan, Himal, n , Myanmar,

Vit Nam, Philippines. New Caledonia. Khu vc Bc M: ng Nam Arkansas ti

California, ng Canada, ng M, Florida, Mexico, Guatemala, El Salvador.

Khu vc Nam M [31].

Hu ht cc chi trong h Taxaceae rt him hoc phn b hn ch mt s

vng nht nh, tuy nhin c mt s loi thuc chi Taxus phong ph v phm vi

phn b rng hn.

Torreya taxifolia Am. v Taxus florina Nutt. thuc nhm thc vt c nguy c

tuyt chng cao phn b hn ch Florida v Georgia (Godfrey & Kurz, 1962;

Ward, 1979) (theo Cope, 1998) [16]. Taxus globosa Schldl. l mt loi c hu qu

him ca min Trung Mexico. Austrotaxus v Pseudotaxus ch c tm thy

New Caledonia v tnh Chit Giang (Trung Quc), tng ng vi tng loi.

Torreya californica ch trng c min Bc California v min Nam Oregon.

Ba loi khc thuc chi Torreya ch phn b hn ch mt s tnh ca Trung Quc,

v Torreya nucifera ch yu c trng Nht Bn v Hn Quc [16].

Ch c Torreya v Taxus c trng theo quy m ln M. Tuy nhin,

Torreya phn ln c trng trong cc vn thc vt v gn nh tt c chi Taxus

c trng lm cnh nh T. baccata, T. cuspidata, v dng lai gia chng, T.

media, c trng rng ri trong vng ng Bc v Trung Ty M.

Hnh 2.6: Phm vi phn b ca h Taxaceae [16].

Chng 2: TNG QUAN

9

2.1.2 Gii thiu chung v chi Taxus:

Chi Taxus (Taxaceae) t lu c ch nh bao gm 7 - 12 loi hoc phn

loi (Cope, 1998; Farjon, 1998, 2001; Pilger 1903, 1916; Silba 1984, 1986; Spjut

1992), tuy nhin, Spjut (2000c; www.worldbotanical.com) ngh cng nhn

chi Taxus bao gm 24 loi, 54 ging [26].

H thng phn loi ca Taxus c tranh lun t rt lu do qun th loi ny

khng c cch ly v mt sinh sn m ch c cch ly a l (Farjon 1998; Pilger

1903; Silba 1984). Cc chi phn b t vng n i Bc M ti cn nhit i Trung

M, t vng n i - u ti vng cn nhit ti ng Nam (Cope, 1998) [16].

2.1.2.1 Tn thng gp

Yew.

2.1.2.2 M t c im chung

Taxus spp. l cy thng xanh, n tnh cng gc hoc n tnh khc gc. V

mu nu , c vy. Nhnh thng sau r xung, mu xanh l cy hoc mu

vng lc khi cn nh, sau chuyn thnh mu nu khi trng thnh.

L thng xut hin 2 hng, mm do, kh khng xp dc theo trc, gia 2

hng c cc vng nht mu hn, nh l mm, nhn, khng sc cnh, c nha

trong cc ng n [31].

Nn phn hnh cu, mu vng, vi 4 - 16 l bo t hnh khin, mi ci mang 2 -

9 ti bo t. C mt non. Ht cng trong ma u tin, mu nu; o ht mu

cam hoc ti, mm, nhy, dy, o ht m nh l ra cc ht cng bn

trong. Phi nh ng nht. n = 12. (Hils, 1993) [24].

2.1.2.3 c im sinh trng:

Taxus spp. l loi a m, pht trin ch yu di tn rng, mi trng mt m,

kh hu n i hoc cn nhit i, cao trn mc nc bin (rng n i) n

khong 3000 m (rng cn nhit i). Hnh thc sinh trng c th l cy thn g

hoc cy bi. Cy c nhiu cnh v tn rng c th hp thu c ti a nh sng

di tn rng. Cy c th chuyn thnh dng cy bi nu chi ngn b tn thng

v c thay th bng cc chi bn hoc mc chi mi [31].

Chng 2: TNG QUAN

10

Trong nhiu ti liu cng b cho thy Taxus spp. c thi gian sinh trng

chm v c tui th cao. c th t c kch thc trung bnh ca loi, thi

gian sinh trng c th ln n hn 100 nm. Ht nm ring l, tc pht tn ht

ging chm v sc sng ca ht ging rt thp.

Cy con thng chm pht trin trong iu kin t nhin cng nh trong trng

trt. Qu trnh nhn ging cng rt chm (thng thng hai nm l thi gian cn

thit cho s ny mm t nhin ca ht ging, t 2 n 3 thng nu nhn ging

nhn to bng phng php gim cnh).

Chiu cao ca mt s loi Taxus nh T. wallichiana (Himalayan yew) t 20 -

30 m ng knh 1 (1.5) m (Nguyn v cng s, 2004). T. brevifolia (Pacific yew)

cao khong 20 m (Farrar, 1995). T. baccata (English yew) chiu cao t c t

12 ti 25 m (Krussman, 1983). T. floridana (Florida yew) khi trng thnh chiu

cao ti a khong 5 m (Vance v Rudolf, 1974). T. canadensis (Canada yew) l

cy bi vi tn rng, chiu cao him khi vt qu 2 m (Farrar, 1995) [26].

Tui th ca loi Taxus spp. cao, thng thng t 250 - 500 nm tui. Loi T.

baccata c tui th trong bnh khong 250 nm, tuy nhin vn c nhng trng

hp ring bit tui th ca loi ln ti 1000 nm tui (Vance v Rudolf, 1974)

(theo Spjut, 2007) [26].

2.1.2.4 Phn loi v phm vi phn b:

y trnh by mt kha phn loi gm 24 loi v 26 ging ca Taxus da

trn bn cht ha hc (sn phm ph) v s khc bit hnh thi. M t v mu vt

c trch dn c cung cp ch yu trn d liu a l sinh hc ca Taxus (Spjut

2007). N cng bao gm cc nghin cu hin nay trn cc ging T. brevifolia, T.

caespitosa Nakai, T. canadensis, v T. umbraculifera, khng c cp trong d

liu ca Spjut (2007) [26].

Taxus c phn loi thnh 3 nhm, trong nhm bao gm 2 phn nhm v 2

lin minh (alliance) da vo hnh dng t bo biu b l, s pht trin ca nh, v

mu sc ca cc dy kh khng vi cc vng ln cn ch cha t bo biu b (Spjut

1998b). Nhm Wallichiana bao gm phn nhm Wallichiana v Chinensis, nhm

Baccata bao gm 2 lin minh Baccata v Cuspidata, nhm Sumatrana [26].

Lin minh da trn cc n v phn lai c chung cc c im hnh thi trong

khu vc a l, trong khi phn nhm v nhm khng c cch ly v mt a l.

Chng 2: TNG QUAN

11

Trong cc loi lin minh hoc nhm, loi lin hp (complex) c cng nhn

phn bit, v d, s phn b i xng ta trn ca l (T. umbraculifera complex)

so vi l xp thnh 2 hng (T. cuspidata complex).

Hnh 2.7: Phm vi phn b ca mt s loi thuc chi Taxus [16].

Cha kha phn loi loi v ging ca chi Taxus [26].

NHM WALLICHIANA.

1. PHN NHM 1A WALLICHIANA.

1. S lng kh khng : 12 kh khng/dy; ng Himalaya, Ty Nam Trung

Quc.

2. Cm chi n nh, tng i ln, di 2 - 3 mm, l phng vi gn l ring

bit; Myanmar. ......................................................................... T. suffnessii

2. Cm chi n nh khng c gn l hoc gn nh khng c, lm xung,

chiu di > 2 mm v rng 1 mm; ng Himalayan, Nepal ti Ty Nam

Trung Quc (var. yunnanensis c phn bit bi dc theo mp l c cc t

bo di v hp, gn mp ngn hn, t bo nh rng hn vi nh trung gian,

hoc l c hnh mi mc, Ty Nam Trung Quc). ............... T. wallichiana

1. S lng kh khng: < 12 kh khng / dy.

3. T bo biu b dc theo trc hp v ngn ti dy kh khng mp l, phn

ln c cng kch thc dng ch T, hnh thoi v ln sng (ln theo vch

t bo) trn b mt dc theo trc, i khi l hnh ch nht. .... Taxus globosa

4. Nh ni trn hu ht b mt l dc theo trc, cc t bo mp ch yu

dng ln sng; t El Salvador ti Ty Bc Mexico.

.............................................................................. T. globosa var. globosa

Chng 2: TNG QUAN

12

4. Nh t ni hn trn gn gia v mp l trn dy kh khng, t bo

mp l hnh ch nht; Mexico (Nuevo Leon/Tamaulipas, Veracruz),

U.S. (Florida).

.......................................................................... T. globosa var. floridana

3. T bo biu b ngn t ngt v rng hn mp l, thng cao hn chiu

rng dng ch T.

5. Kh khng 7 - 10( - 12) hng; Trung Quc (Vn Nam, T Xuyn).

.......................................................................................................... T. florinii

5. Kh khng 4 - 7( - 9) hng; ng Bc M. ........................ T. brevifolia

6. Nn thun di, thng gn trn cung hp.

................................................................ T. brevifolia var. polychaeta

6. Nn khng c cung.

7. Cy thn g, chi mc ngu nhin. .... T. brevifolia var. brevifolia

7. Cy bi, thng mc thnh tng cm.

............................................................. T. brevifolia var. reptaneta

1. PHN NHM 1B CHINENSIS.

1. B mt l kh, gn nh cng mu, hoc mu vng lc dc theo trc.

2. Cm chi d thy ti gc ca cnh; Vn Nam, T Xuyn.

................................................................................................. Taxus sp. SCU

2. Cm chi nh, ch c vt hoc khng c cnh ca cy 1 nm tui.

3. L dng trn, thng l thun; Vit Nam, Trung Quc. ..... T. chinensis

3. L nhn; Vit Nam, Philippines, Trung Quc (i Loan), Indonesia.

........................................................................................... Taxus sp. REH

1. B mt l kh, khng mu hoc mu vng cam dc theo trc.

4. L dng trn, b mt nhn; Vn Nam, T Xuyn. .............. Taxus sp. OCR

4. L nhn, mn, bng trn b mt khi l kh.

5. L phn b song song gn gc phi; Nepal, Ty Bc n ,

Malaysia, Trung Quc (i Loan, Vn Nam), Philippines.

............................................................................................. T. phytonii

5. L phn b theo gc xin, an cho trong cc mu p; Myanmar,

China (Phc Kin, i Loan), Philippines, Indonesia (Sulawesi,

Sumatera).

