436
Antitumor Agents: Taxol and Taxanes – Production by Yew Cell Culture
Tab. 5
Examples of bioreactor production of taxanes to industrially signiFcant amounts.
Species
Equipment
Taxane
Production
[mg L
1
]
Productivity
[mg L
1
×
d]
Treatment
Taxus
Stirred
Taxol
21.1
1.06
Methyl jasmonate,
media
reactor, 5 L
capacity
Baccatin III
56.0
2.8
Precursor
feeding, 2-stage
media
T. cuspidata
Baloon
(bubble
reactor),
20 to 500 L
Total taxanes
74
2.74
±eeding or medium
replacement
T. chinensis
Bubble
column,
1L
Taxuyunnanine C
229
13.5
Ethylene addition
Airlift, 1 L
Taxuyunnanine C
336
20.2
Methyl jasmonate,
ethylene addition
and sucrose
feeding
Airlift, 1 L
Taxuyunnanine C
612
24.7
Repeated methyl
jasmonate
application and
sucrose feeding
of
Taxol
and
related
taxanes, which
c
a
nb
eu
s
e
di
nt
h
ep
r
o
d
u
c
t
i
o
na
n
d
semisynthesis of this antineoplastic agent
and its analogs. Scaled-up cell cultures
and alternate modes of taxane production,
such as protoplasts and perfusion culture
systems need to be further developed
by combining the knowledge that has
been successfully applied to suspension
cultures with the particular features of
these culture methods.
The molecular characterization of tax-
ane biosynthetic genes, the availability of
their sequences, and protein products ex-
pressed in microorganisms for detailed
kinetic studies open important perspec-
tives for the establishment of engineered
yew cell cultures transformed with genes
controlling slow or limiting biosynthetic
steps driven by strong or easily inducible
promoter sequences. The knowledge of
cis elements in promoter sequences of
taxane biosynthetic genes may shed light
on their modes of regulation and con-
tribute to their efFcient manipulation.
Alternatively, antisense transformation or
the use of RNA interference techniques
may be useful for the suppression or in-
hibition of competing pathways, making
more carbon, nitrogen, and energy flux
available for relevant taxane assembly. In
that regard, the recently observed preferen-
tial induction of C-13 oxygenated taxanes
(more pharmaceutically relevant) by MJ in
T. media
cell cultures points to taxoid 14
β
-
hydroxylase, a recently cloned cytochrome
P450-dependent monooxygenase, as an in-
teresting target for inhibition in cultures
that produce C-14 oxygenated taxanes. As
the molecular basis of taxane biosynthe-
sis if further detailed, the identiFcation
of trans-activating factors (DNA binding
proteins) controlling the coordinated ex-
pression of multiple biosynthetic genes
previous page 436 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 438 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off