............................................................................................. T. obscura

Chng 2: TNG QUAN

13

NHM SUMATRANA

1. L kh mu cam bc, gn nh thng bc mu tng phn vi mu xanh

m hoc mu ng b mt l, xon xin vi trc thn, thng un ngc

dc theo phin l ti nh nhn, vi gn gia trn u trn c 2 b mt; Ty

Bc n ti Trung Quc (bao gm i Loan). ............................ T. kingstonii

1. L kh mu xanh , hoc mu mu phai dc theo mp l v trn gn gia,

xon gn nh vung gc vi trc, cc mp l lin k thng song song, l trn

ti nhn, gn gia ni cao v ngn, hoc phng, thng ch c mt gn, mng

v mm; Trung Quc.

2. L thun di, trn ti nhn hoc hnh ellipse nhn, t bo biu b ln

(mammillose) dc theo trc ln hn gn gia, c hnh thang ngn; Nam

Trung Quc. .................................................................................... T. mairei

3. Cnh mm, phn thnh nhiu nhnh, l st nhau, l song song dc theo

mt bn ca cnh, ht mu ta. ................................. T. mairei var. mairei

3. Cnh cng, i khi c phn nhnh, l cch qung khng u dc theo

cnh, ht mu nu. .................................................T. mairei var. speciosa

2. L di thng hnh mi mc, nhn, cc t bo biu b dng ch T (T-sect)

khng ln hn cc t bo dc theo gn gia, hnh ch nht; t ng

Himalaya ti Indonesia, Philippines.

4. L kh phng hoc li trn b mt dc theo trc. ................... T. celebica

4. L kh nhn. ....................................................................... T. sumatrana

NHM BACCATA

1. Trn b mt hng trc, thng c nhiu nh gia mp l v dy kh khng, c

khong 8 hng t bo mp l, nh trung gian, thnh t bo mng, l thng cong

xung dc theo phin l (ngoi tr T. contorta var. mucronata); a Trung Hi,

Ty Himalaya.

.................................................................................................... T. baccata Alliance

2. Tht l vi cc d bo (cc t bo nhu m vi thnh t bo mu ), lin kt

lng lo; t Ty Bc ti min Trung Himalayas. ......................... T. contorta

2. T bo nhu m thng c mu ti, khng c mu , lin kt cht.

2a. Cy hnh tr, l ta trn, un ngc li. .................................. T. fastigiata

2b. Thc vt thay i i theo mi trng sng (thn g hoc cy bi ty

theo mi trng sinh trng), l chng cho, khng phn b ta trn.

2b. B mt l bc mu, phin l un ngc, li, cun ngoi. ..... T. recurvata

Chng 2: TNG QUAN

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2b. L cng mu, thng hoc hnh lim, phng hoc cun ngoi. . T. baccata

2c. L phn b pha ngoi dc theo hai bn ca cnh trn mt mt phng,

xp thnh hai dy.

2d. L khng xp chng cho, cnh phn thnh nhiu nhnh.

.............................................................................. T. baccata var. baccata

2d. L chng cho, cnh khng theo quy lut.

.................................................................... T. baccata var. elegantissima

2c. L mc thng hoc ta trn vo phn di ca cnh.

2e. Cnh v l c mu cam vng khng u, cnh thng un ngc, l

dng ng u cnh. .......................................... T. baccata var. glauca

2e. Cnh c mu xanh l, mu vng xanh hoc mu xanh m ng

nht, cnh khng un ngc, lan rng hoc r xung, l thay i.

2f. Cnh ch yu c hnh lng chim. .............. T. baccata var. variegata

2f. Cnh nhiu hn ngn, xut hin s pht sinh phn cnh hoc

chia nhnh.

2g. L vng xanh, rng vo nm th 3, cnh phn thnh nhiu nhnh.

................................................................. T. baccata var. pyramidalis

2g. L xanh m, lin tc, cnh phn nhnh hnh lng chim hoc

hnh chp. ............................................ T. baccata var. dovastoniana

2. L nhn gia dy kh khng v mp l, thng khng c nh qua t 8-24 hng

t bo, cc nh thng sinh trng mt trn ca t bo gn thnh t bo,

phin l cong ln trn hoc un t ngt hoc cong xung di dc theo cung

l; ng , ng Bc M, a Trung Hi. ................... T. cuspidata Alliance

3. L tri rng nh cung l hp, cung l cong t ngt, kh khng (4- ) 5 -

9(- 11) hng trn mt dy, nh l thng khng r, cy thp, cy bi tng

trng chm. .............................................................. T. canadensis complex

4. L nhn, thon dn cho ti mp l ging dng ch T, thng cun ngoi

dc theo mp l, b mt dc trc vi gn gia lt p v t bo biu b

hnh ch nht; ph bin ng Bc M, xut hin t hn a Trung

Hi, Marocco, B o Nha (Madeira), Ty Ban Nha, Thy in,

Estonia.

.................................................................. T. canadensis var. canadensis

4. L trn ti nhn, mp trn trong dng ch T, khng cun ngoi, vi gn

gia bng v t bo biu b hnh thang hoc hnh ch nht.

5. L nhiu, dng ng, un ngc li; ng Bc Amer, Madeira.

..................................................................... T. canadensis var. minor

Chng 2: TNG QUAN

15

5. L tha, thng, gn nh vung gc; Anh, Madeira, Php, Thy

in, Na Uy, Slovenia, M (him). ....... T. canadensis var. adpressa

3. Cung l cong t, un cong gn ch giao vi phin l, phin l thng p vo

cnh nh, kh khng (7-) 9 - 14(- 17) hng trn 1 dy, nh thng ni bt trn

dy kh khng, cy thay i theo mi trng sng.

6. L xp thnh hai hng ti u cnh, ht c gc cnh. . T. cuspidata complex

7. Cnh ngn v chia nhiu on, l trn cnh nh, cng hn khi kh, ch

yu thuc nhm cy bi; ng Bc Chu . .................... T. biternata

7. Cnh ch yu hnh lng chim di, l dng ng, cun ngoi ng u

dc theo mp l khi sy kh, cy bi hoc cy thn g-xut hin khi

thch nghi tt vi mi trng sng; Nht Bn, Hn Quc.

............................................................................................... T. cuspidata

6. L hai hoc nhiu hng xp chp hnh ch thp hoc ta trn, ht trn.

............................................................................. T. umbraculifera complex

8. L dng ng v xp gi ln nhau. ...................................... T. caespitosa

9a. Cnh dn thng ng vi nhiu cnh nh v ngn, l ch yu ta

trn; Nht Bn. ........................................ T. caespitosa var. caespitosa

9a. Cnh phn b rng, cnh nh vi s ln ln hai hng v dng ng

mt pha.

9b. Cnh lan rng pha ngn , l thun hoc thng, rng 2 - 4 mm;

Hn Quc, Nht Bn, ng Nam Nga, ng Bc Trung Quc.

...................................................................... T. caespitosa var. latifolia

9b. Cnh c ph vi cnh nh dng ng, l thng, tng i hp,

rng 2 mm; Hn Quc, Nht Bn. ...... T. caespitosa var. angustifolia

8. L xp cho hnh ch thp v un ngc. .................... T. umbraculifera

10a. Cy bi phng, xp lp.

.......................................................... T. umbraculifera var. microcarpa.

10a. Cy bi dng chm cu, dng ct hoc cy thn g.

10b. Cy bi thp, trn. .............................. T. umbraculifera var. nana

10b. Cy bi cao hoc cy thn g.

10c. Dng ct vi cnh nh dng ng. T. umbraculifera var. hicksii

10c. Dng kim t thp, cnh sp xp ln xn.

.................................................. T. umbraculifera var. umbraculifera

Chng 2: TNG QUAN

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2.1.3 Mt s loi Thng trn th gii

2.1.3.1 Taxus baccata

a. Tn thng gp

European, English, hoc common yew (Hartzell, 1991) [31].

b. M t c im [16, 26]

Taxus baccata ch yu l cy n tnh khc gc, cy cao t 10 20 (- 40) m v

ng knh ln n 4 m. Tn cy c hnh kim t thp, thay i ty theo tui

cng nh iu kin mi trng. V mng, c vy, mu nu. L phng, sp xp 2

hng theo hnh xon c. 10 - 40 2 - 3 mm, c mu xanh m.

Nn c hnh cu, ng knh t 3 - 6 mm, phn hoa rng vo u ma xun.

Ht ging hnh nn bao gm mt ht c bao xung quanh bi o ht c mu

ti, di t 8 - 15 mm.

Khong t 1 - 2 chi c 1 o ht, 10 6 mm, mu ti, ht c hnh ellip, 6

- 7 5 mm, mu xanh nu hoc mu nu. o ht trng thnh sau 6 - 9 thng k

t khi th phn, v ht c pht tn ch yu nh chim.

Hnh 2.8: Taxus baccata L [32].

A. Bi cy. B. Nn c. C.o ht v ht ging. D.Ht ging. E. V v thn cy.

A B C

D E

Chng 2: TNG QUAN

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c. Phm vi phn b

T Anh cho ti pha Bc Iran (Silba, 1986); c trng rng ri khu vc Bc

M (Hils, 1993) [24]. Ngoi ra cn phn b ri rc Croatia, Slovenia v Balan

[31].

Hnh 2.9: Phm vi phn b ca Taxus baccata khu vc Bc M [32].

d. Cng dng [31]

T xa xa, g c dng lm cung tn s dng trong c sn bn cng nh

tronng chin tranh cho ti khi sng c pht minh. Taxus baccata cng c s

dng lm cht c tm vo u mi tn gy c cho qun i phng cng nh

cc loi ng vt. Trong i sng hng ngy, g cy c s dng lm ct bum,

trc bnh xe, n, lc

Trong y hc, T. baccata c s dng iu tr vt rn cn, hi chng s

nc (hydrophobia) v mt s bnh lin quan ti tim mch. Hin nay, Taxus

baccata ch yu c s dng lm cy cnh.

Cc nghin cu chng minh, Taxus baccata c cha hp cht Taxol, mt

hp cht dng trong iu tr ung th. L v ht c cha nhiu alkaloid, c bit l

taxine, cc c, d b thy phn thnh hydrotaxine, ngoi ra cng cha cc hp

cht glucoside v taxicatine. L gi v kh c hn so vi l cn non, thng

xuyn gy c cho ng vt, nga v la c th b cht trong vng mt gi sau khi

n. i vi ngi, n tc ng ln h tiu ha, h hp, tim mch v h thn kinh

c th dn ti t vong. Triu chng bao gm: nhp tim v nhp th tng nhanh, tip

n tim p chm, h huyt p, au bng, au d dy, tiu chy cp, chng mt, co

git, hn m v t vong.

Ghi ch:

Taxus baccata

Chng 2: TNG QUAN

18

o ht mu c th s dng lm thc n, n c v ngt v nhy, c tc dng

li tiu, nhun trng.

2.1.3.2 Taxus brevifolia

a. Tn thng gp

Pacific hoc western yew, mountain mahogany (g g ni) (Peattie, 1950) [31].

b. M t c im [26]

Taxus brevifolia l cy n tnh khc gc, cy bi hoc cy g nh, chiu cao

t 15(- 25) m, ng knh 50(- 140) cm. Thn cy thng, tn c hnh nn. V cy

c vy, vy bn ngoi mu nu tm hoc nu ta, vy bn trong mu hoc

tm, vy c kch thc khc nhau (20 - 50 mm). Nm u tin, chi non c mu

xanh c bao ph bi l vy, cnh cy c mu nu ging v cy vo nm th

3. L xanh, thng, nhn, di 8 - 35 mm, rng 1 - 3 mm, mm do, c hnh dng

ging ci lim vi sng l hp mt trn ca l, c t 5 - 8 dy kh khng, c nh.

Cung l di 5 - 8 mm. Nn c nm n c hoc thnh cm, cn non c mu

xanh, hnh cu, ng knh 1,5 mm. Ht hnh cu, 5 - 6.5 mm, trng thnh vo

cui ma h, c bao trong cc o ht mu , ng knh 10 mm. G cng.

(Hils, 1993; Peattie, 1950).

Hnh 2.10: Taxus brevifolia Nutt [32].

A. Cnh. B. Nn c cha trng thnh. C. o ht. D.Ht ging. E. V v thn cy.

A B C

D E

Chng 2: TNG QUAN

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c. Phm vi phn b

M: ng Nam Alaska, Montana, Idaho, Oregon, Washington v Bc

California; Canada: Columbia, Alberta (dy Rockie) [31].

c tm thy cao 0 - 2200 m c m cao nh ven sui, sn ni, hm

ni v cc vnh nh (Hils, 1993) [24]. Trong rng l kim, cy ch yu pht trin

nh cy bi di tn rng. Tuy nhin trong rng l rng, cy tng v kch thc

cng nh chiu cao, thay i hnh thi sinh trng thnh cy thn g.

Hnh 2.11: Phm vi phn b ca Taxus brevifolia khu vc Bc M [32].

d. Cng dng [31]

Dn tc bn a vng Ty Bc Thi Bnh Dng coi loi thng ny l loi cy

rt c gi tr, c s dng lm v kh nh cung, lao mc ( nh c), lm mi

cho, cc dng c sinh hot hng ngy nh mung, a, kim Dng trong iu tr

vt thng, h nhai l v p ln vt thng. Cy c lt v, sy kh v c

pha vi nc si lm thuc tr bnh phi.

V cy ca Taxus brevifolia l mt ngun cung cp Taxol t nhin, dng trong

iu tr nhiu loi ung th (c bit l ung th bung trng) [22].

2.1.3.3 Taxus canadensis

a. Tn thng gp

Canadian yew, American yew, cy c cn (ground-hemlock), li du Canada,

sapin trainard (Hils, 1993) [24].

Ghi ch:

Taxus brevifolia

Chng 2: TNG QUAN

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b. M t c im [26, 31]

Cy bi, cao khong 2 m, thng l cy n tnh cng gc, thp, cnh rm rp,

lan rng. V c mu , rt mng. L 1 (2.5) cm 1(2.4) mm, nhng vng

khng c nh dc theo cc dy kh khng l c mu xanh nht, dy kh khng c

mu xanh m hay hoc vng xanh. Mt trn l c mu xanh sng, mt di l c

mu vng xanh, i khi tr thnh mu hoc tm trong ma ng. Cung l di

0.5 - 1 mm. nh l trn nhiu hn nhn. Gn gia khng r rng mt trn cu

l.

o ht hnh cu hoc gn nh hnh cu, 6(8) 6 mm, mu cam hoc ti.

Ht c hnh trng, 4 - 5 mm, c gc cnh nh. 2n = 24. Ht trng thnh vo

cui h u thu (Hils, 1993) [24].

Ht pht tn ch yu nh cc loi chim.

Hnh 2.12: Taxus canadensis Marsh [32].

A. Cnh. B. Nn c. C. o ht trng thnh v cha trng thnh. D.Ht ging.

E. V v thn cy.

A B C

D E

Chng 2: TNG QUAN

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c. Phm vi phn b

Taxus canadensis l loi bn a ca min ng Hoa K v Canada, pha nam

ti Virginia, pha Bc ti Manitoba v Iowa.

Thng c tm thy cao t 0 1500 m, di tn rng (rng l kim,

rng l rng hoc rng hn hp), hoc trong m ly, khe ni v cc dy ni .

Hnh 2.13: Phm vi phn b ca Taxus canadensis khu vc Bc M [32].

d. Cng dng [31]

Tt c cc b phn ca cy (ngoi tr o ht) c c tnh nh, cy c s dng

rng ri bi ngi dn bn x. H s dng cc b phn ca cy nh l cnh lm

thuc tr bnh thp khp, vim khp, mt s bnh lin quan ti ng tiu ha, v

s dng lm dc liu xng iu tr cm st.

Taxus canadensis c chng minh l mt ngun cung cp hp cht Taxol

cng nh c cha 2 loi taxane c th s dng tng hp Taxol. Vi mt hm

lng cao hp cht taxane trong Taxus canadensis, n tr thnh mt trong nhng

ngun cung cp hp cht taxane c gi tr nht trong ngnh cng nghip dc

phm.

2.1.3.4 Taxus cuspidata

a. Tn thng gp

Japanese yew, Ichii, Onko (Japanese) (Hartzell, 1991) [31].

Ghi ch:

Taxus canadensis

Chng 2: TNG QUAN

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b. M t c im

Cy cao khong 20 m, tn cy hnh kim t thp, trong canh tc ch yu l cy

bi. V cy c vy, mu nu hoc nu sm. Cnh mu nu. Chi nm u

tin c mu vng xanh, ngn chi hnh trng thun di, vy lin tc. L sp xp

hnh xon c, xp thnh 2 hng, thng, 15 - 25 2 - 3 mm, mt trn mu xanh

m hoc xn mu, mt di mu vng xanh, cung ngn; gn gia ni bt mt

trn, khng r rng mt di; thn l c 2 dy kh khng [31].

o ht c hnh cu, mu . Ht hnh trng, 6 5 mm, c 3 - 4 gc nh.

Hnh 2.14: Taxus cuspidata Siebold & Zucc [32].

A. Bi cy. B. Nn c. C. o ht trng thnh v cha trng thnh. D.Ht ging.

E. V v thn cy.

c. Phm vi phn b:

Bc Hn Quc; Trung Quc: Heilonjiang, Ct Lm, Nei Mongol, Liu Ninh,

H Bc, Thim Ty, v Sn Ty; Nga: ng v Nam lu vc sng Amur (bao

gm Sakhalin v Kurile) [26].

Nht Bn: Hokkaido, Honshu, Shikoku v Kyushu (Hartzell, 1991; Farjon,

1998) [31].

A B C

D E

Chng 2: TNG QUAN

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Hnh 2.15: Phm vi phn b ca Taxus cuspidata khu vc Bc M [32].

d. Cng dng

Taxus cuspidata l mt loi cy cnh ph bin Nht Bn (Ohwi, 1965) [31]

v phng Ty k t khi du nhp vo Hoa K nm 1833.

Trc y, g cy thng c s dng ch to cc loi vt dng gia nh

nh cc loi t nh, thng cha nc, bn tm, khay, guc, a

Trong y hc, cy c s dng lm dc liu bo ch thuc ph thai v tr

bnh tiu ng. Tuy nhin, hin nay s dng gim ng k do tnh trng khai

thc qu mc (Hartzell, 1991) [31].

2.1.3.5 Taxus floridana

a. Tn thng gp

Florida yew (Hils, 1993) [24].

b. M t c im

Cy n tnh khc gc, cy bi hoc cy nh cao t 2 - 5( -10) m, ng knh

38 cm. Cnh nhiu, rm rp, phn nhnh. V cy mu nu tm, khng c vy,

mt s tui c xut hin vy mng. L mm do, c mu xanh m, 1 - 2.6( -

2.9) cm 1 - 2( -2.2) mm, hnh lim, mt di mu xanh nht vi hai dy kh

khng; cung mu xanh, nh trn, gn gia khng r rt [31].

Ghi ch:

Taxus cuspidata

Chng 2: TNG QUAN

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o ht 1 cm 6 mm, mu ti. Ht hnh trng, 5 - 7 5 mm, thng c 2

gc nh. Ht trng thnh u ma thu.

Hnh 2.16: Taxus floridana Nutt.

A. Bi cy. B. Cnh mang nn c cha trng thnh. C. o ht.

c. Phm vi phn b

Taxus floridana c nguy c tuyt chng cao, l loi c hu ch xut hin trong

mt khu vc nh b ng sng Appalachicola qun Gadsden v Liberty, Ty

Bc Florida. Sinh trng trong iu kin m t, di tn rng, cao t 15 -

30 m [31].

Hnh 2.17: Phm vi phn b ca Taxus floridana khu vc Bc M [32].

A B C

Ghi ch:

Taxus floridana

Chng 2: TNG QUAN

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d. Cng dng

Taxus floridana c cha hp cht Taxol, c hot tnh ging nh hp cht Taxol

c tm thy trong Taxus brevifolia v T. canadensis. Tuy nhin, v y l loi

qu him nn n khng c khai thc lm ngun dc liu.

2.1.3.6 Taxus globosa

a. Tn thng gp

Mexican yew (Hartzell, 1991).

b. M t c im

Cy thn g hoc cy bi, cao khong 4 - 6 m. L c mu xanh nht, ln v sc

nhn hn so vi Taxus baccata. o ht trng thnh c mu , to nht trong s

cc loi Taxus [26].

Hnh 2.18: Taxus globosa

A. Bi cy. B.o ht. C. Cnh mang nn c cha trng thnh.

A B

C

Chng 2: TNG QUAN

26

c. Phm vi phn b

Mexico: Nuevo Len, Tamaulipas, San Luis Potos, Veracruz, Quertaro,

Hidalgo, Tlaxcala, Puebla, Oaxaca; Guatemala; Honduras; El Salvador (Hartzell,

1991) [31].

Hnh 2.19: Phm vi phn b ca Taxus globosa [34].

2.1.3.7 Taxus chinensis

a. Tn thng gp

Chinese yew.

b. M t c im [16, 28]

Cy cao khong 15 m, trong canh tc l mt loi cy bi vi tn rng, v mu

-nu i khi c mu xm. L mc tha tht trn cnh, mt s l cong ngc,

1.2 - 3 cm 2 - 3mm, mt trn l mu xanh m, mt di mu xanh-xm hoc

vng lc, nh l thay i t ngt, nhn, gn gia khng ni r mt trn ca l.

o ht hnh cu hoc gn ging hnh cu, ng knh 4 - 7mm, mu i khi

c mu xanh. Ht c hnh trng, 4 - 6 4 mm, c t 2 - 4 gc nh.

Ghi ch:

Taxus globosa

Chng 2: TNG QUAN

27

Hnh 2.20: Taxus chinensis Rehd. var mariei.

A. Bi cy. B. Cnh. C. Cnh mang o ht. D. Cnh mang nn c.

E. o ht v ht ging.

c. Phm vi phn b

Taxus chinensis mt loi c hu Trung Quc v i Loan, c tm thy

cao t 0 - 900 m. Loi ny him khi c trng Bc M, c trng nhiu

hn chu u. N c du nhp vo Anh t nm 1908.

Hnh 2.21: Phm vi phn b ca Taxus chinensis [34].

A B C

D E

Ghi ch:

Taxus chinensis

Chng 2: TNG QUAN

28

d. Cng dng

Ch yu lm cy cnh.

2.1.3.8 Taxus wallichiana

a. Tn thng gp

Himalayan Yew, Thng Nam.

b. M t c im [32]

Cy g c kch thc trung bnh, thng xanh, cao n 20 m, ng knh thn

40 50 cm. Cnh c mu xanh nm u tin, v bin i thnh mu nu sau 3

n 4 nm. L mc xon c, gc vn nn xp thnh hai dy, hnh di di, cong

hnh ch S, di 2.5 4 cm, rng 2 3 cm, tht dn, nhn u. Cy n tnh khc

gc.

Nn c mc n c nch l. Nn ci mc n c. Ht nm trong v o

ht mu , hnh trng, c cnh di 6 7 mm.

c. Phm vi phn b

Mc ri rc trong rng rm nhit i thng xanh, ma ma m trn ni

vi.

L loi thng bn a ca vng Himalaya, t ng Afghanistan (Nepal, Bhutan,

ng Bc n (Assam, Manipur, Khasia Hills, West Bengal)) n pha Ty

Nam Trung Quc (Ty Nam Ty Tng, T Xuyn, Vn Nam), cao 2.000

3.500 m.

d. Cng dng

S dng lm cy cnh. Trong y hc, T. wallichiana l dc liu rt c gi tr,

v v l cy c cha Taxol c s dng trong iu tr ung th.

Chng 2: TNG QUAN

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Hnh 2.22: Taxus wallichiana Zucc.

A. Bi cy. B. Cnh mang o ht. C. o ht v ht ging.

2.1.4 Tnh trng hin ti v bo tn loi Thng Vit Nam

Phn loi v phn b ca chi Thng (Taxus) Vit Nam khng r rng.

Danh sch Thng th gii (Farjon, 2001) (theo dng ging T. chinensis (Pilg.)

Rehder var. mairei (Leme & Lv.) W.C. Cheng & L.K. Fu nh l loi Taxus duy

nht c Vit Nam.

Thc vt ch ng Dng (Nguyn Tin Hip v Vidal, 1996) cng vi nhng

ti liu khc ghi nhn Vit Nam c hai loi: T. wallichiana Zucc. trn cao

nguyn Lm Vin min Nam Vit Nam v T. chinensis (Pilg.) Rehder ca vng

ni vi Bc v Ty Bc Vit Nam (Anon., 1996; Vu Van Dung, 1996; Nguyn

c T Lu & Thomas, 2004) (theo Nguyn Tin Hip, 2004) [1].

Cc qun th pha Bc c phn b a l gn vi ng Nam v Ty Nam Trung

Quc ni loi Taxus chinensis mc ph bin v c hnh thi gn vi cc chun

ca loi ny (T. chinensis). Cc qun th pha Nam bit lp v vic nh danh

chnh xc chng vn cha thc hin c, ph thuc vo nghin cu v phn loi

A B

C

Chng 2: TNG QUAN

30

ca loi Thng Himalaya T. wallichiana, ca cc qun th Ty Nam Trung

Quc ca th T. chinensis var. mairei v ca cc qun th Indonesia v

Philippines ca loi T. sumatrana.

Hin trng phn loi khng xc nh ny cn c th hin vic cc tc gi ca

Thc vt ch Trung Quc (Fu Likuo v cng s, 1999) a th var. mairei ca

loi T. chinensis thnh mt ging thuc loi T. wallichiana.

2.1.4.1 Thng Bc (Taxus chinensis Pilg.)

a. Tn thng gp

Yew (ting Anh), hong du shan (ting Trung).

Tn ng ngha: T. wallichiana Zucc. var. chinensis (Pilg.) Florin.

Hnh 2.23 : Thng Bc (Taxus chinensis Pilg.) [1].

(V t DKH 7125 bi Nguyn Quang Hng)

1. Cnh mang nn v cc nn phn cn non. 2. L, mt di.

b. M t c im

Cy mc ng vi cc cnh tri rng (tu tng ni), t chiu cao ti 15 m

(i khi ti 20 m) vi ng knh ngang ngc ti 1 (i khi ti 1,5 m).

Cy mc ri rc trong rng nguyn sinh rm thng xanh nhit i gi ma,

ni thp trn cc dng ni vi kt tinh trng b bo mn mnh v cc sn

Chng 2: TNG QUAN

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dc (nhit trung bnh nm 15200C, lng ma trn 1300 mm) cao 900

1500 m trn mt bin. Gp trong cc qun x Thit sam gi (Pseudotsuga

sinensis), Thng P C (Pinus kwangtungensis), P mu (Fokienia hodginsii) hoc

Bch vng (Xanthocyparis vietnamensis), xen vi Thng tre l ngn (Podocarpus

pilgeri), Kim giao ni (Nageia fleuryi) v Thit sam ni (Tsuga chinensis).

Thnh thong c ti sinh t nhin [1].

c. Phm vi phn b

Thng bc gp cc tnh Sn La, H Giang, Tuyn Quang, Cao Bng, Ho

Bnh v Thanh Ho [1]. Trn th gii loi cn gp Nam Trung Quc.

Hnh 2.24: Phm vi phn b ca Thng Bc (Taxus chinensis Pilg.) Vit Nam [1].

d. Cng dng

G Thng Bc c mu vi cu trc mn, chu ngm v c th s dng

lm cc gung tt nc. Ht c tnh cht cha bnh v cy c dng lm cy th.

Vit Nam nghin cu v dc tnh ca loi ny cn hn ch. Nhng hot

cht quan trng sn xut Taxol nh 7xylosyl10deacetylbaccatine III v 10

deacetylbaccatine III c phn lp v m t t v v l cy Thng Bc

(Taxus chinensis) Ho Bnh (Mai Vn Tr v cng s, 1995) (theo Nguyn Tin

Chng 2: TNG QUAN

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Hip, 2004) [1]. Vic thu hi ch c th bn vng nu cy c trng v cc qun

th t nhin u qu nh.

e. Hin trng bo tn [1]

Hin trng quc t CHA NH GI [T LIN QUAN]

Hin trng quc gia hin ti HIM

Hin trng quc gia qua xut nh gi SP TUYT CHNG

Do loi c phn b rng Nam Trung Quc nn mc quc t khng c coi

l b e do tuyt chng. Vit Nam kch thc cc qun th u nh hn rt

nhiu, v nhiu qun th b cht h. mc quc gia loi ny c coi l

Him. Theo cc tiu ch mi ca IUCN (2001) mc nh gi ca loi ny cn c

chuyn thnh Sp b tuyt chng.

Cc mi e da

Sinh hc sinh sn phc tp v kh nng ti sinh km ca Thng Bc i lin

vi nhng e do b cht h, rng b chia ct, ni sng b suy gim v chy rng.

S hin din trong cc khu bo tn

Cc qun th nh Thng Bc Ho Bnh c thy khu bo tn t nhin

Hang Kia P C. Qun th ny c th l mt phn ca qun th Sn La, ni cha

c cc khu bo tn (Thomas v Nguyen Duc To Luu, 2004c) [1].

H Giang, Thng Bc c bit c khu bo tn t nhin Bt i Sn,

Tuyn Quang c trong khu bo tn t nhin Na Hang. Cy cn c tm thy

trong khu bo tn xut P Lung.

Cc bin php bo tn thc hin

Cha c nhng th nghim bt k qui m no nhm thun dng Thng

Bc min Bc Vit Nam. Mt s nghin cu phng php nhn ging c Vin

Khoa Hc Lm Nghip Vit Nam (Nguyen Hoang Nghia, 2000) [1] thc hin.

Thng Bc v cc loi Thng chu khc c a vo Ph lc II ca

Cng c CITES.

Hot ng bo tn xut

Chng 2: TNG QUAN

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Thng Bc cn c a vo Nhm IIA ca Danh mc cc loi ng vt v

thc vt qu him nhm to khung php l cho vic bo v cc khu vc c cc

qun th ch yu v km theo vic o to cc cn b kim lm a phng.

Nghin cu phn loi tip theo l cn thit nhm lm r v tr phn loi ca loi

. Vic bo tn chuyn v cng cn c thit lp.

2.1.4.2 Thng Nam (Taxus wallichiana Zucc.)

a. Tn thng gp

Thng l di (ting Vit), Himalayan Yew (ting Anh), xu mi hong dou

shan (ting Trung).

Tn ng ngha: T. yunnanensis W.C. Cheng & L.K. Fu.

Hnh 2.25: Thng Nam (Taxus wallichiana Zucc.) [1].

(V t DKH 7125 bi Nguyn Quang Hng)

1. Cnh mang nn v cc ht chn. 2. L, mt di.

b. M t c im

Cy g mc ng, n tnh khc gc vi cc cnh tri rng tu theo a im,

t chiu cao ti 20 (i khi ti 30) m vi ng knh ngang ngc ti 1 (i khi

1,5) m. Cy mc thnh cc qun th nh cc b trong rng nguyn sinh rm

thng xanh hn giao hoc cy l rng chim u th nhit i gi ma ni thp

(nhit trung bnh nm 15 21 C, lng ma trn 1500 mm) trn t phong ho

t granite hoc cc m silicat khc cao 900 1600 m.

Chng 2: TNG QUAN

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Cc loi Thng mc cng gm nh tng (Cephalotaxus mannii), Kim giao ni

t (Nageia wallichiana), Thng tre l di (Podocarpus neriifolius), Thng nng

(Dacrycarpus imbricatus) v Du sam ni t (Keteleeria evelyniana). Ti sinh t

nhin khng thng xuyn, cy m v cy con chu bng tt.

c. Phm vi phn b

Vit Nam Thng Nam hin ch c bit chc chn c Lm ng (c

Trng, Xun Th, n Dng, Lc Dng) [1]. C cc mu vt kh c t nhng

nm 1930 ghi nhn loi ny c Khnh Ho (Nguyen Tien Hiep v Vidal, 1996)

[1] nhng khng c cc thng tin mi t cc im ny. Nhng thng tin c Ninh

Thun v c Lc cn c kim tra thm. Trn th gii loi ny c thy Ty

Nam Trung Quc v dy Himalaya.

Hnh 2.26: Phm vi phn b ca Thng Nam (T. wallichiana Zucc.) Vit Nam [1].

d. Cng dng

Nghin cu Vit Nam v dc tnh ca Thng Nam cn hn ch. Mt

phn tch cc mu cy thu t Lm ng cho thy n c hm lng 10

deacetylbaccatine III cao hn loi Taxus baccata (L Th Xun v cng s, 1996)

(theo Nguyn Tin Hip, 2004) [1].

Chng 2: TNG QUAN

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e. Hin trng bo tn [1]

Hin trng quc t THIU THNG TIN [T LIN QUAN]

Hin trng quc gia hin ti HIM

Hin trng quc gia qua xut nh gi ANG B TUYT CHNG

Do c phn b rng trn th gii nn Thng Nam hin nay cha c coi l

b e do tuyt chng mc d nhiu qun th b khai thc qu mc.

Vit Nam loi ny c nh gi l loi Him (Anon., 1996), Thiu thng

tin hoc ang b tuyt chng trm trng (C2a) (Nguyen Hoang Nghia, 2000) [1].

nh gi sau cng da trn nhng iu tra hin trng ti Lm ng t nm

1998 m c tnh tng kch thc qun th t hn 250 cy trng thnh vi mi

tiu qun th khng c qu 50 cy. T ti nay, nhng iu tra hin trng tip

tc c tin hnh Lm ng, v mt qun th c t nht 250 cy c pht

hin. Tng s cy trng thnh Vit Nam hin nay c tnh nhiu hn 250 c

th, nhng chc chn t hn 2500 cy, mc ri rc thnh cc qun th b chia ct

mnh [1].

Nh vy, hin trng ca loi ny Vit Nam cn c nh gi mc ang b

tuyt chng (C1) theo cc tiu ch ca IUCN (2001). V tt c cc qun th u i

mt vi nhng e do ln, c bit l chy rng t cc khu vc ln cn nn hin

trng bo tn ca loi ny c th phi c nng ln trong tng lai. Cc qun th

Lm ng l im phn b cc nam ca chi Thng lc a ng Nam .

Do cc qun th ny phn b bit lp nn c th l mt xut x ring bit (Thomas,

Gardner v Nguyen Duc To Luu, 2002) [1].

Cc mi e da

Nhn chung Thng Nam b e do tuyt chng do mt cc ni sng, c th

l do chy rng cc khu rng ln cn. Vic bun bn cc b phn hoc cc cht

chit ca loi ny lm ngun ch Taxol l e do i vi cc qun th t nhin

nhiu ni phn b trn th gii (Thomas v Nguyen Duc To Luu, 2004c) [1].

S hin din trong cc khu bo tn

Nam Vit Nam tt c cc qun th Thng u nm trong cc khu vc

rng c dng nhng khng phi l cc khu vi mc ch bo tn a dng sinh

Chng 2: TNG QUAN

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hc. Hai qun th chnh Ni Voi (c Trng) v H Tin (n Dng) l rng

phng h u ngun c qun l bo v.

Qun th th ba Xun Th ( Lt) nm trn t X nghip ging lm nghip

qun l v l rng th nghim (rng ging). Ni B p l khu Bo Tn Thin

Nhin nhng y mi ch quan st thy c 1 c th, tuy vn c nhiu kh nng

tm thy nhng cy khc (Thomas v Nguyen Duc To Luu, 2004c) [1].

Cc bin php bo tn thc hin

Loi ny c bo v bi lut php t khi c xp vo Nhm IA ca Danh

lc cc loi ng vt v thc vt qu him. Vin KHLN Vit Nam (Nguyen Hoang

Nghia, 2000) v Cng ty ging LNT (Dick v cng s., 2004) tin hnh nhn

ging sinh dng v trng bo tn chuyn v . Taxus wallichiana cng vi cc loi

Thng chu khc c a vo Ph lc II ca Cng c CITES.

Hot ng bo tn xut

Thng Nam Ni Voi, c Trng, Lm ng cn c ngh l mt khu

bo tn (v d nh khu bo tn ni sng cho loi) i vi Thng, c bit l Thng

Nam (Taxus wallichiana). Do loi ny c php lut bo v nn cn nng cao

nhn thc cho cc c quan lin quan v nhn dn nhng a im c cy cn li

nhm mc ch bo tn lu di. Qun th ny cng l a im tt cho nghin cu

v sinh thi v ht ging cho Thng Nam. Cn tip tc cc nghin cu v phn

loi nhm lm r v tr phn loi ca loi.

2.2 Taxol

2.2.1 Lch s nghin cu

Hp cht diterpenoid Taxol l mt trong nhng hp cht t nhin c ngun gc

t thc vt c kh nng chng ung th hiu qu nht hin nay. Taxol cng l loi

thuc iu tr ung th c gi tr thng mi hng u th gii, c tnh doanh thu

hng nm trn 3 t USD trn ton th gii [11].

Taxol cho hiu qu trong iu tr ung th bung trng v ung th v v cho

thy trin vng trong iu tr mt s loi bnh ung th khc nh no, c, phi v

bng quang (Holmes v cng s, 1995; Suffness, 1995) [11].

Taxol ban u c chit sut t v cy Taxus brevifolia Nutt. Cu trc Taxol

c xc nh bi Wall v Wani v cng s vo nm 1971 (Wani v cng s,

1971) [29] v c chp thun thnh sn phm thng mi ln u tin bi Cc

Chng 2: TNG QUAN

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qun l Thc phm v Dc phm Hoa k trong iu tr ung th bung trng vo

nm 1992 v iu tr di cn ung th v vo nm 1994 (Suffness v Wall, 1995)

(theo Croteau v cng s, 2006) [14].

Thi gian pht trin lu di ca loi thuc ny do nhiu nguyn nhn: ngun

gc cung cp hp cht ny t Taxus brevifolia (Pacific yew) cn hn ch (vic thu

hoch lm tn ph ngun cung cp t nhin, qu trnh tch chit phc tp, sn

phm thu c khng cao, nhng ngc li hiu qu iu tr cao), ngoi ra cn do

tnh cht k nc ca cc nhm diterpenoid t nhin v cc tc dng ph trong th

nghim iu tr lm sng (Arbuck v Blaylock, 1995) [11].

C ch tc ng ca Taxol l kh mi l v c o. Tri ngc vi Vinca

alkaloid, cochicine v mt s cht chng ung th khc vi c ch tc ng l ngn

cn s trng hp ca tubulin vo trong vi ng (microtubule), Taxol y nhanh qu

trnh lp rp ca microtubule v ngn cn qu trnh depolymerization (kh trng

hp) (Horwitz, 1992; Jordan v Wilson, 1995; Arbuck v Blaylock, 1995) [22].

Vic thu hoch Taxus sn xut Taxol c nguy c dn ti ph hoi mi

trng t nhin v sn lng Taxol thu c qu thp khng cung cp cho nhu

cu iu tr ngy mt tng. Do , nhiu phng php thay th ngun cung cp

Taxol c nghin cu.

Mc d, mt vi nhm (Cragg v cng s, 1993; Holton v cng s, 1994;

Nicolau v cng s, 1994, 1995; Masters v cng s, 1995) [11] t c kt

qu tng hp Taxol bng phng php ha hc nhng chi ph cao ca phng

php ngn cn kh nng thng mi ha ca n.

Taxol c cng c sn xut bng phng php bn tng hp t tin cht

mi (v d: baccatin III) c th d dng thu nhn t cc loi cy l kim khc nh

mt ngun cung cp nguyn liu c trin vng.

Mt phng php tip cn khc l s dng phng php nui cy dch treo t

bo ca T. brevifolia. Mt vi nhm nghin cu t c thnh cng trong sn

xut Taxol hoc bacatin t dch treo t bo Taxus (Yukimine v cng s, 1996;

Hezari v cng s, 1997) [11].

Taxol cng c tch chit t v, l, cnh v tri ca cy ph (hazelnut) nhng

sn lng thu c ch bng 10% so vi t cy Thng . Gn y, mt loi nm

Taxomyces vreanae c tm thy c kh nng sn xut Taxol v kt qu cng

Chng 2: TNG QUAN

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tng t nh Taxol thu c t Thng (Stierle v cng s, 1993; Strobel v

cng s, 1996).

Bng 2.1: Tm tt lch s nghin cu v hp cht Taxol (Wall v Wani, 1998) [25].

Thi

gian S kin

1963

Hot ng chng ung th trong cc hp cht chit sut t v cy T.

brevifolia c khm ph trong mt cuc kim tra quy m ln trn

35000 loi thc vt.

1971 Taxol c xc nh l hp cht c kh nng chng ung th.

1979 C ch duy nht ca Taxol c xc inh l hot ng lin kt to s n

nh cu trc ca tubulin.

1983 NCI tin hnh th nghim lm sng v s an ton v hiu qu ca Taxol

chng li nhiu loi ung th.

1989 Taxol p ng nhu cu iu tr mt phn hoc hon ton 30% bnh nhn

c iu tr trc vi ung th bung trng.

1991 Cng ty BristolMyers Squibb c chn l i tc ca NCI trong vic

pht trin tim nng ca TAXOL v k kt CRADA vi NCI

1992

FDA chp thun vic s dng Taxol trong iu tr ung bung trng. Tin

hnh th nghim lm sng chng minh tc dng ca thuc trong iu tr

ung th v di cn.

1993

Cng ty BristolMyers Squibb kt thc qu trnh thu hoch v cy T.

brevifolia v bt u pht trin cc ngun cung cp nguyn liu sn xut

Taxol khc.

1994

FDA chp thun vic s dng Taxol trong iu tr ung th v di cn, nu

bnh nhn ti pht trong vng 6 thng k t khi dng phng php ha tr

liu hoc khng p ng vi phng php ha tr liu kt hp.

1995 Dng bn tng hp ca Taxol c FDA chp thun a vo th trng.

1997

FDA chp thun dng bn tng hp ca TAXOL trong iu tr AIDS giai

on 2, lin quan ti Kaposis sarcoma. Taxol sn xut bng phng php

nui cy t bo c ph chun ti Hn Quc v c xut khu nh l sn

phm Genexol ca Samyang Genex.

1998

FDA chp thun cho dng bn tng hp ca TAXOL kt hp vi cisplatin

trong giai on u iu tr ung th phi cho nhng bnh nhn khng th

iu tr bng phu thut hoc x tr.

Chng 2: TNG QUAN

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2.2.2 Cu to Taxol

Trong cc hp cht th cp c dng trong iu tr ung th, Taxol l mt

diterpene phc tp thu c t Taxus spp., c cho l quan trng nht.

Taxol i din cho khong 400 nhm taxoid c xc nh (v d, taxane

diterpenoid) ca Taxus spp., tt c u da trn mt b khung taxane duy nht

(pentamethyl [9.3.1.0] tricyclopentadecane) hoc do s sp xp li sn phm ca

khung tricyclic (v d, abeo-taxoids c to thnh do s sp xp v tr A/B hoc

B/C trn vng). Cc nhn taxane mang 3 nhn lp th (stereocenter) v bn thn

Taxol mang 11 trung tm nh vy, chnh s lng ln nhn lp th nh vy dn

ti nhng kh khn nht nh trong tng hp Taxol [27].

Tn ha hc ca Taxol l 5, 20-epoxy-1,2,4,7,13-hexahydroxytax-11-en-

9one-4, 10-diacetate-2-benzoate 13 ester vi (2R,3S)-N-benzoyl-3-

phenylisoserine.

Cng thc phn t C47H51NO14 v khi lng phn t 853.9 Da.

Ti nhn ca Taxol l h thng vng A, B v C, vi mt s nhm chc bao

gm hai nhm OH, mt nhm benzoyl, hai nhm acetyl v mt vng oxetane. Lin

kt vi C13 ca nhn l mt chui bn hoc C13 (2R,3S)-N-benzoyl-3-

phenylisoserine vi mt nhm OH v mt nhm benzoyl.

Hnh 2.27: Cu trc ca Taxol [20].

Chng 2: TNG QUAN

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2.2.3 Con ng sinh tng hp Taxol

S gia tng nhu cu s dng kt hp Taxol trong iu tr ung th, v ngun

cung cp hn ch trong t nhin i hi phi c mt s hiu bit cn k v c ch

sinh tng hp ca n, c bit l c ch phn ng ca cc enzyme.

2.2.3.1 Cc nghin cu trc v qu trnh sinh tng hp Taxol [11]

Cu trc ca Taxol l kh phc tp c mang mt b khung C diterpene khc

thng, tm nhm oxy chc nng v phi hp vi mt chui acyl, vi 11 trung

tm phn ng (Wani v cng s, 1971) [29]. Theo xut ban u ca Harrison v

cng s (1966) [11], qu trnh sinh tng hp Taxol bt u vi s hnh thnh b

khung olefinic taxane, tip sau l mt lot cc phn ng oxy ha, cui cng l

phn ng acyl ha (Zamir v cng s, 1992; Eisenreich v cng s, 1996) [11].

Da trn cc nghin cu v s trao i cht ca cc nhm terpenoid khc

(Gershenzon v Croteau, 1993) [11], con ng sinh tng hp Taxol cng c

bt u t tin cht chung ca diterpenoid l GGPP lin quan ti hn mi phn

ng enzyme. Gii m qu trnh sinh tng hp Taxol t ra mt thch thc ng k

v cu trc phc tp ca n, nng sut thu nhn thp v qu trnh th nghim kh

khn i vi cc loi Taxus.

Cc nghin cu trc y, c thc hin in vivo vi cc tin cht c nh

du ng v phng x cho thy, acetate, mevalonate, v phenylalanine xy dng

nn cu trc ca Taxol (Zamir v cng s, 1992) [11]. Tuy nhin, gn y

Eisenreich v cng s (1996) ch ra rng h thng vng taxan c hnh thnh

t con ng c lp vi con ng mevalonate c tm thy bi Rohmer trong

sinh tng hp isoprenoid (Schwender v cng s, 1996) [11].

Nm 1996, Eisenreich v cng s trong bo co th nghim vi tin cht c

nh du ng v phng x 13C trong dch treo t bo ca Taxus chinensis. Phng

php ny to ra 2.6 % diterpene taxuyunnanine C trong sn phm (da trn trng

lng kh). Cc mu ng v phng x chng minh taxuyunnanine C c tng

hp thng qua con ng ngoi mevanlonate.

2.2.3.2 Con ng sinh tng hp Taxol

Qu trnh sinh tng hp Taxol trong chi Taxus cha c khm ph y .

Terpenoid l mt nhm hp cht th cp c cu to rt a dng vi tham gia cu

trc v chc nng trong thc vt. Mt s terpenoid ng vai tr thit yu i vi 1

Chng 2: TNG QUAN

41

s loi thc vt, v d nh phytohormone (hormone thc vt), cc sc t quang hc

hoc tham gia thnh phn cu trc mng t bo, trong khi cc nhm khc tham

gia trong cc phn ng phng v v thch ng ca thc vt vi mi trng sng.

Tuy nhin, tt c chng u c hnh thnh t cng mt tin cht, isopenthenyl

diphosphate (IPP) v dimethylallyl diphosphate (DMAPP) [18].

Trong nhiu loi thc vt, c s chia i trong con ng sinh tng hp cc

tin cht ca terpenoid.

Trong t bo cht, con ng mevalonate sn xut IPP t acetyl coenzyme A

sinh tng hp, sterol, triterpene v mt s sesquiterpene. Cc lp th l ni din

ra con ng thay th ngoi mevalonate sn xut IPP v DMAPP t pyruvate v

glyceraldehyde-3-phosphate to thnh cc isoprenoid: monoterpene, diterpene v

tetraterpene. Theo Eisenreich v cng s (1996), cc nghin cu v sinh tng hp

Taxol kt lun h thng vng taxoid khng c tng hp qua con ng

mevalonate., iu ny ph hp vi cc diterpene t nhin. Tuy nhin, mt s

nghin cu trc thc hin vo nm 1991, cho rng h thng vng taxoid c

tng hp t con ng mevalonate. ng thi, kt qu khi nui cy t bo T.

media (T. cuspidata x T. baccata) c b sung mevalonate cho thy c s tham gia

ca c hai con ng.

Cc kin hin ti u chp nhn rng, mt s t bo Taxus s dng con

ng mevalonate l ngun cung cp IPP sinh tng hp Taxol, v tin cht

chnh tng hp terpenoid l GGPP t con ng ngoi mevalonate.

Bc phn ng u tin trong con ng sinh tng hp Taxol l s to vng

ca geranylgeranyl diphosphate (GGPP) thnh taxa-(4,5),(11,12)-diene, mt phn

ng xc tc bi taxadiene synthase (TS), mt protein monomer 79kDa. Enzyme

ny c tinh ch v m t bi Hezari v cng s, v gen m ha cho TS c

to dng v biu hin chc nng trong E.coli bi Wildung v Croteau.

Sau , oxy v cc nhm acyl c b sung thm vo nhn taxane bi phn

ng oxy ha nhiu v tr trung gian bi cytochrome P450 mono-oxygenase.

Phn ng hydroxyl ha ti v tr C5 ca vng taxane c xc tc bi enzyme

cytochrome P450 taxadiene-5-hydroxylase (T5H), kt qu dn ti s hnh thnh

ca taxa-4(20),11(12)-dien-5-ol, l bc th 2 trong sinh tng hp Taxol. T5H

l mt protein c khi lng 56 kDa vi trnh t N cui cng, enzyme ny c

Chng 2: TNG QUAN

42

gn trn mng ca mng li ni cht. Enzyme ny ngoi hot ng xc tc cho

phn ng hydroxyl ha, n cng xc tc chuyn v ni i t 4(5) thnh 4(20).

Mc d 2 bc chuyn ha, to vng v hydroxyl ha din ra chm, nhng n

khng hn ch t l trong sinh tng hp Taxol.

Bc tip theo trong con ng sinh tng hp c xc tc bi taxadiene-5-

ol-O-acetyl transferase (TDAT), acyl ha taxa-4(20),11(12)-dien-5-ol thnh taxa-

4(20),11(12)-dien-5-yl-acetate. Enzyme ny c khi lng 50kDa khng mang

trnh t N cui cng. Cc sn phm ca phn ng ny sau c hydroxyl ha

bi taxoid 10-hydroxylase (T10H) ti C10. T10H l mt P450-dependent

monooxygenase c to dng v c biu hin c im trong nm men.

Mt Cyt P450-dependent hydroxylase dn ti s hnh thnh ca taxa-

4(20),11(12)-dien-5-13-diol c tm thy. Thc t l enzyme ny s dng

c cht tng t nh (TDAT), taxa-4(20),11(12)-dien-5-ol, cho thy qu trnh

sinh tng hp Taxol khng phi ch c duy nht mt con ng m c nhiu im

phn nhnh dn ti s hnh thnh cc nhm taxoid khc c lin quan. Trng hp

thay th ny c quan st, c bit n thng xy ra trong qu trnh nui cy

t bo vi s c mt ca methyl jasmonate.

Taxoid 14-hydroxylase (T14H) xc tc s hnh thnh ca taxa-4(20),11(12)-

dien-5-acetoxy -10-14-diol. Enzyme ny khng s dng c cht c

hydroxyl ha ti v tr C13, m ch nhng c cht c hydroxyl ha ti v tr C10,

cho thy T14H khng th tham gia vo vic sn xut Taxol, m cng khng xut

hin phn ng hydroxyl ha ti v tr C14.

Bc cui cng trong con ng sinh tng hp Taxol, sau khi hnh thnh taxa-

4(20),11(12)-dien-5-yl-acetate, bao gm 1 s v tr c hydroxyl ha ti C1,

C2, C4 v C7, oxy ha ti v tr C9, v epoxide ha ti v tr ni i C4, C5. Phn

ng hydroxyl ha c xc tc bi cc enzyme Cyt P450 nhng n khng chnh

xc trong mt s trng hp.

Chng 2: TNG QUAN

43

Hnh 2.28 : Con ng sinh tng hp Taxol bt u vi geranylgeranyl diphosphate

v kt thc vi tin cht gi nh c polyhydroxyl ha [18].

Mc d, c nhiu c ch khc nhau cho s hnh thnh vng oxetane c

xut, tuy nhin hin ti c ch c chp nhn l: qu trnh ny c lin quan n

qu trnh epoxide ha ti v tr ni i 4(20) vi s chuyn v ca nhm -acetoxy

t v tr C5 n C4 cng vi vic m rng nhm oxirane thnh nhm oxetane.

Chng 2: TNG QUAN

44

C th bc ny trc bc hydroxyl ha ti v tr C1 trong sinh tng hp

Taxol, v trong trng hp ny gi nh polyhydroxyl ha l cht trung gian s l

taxadien-hexaol hn l heptaol hydroxyl ha ti C1. Enyme xc tc phn ng

epoxide ha ti ni i C4-C20, v c ch m rng vng oxirane thnh oxetane

cng cha c bit n y .

Hnh 2.29: Qu trnh hnh thnh vng oxetane trong sinh tng hp Taxol [18].

Sau khi hnh thnh cc tin cht gi nh c polyhydroxyl ha

(hypothetical polyhydroxylated precursor), n c xc tc phn ng tip tc bi

2-O-benzoyl transferase (DBT), protein c khi lng 50 kDa, hp cht thu c

tip theo l 10-deacetylbaccatin III. Mt phn ng chuyn nhm acetyl c xc

nh trong con ng sinh tng hp Taxol lin quan ti phn ng hydroxyl ha ti

v tr C10 ca 10-DAB (10-deacetylbaccatin III) vi s xc tc ca enzyme 10-

deacetyl-baccatin III-10-O-acetyl transferase (DBAT). Dn ti s hnh thnh mt

diterpene trung gian, baccatin III, s dng c cht l 10-DAB v acetyl CoA.

Mt bc cn thit trong sinh tng hp Taxol l phn ng ester ha ca nhm

hydroxyl C13 ca baccatin III vi phenylalanoyl-CoA ca chui bn. Cc chui

bn hnh thnh t cc acid amin- phenyalanine bi tc ng ca phenylalanine

aminomutase (PAM). Mt ester CoA ligase cha c bit n c th kch hot

hp cht ny v n c th lin kt vi cc baccatin III. Enzyme xc tc cho phn

ng lin hp ca chui bn phenylalanoyl-CoA v baccatin III l C-13-

phenylpropanoyl-CoA transferase (BAPT), sn phm l cc hp cht 3-N-

debenzoyl-2-deoxytaxol. Hp cht ny c chuyn ha bi enzyme Cyt P450-

dependent hydroxylase c ch cha c bit r, xc tc phn ng hydroxyl v

tr C2 v enzyme 3-N-debenzoyl-2-deoxytaxol N-benzoyl transferase

Chng 2: TNG QUAN

45

(DBTNBT) xc tc phn ng lin hp vi benzoyl-CoA thnh 3-N-debenzoyl-2-

deoxytaxol, Taxol l hp cht cui cng.

Hnh 2.30: Con ng sinh tng hp Taxol t tin cht gi nh c

polyhydroxyl ha [18].

2.2.4 C ch tc ng ca Taxol

Hot ng chng ung th ca Taxol ch yu do chui mch bn, vng A, nhm

benzoyl C2 v vng oxetane. Hot ng ny c duy tr bi nhm amide-acyl

vi tr C3 trong chui gn v tr C13 v c tng cng bi nhm hydroxyl v

tr C2 [27].

Chng 2: TNG QUAN

46

S tng tc ca cc thnh phn trn vi -tubulin ca vi ng, thc y qu

trnh polymer ha sn xut cht c v n nh vi ng.

Taxol c ch s pht trin t bo bng cch lin kt vi b mt ca vi ng, c

th l lin kt vi tiu n v ca tubulin l cc heterodimer, do thc y qu

trnh trng hp ca n, ngay c trong trng hp khng c GTP.

Hnh 2.31: C ch tc ng ca Taxol i vi t bo gy ung th [25].

Taxol

Taxol

Qu trnh polymer ha ca tubulin

n nh cu trc vi ng (c ch phn ng depolymerization)

T bo ung th khng thc hin c cc

hot ng thng thng

Chu k phn chia t bo ngng giai on G2/M

T bo ung th cht hng lot

Chng 2: TNG QUAN

47

Vi ng bao gm cc polymer ca tubulin heterodime trng thi cn bng

ng. Tubulin heterodime gm c cc protein tiu n v v . Vi ng c hnh

thnh t s nh trng hp 2 loi tubulin l v . Mi loi tubulin c khng 450

loi acid amin, s tng ng v acid amin gia chng l khong 40%, v chng

c cu trc tng t nhau. Mi monomer ny c cu trc xon v gp np . N

cng bao gm mt khu vc lin kt vi nucleotide, lin kt vi cc protein khc v

3 v tr lin kt vi Taxol [18, 25].

C mt trng thi cn bng ng lin tc gia tubulin nh trng hp v vi ng,

do c s cn bng gia qu trnh trng hp v kh trng hp

(depolymerization). Tc ng ca Taxol ti a khi t l gia Taxol/tubulin l 1/1 v

qu trnh polymer ha ca tubulin c thc y khi nng ca Taxol l 0.05

mM. Lin kt ca Taxol vi cc vi ng s khng thay i, vi hng s lin kt vo

khong 0.9 mol/L [18].

Mc d, chc nng ch yu l hnh thnh thoi v sc trong qu trnh phn chia

t bo, vi ng cng tham gia nhiu chc nng quan trng k trung gian bao gm

duy tr hnh dng, vn ng, dn truyn tn hiu v vn chuyn ni bo.

Khng ging nh cc loi thuc ngn cn s hnh thnh vi ng, nh vinca

alkaloid, gy ra s tch ri ca vi ng, Taxol li thc y qu trnh trng hp ca

tubulin. nng nh hn 10-9, Taxol c ch s tch ri ca vi ng, trong khi

n lm tng s lng v khi lng ca chng, y l nng trong iu tr lm

sng.

Cc vi ng hnh thnh khi c mt Taxol cc k n nh v gy ra ri lon chc

nng, do lm cht t bo bng cch ph v trng thi cn bng ng bnh

thng ca qu trnh phn chia t bo cng nh cc qu trnh chun b k trung

gian. Taxol cng gy ra nhng biu hin trn gen i vi nhn t gy ra khi u

hoi t, nhng nghin cu v cu trc v hot ng cho thy hot ng ny khng

lin quan ti tc ng ca Taxol i vi s lp rp vi ng, qu trnh nui cy m

cho thy mt phn vai tr ca cytokines trn hot ng khng ung th ca Taxol.

V tr lin kt ca Taxol l khc bit so vi v tr lin kt ca guanosine

triphosphate, colchicine, vinblastine, v podofilox (podophyllotoxin). Taxol lin

kt vi N-teminal 31 amino acid ca -tubulin, nhiu hn l lin kt vi tubulin

nh hp gia v .

Chng 2: TNG QUAN

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Hnh 2.32: C ch phn ng ca Taxol trong h thng vi ng ca t bo [18].

Hai c ch khng thuc i vi Taxol:

C ch th nht, mt s khi u c cha c v -tubulin lm gim

kh nng tc ng ca Taxol vo qu trnh polymer ha cng nh lm chm tc

lp rp ca vi ng.

C ch th 2 lin quan ti s khuych i ca phn t

phosphoglycoprotein trn mng, n c chc nng nh mt my bm thuc ra

ngoi.

Trong cc t bo nguyn vn, Taxol to thnh tng b vi ng, v tc ng ti

s hnh thnh mt s lng ln thoi v sc. Taxol cng tng cng hot ng khi

c s tc ng ca bc x ion in vitro, bng cch ngn chn trong giai on G2 ca

k trung gian v trong qu trnh phn bo l nhng giai on nhy vi bc x.

Tnh kh thi ca vic s dng Taxol kt hp vi bc x iu tr cho bnh

nhn ung th phi, u v c, ung th thc qun c th p ng vi c hai phng

php iu tr hin ang c nh gi.

Chng 2: TNG QUAN

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Trong khi s lng bnh ung th c iu tr bng Taxol ngy cng c m

rng, cho n nay n c ch yu dng trong iu tr ung th bung trng, ung

th v di cn v mt s lng nh trong iu tr ung th phi cng nh iu tr

AIDS giai on 2-lin quan ti ung th m lin kt (Kaposis sarcoma).

Taxol hin ang c nghin cu iu tr cc bnh khc do n c kh nng

n nh vi ng cng nh ngn cn s pht trin ca t bo v s hnh thnh mch,

v d nh bnh psoriasis (bnh vy nn).

Taxol cng ang c nghin cu iu tr taupathies (tc ng ti cc

protein tau-protein n nh vi ng, chng c nhiu t bo thn kinh trong h thn

kinh trung ng), chng hn nh bnh Alzheimer, hi chng Parkinson lin qun

ti nhim sc th s 17, v mt s bnh khc.

2.2.5 Mt s phng php tng hp hp cht Taxol

2.2.5.1 Tng hp bng phng php ha hc

Cu trc ca Taxol, ngoi b khung chnh: vng A, B v C, n cn bao gm

vng oxetane (vng D), chui bn N-benzoyphenylisoserine ni vi C13 ca vng

A v nhm benzoate v tr C2 ca vng B.

Nm 1994, hai nhm nghin cu (Holton v cng s, 1994; Nicolaou v cng

s, 1994) [11] bo co v hp cht Taxol tng hp bng phng php ha hc

vi mt t l thp, tng ng l 2.7% v 0.07% [21].

Theo nhm ca Nicolaou v cng s, phng php tng hp c s dng l

xy dng cc vng A v C ring bit sau ni 2 phn t li vi nhau bng cch

s dng phn ng Shapiro v lin kt McMurry hnh thnh vng B. Tip theo

sau l mt lot cc phn ng gn vng oxetane (vng D) v cc nhm chc

bn ngoi ca vng B v C. cui giai on, l qu trnh oxy ha v ester ha v

tr C13 gn chui bn v hon thnh cu trc Taxol.

Chng 2: TNG QUAN

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Hnh 2.33: Phng php phn tch retrosynthetic ca Nicolaou [11].

Holton v cng s, c mt cch tip cn khc, phng php a ra l s dng

(-)-borneol l vt liu khi u, sau c bin i thnh ketone khng bo ha

vi khong trn 13 bc tng hp.

Chng 2: TNG QUAN

51

Hai nm sau, Danishefsky v cng s (1996) xut con ng tng hp th

ba vi cc bc tng hp t hn so vi 2 phng php ca Nicolaou v Holton.

Phng php c khi u vi Wielv-Miescher ketone, tip c bin i

thnh hp cht enol triflate c mang olefin trn vng C cho php pht trin thnh

Taxol thng qua phn ng Heck ni phn t.

Ngoi ra, nm 1998 Morihira v cng s bo co tng hp thnh cng hp

cht Taxol. Mc d, tng hp thnh cng hp cht Taxol bng phng php ha

hc l mt thnh tu khoa hc ln, nhng n khng th c thng mi ha

trong tng lai gn v cc phng php ny cn t nht 20 bc tng hp ha hc

v nng sut mt s bc l tng i thp. iu ny lm cho phng php ny

rt phc tp v tn km nhiu chi ph.

2.2.5.2 Nui cy t bo Taxus

Nhu cu i vi vic cung cp Taxol trong iu tr ung th ngy mt tng, y

l kt qu ca vic s dng m rng Taxol trong cc liu php can thip sm cng

nh kt hp ci cc tc nhn ha tr liu khc.

Do nhng vn bao gm: khai thc t cc ngun t nhin v nhng kh khn

ca ca phng php bn tng hp, c nhng nghin cu thu nhn Taxol

da trn nui cy t bo. Cng ngh sinh hc ng dng trong sn xut Taxol c

nghin cu t nhng nm u thp nin 90. Ban u cng vic c thc hin bi

nhiu nhm nghin cu khc nhau cho thy m so v dch treo t bo t thn cy

non ca Taxus sp. c th sn xut Taxol t nht l mc tng t nh cy

trng.

tng nng sut ca Taxol v cc taxoid c lin quan trong nui cy m v t

bo, c th s dng nhiu phng php khc nhau bao gm: ti u ha cc iu

kin nui cy, la chn dng t bo c nng sut cao, s dng cht cm ng

(elicitor), v b sung tin cht, cc phng php ny c kim tra bi nhiu

nh nghin cu. y l nhng bo co nh gi cng ngh sinh hc trong sn

xut Taxol v cc kin thc hin ti v s trao i cht ca Taxol trong nui cy t

bo.

Bng 2.2 tm tt cc nghin cu quan trng gn y trn kh nng nng cao

sn xut Taxol bng k thut nui cy t bo v phng php chnh c s dng

t c mc tiu ny.

Chng 2: TNG QUAN

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Bng 2.2: Cc nghin cu gn y v kh nng thu nhn Taxol v cc hp cht

c lin quan bng phng php nui cy t bo [18].

Tm tt nghin cu Tc gi

Mt dng bioreactor mi c pht trin

thnh cng sn xut Taxol v tin cht

ca n bng cch nui cy t bo

T.cuspidata trn quy m th nghim. Tng

sn lng thu c khong 3 mg/l Taxol

v 74 mg/l taxoid sau 27 ngy nui cy.

Son, S.H.; Choi, S.M.; Lee, Y.H.; Choi,

K.B.; Yun, S.R.; Kim, J.K.; Park, H.J.;

Kwon, O.W.; Noh, E.W.; Seon, J.H.;

Park, Y.G.(2000)

Cc dng lp th ca methyl jasmonate v

tc ng ca chng i vi nng sut t

bo v thc y sn xut Taxol v

baccatin III c nghin cu trn dch

treo t bo T.media.

Yukimune, Y.; Hara, Y.; Nomura, E.;

Seto, H.; Yoshida, S. (2000)

Nui cy t bo T.media gm 2 giai on

c thc hin vi bioreactor 5L c

khuy trn. Sn lng thu nhn c l

21.12 mg/l Taxol v 56.03 mg/l baccatin

III sau 20 ngy nui cy.

Cusid, R.M.; Palazn, J.; Bonfill, M.;

Navia-Osorio, A.; Morales, C.; Piol,

M.T. (2002)

Nhng nh hng ca cht cy

(inoculum) ti kch thc, tui tng

trng ca sinh khi v kh nng sn xut

Taxol trong qu trnh nui cy t bo T.

yunnanensis.

Zang, C.H.; Wu, J.Y.; He, G.Y. (2002)

Dch treo t bo ca T. baccata v T.

wallichiana tng trng trong bioreactor

20 L, tc tng trng v kh nng tch

ly Taxol v baccatin III ca 2 loi Taxus

c ghi nhn.

Navia Osorio, A.; Hermann, G.; Cusid,

R.M.; Palazn, J.; Alfermann, A.W.;

Piol, M.T. (2002)

Chng 2: TNG QUAN

53

Bng 2.2: (Tip theo).


Tc ng ng h tr ca cc elicitor

khc nhau c nghin cu trn dch treo

t bo ca T. chinensis, kt qu cho thy

hn hp cc elicitor vi cc tc ng khc

nhau c kh nng ng h tr trong khi

cc elicitor c tc ng ging nhau li

khng th.

Yuan, Y.J; Wei, Z.J.; Miao, Z.Q.; Wu,

J.C. (2002)

S vn chuyn ca Taxol trong dch treo

t bo T. baccata c nghin cu bng

cch s dng Taxol [14C] c nh du.

Cc phn t c hp th trong c thnh

t bo (20%) v trong t bo cht (80%),

cho thy s tch t trong khng bo.

Fornal, S.; Esposti, D.D.; Navia-Osorio,

A.; Cusid, R.M.; Palazn, J.; Piol,

M.T.; Bagni, N. (2002)

c ch s tch ly Taxol v baccatin III

vi mevinolin v fosmidomycin c

nghin cu trn dch treo t bo T.

baccata.

Palazn, J. Cusid, R.M.; Bonfill, M.;

Morales, C.; Piol, M.T. (2003)

M t cc taxoid ch yu c sn xut

bi dch treo t bo T. media trong iu

kin nui cy bnh thng v vi s b

sung methyl jasmonate.

Ketchum, R.E.B.; Rithner, Ch.D.; Qiu,

D.; Kim, Y.S.; Williams, R.M.; Croteau,

R.B. (2003)

S nh hng ca cc elicitor trn s sn

xut taxoid v hot ng ca 3-hydroxy-

3-methylglutaril coenzyme A reductase

trong t bo T. media c nghin cu.

Bonfill, M.; Palazn, J.; Cusid, R.M.;

Joly, S.; Morales, C.; Piol, M.T. (2003)

Chng 2: TNG QUAN

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Nhng nh hng ca sng siu m

cng thp trn cm oxy ha

(oxidative burst), sinh tng hp acid

jasmonic v sn xut Taxol trong dch

treo t bo T. chinensis c nghin

cu.

Wu, J.; Ge, X. (2004).

Tc ng lun phin v trc tip ca t

trng ln s tng trng v sn xut

Taxol trong nui cy t bo T. chinensis

var. mairei c nghin cu.

Shang, G.-M.; Wu, J.-Ch.; Yuan, Y.-J.

(2004).

S cm ng ca methyl jasmonate v

salicylic acid (SA) i vi s sinh tng

hp Taxol v cc taxoid c lin quan

trong dch treo t bo ca T. chinensis

c nghin cu. Kt qu cho thy SA c

th lm tng qu trnh sn xut Taxol

bng cch ngn chn con ng sinh tng

hp t baccatin III thnh cephalomannine.

Wang, Y.D.; Yuan, Y.J.; Wu, J.C. (2004,

2007).

Sn xut Taxol v baccatin II bi t bo

T. baccata t do v c nh c nghin

cu trn ba loi bioreactor khc nhau

(khuy trn, sc kh v to sng).

Bioreactor khuy trn c hiu qu nht

trong vic thc y t bo c nh sn

xut Taxol, hm lng Taxol thu c l

43,43 mg/l sau 16 ngy nui cy.

Bentebibel, S.; Moyano, E.; Palazn, J.;

Cusid, R.M.; Bonfill, M.;

Piol, M.T. (2005)

Chng 2: TNG QUAN

55



Phn ng ca dch treo t bo T.

yunnanensis (cy Thng c ngun gc

t tnh Vn Nam, Trung Quc) khi b sc

nhit cng c nghin cu. T bo b

sc nhit 35 - 50oC trong thi gian 30 -

60ph. Kh nng sn xut Taxol v cm

ng ca t bo trong qu trnh nui cy

gim xung r rt. Vic b sung ABA vo

nui cy cng c kho st.

Zhang, Ch.; Fevereiro, P.S. (2007)

C ch cm ng sn xut Taxol trong

nui cy t bo T. cuspidate khi b sung

vi Ce4+ hoc methyl jasmonate c

nghin cu. Kt qu cho thy rng s cm

ng lin quan n thnh phn lipid ca

mng t bo. Sn lng Taxol c nng

cao.

Yang, S.; Lu, S.H.; Yuan, Y.J. (2008)

Phng php nui cy t bo l mt phng php thay th gp phn vo s

pht trin mi trng bn vng. Phng php ny c mt s u im nh khng

ph thuc vo iu kin thi tit, ma v nhim, v nguyn liu c th pht trin

c lp so vi ngun gc ban u, iu kin c qu trnh v v tr kch

thchy l phng php c tim nng kinh t ln so vi phng php truyn

thng, v n c kh nng sn xut mt lng ln taxoid tinh khit.

Hin nay, Python Biotech l nh sn xut Taxol ln nht bng phng php

nui cy m t bo, s dng h thng fermentor ln ln ti 75000 L. Mt cng ty

khc, Corean Samyang Genex, s dng nui ct t bo Taxus sn xut Taxol

vi tn thng mi l Genexol [27].

2.2.5.3 Bn tng hp t DAB

Taxol cng c sn xut trn quy m ln bng phng php bn tng hp

t baccatin III hoc 10-deacetylbaccatin III, y l mt n lc ln cho vic khm

Chng 2: TNG QUAN

56

ph ra cc phng php ci thin hoc thay th cho qu trnh sinh tng hp t

nhin.

BMS (Bristol-Myers Squibb), l nh cung cp Taxol hng u th gii, c mt

trang tri ln ti 30 triu cy cung cp v v l cho vic tch chit cc hp cht

trung gian. Trong nm 2007, Indena pht trin phng php bn tng hp Taxol

theo mt quy trnh c cp bng sng ch da trn 10-deacetylbaccatin III [27].

S tng hp Taxol v cc hp cht tng t n c bt u vi 10-DAB, hp

cht ny phi c bo v v tr C7 v C10 trc khi acyl ha ti v tr C13. Nu

hp cht 10-acyl, tng t nh Taxol l sn phm mong mun, 10-DAB thng

c bo v bng 7-triethylsilyl ether ca n v sau acyl ha chn lc C10

cay thong do va hop chat taxol

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