AGENTS

423
ANTICANCER
DERIVED
THE SEARCH FOR NATURALLY

and
mucronate apex
base, a rounded or
tile didemnin B, iso Oblong with a petiolate acute
of the
conmon
cular resemble those
In form the flowers
C o m p o u n d s o fp a r t i c u
solidum, the bryosta- an entire margin. (Var.
se
coloured violet, rose,
white avus)
periwinkle Vinca majorand are
C a r i b b e a n

from
the e
Bugula
Dryozoan
is a divergent
follicle.
macrocyclic
The fruit
Jated ot he sea hare, Dolabella Or white with a red eye (var. ocellatus). habit

a group 10., have a more vigorous growth

are reported to
d o l a s t a t i n

ins.
auricularia.
and
Didemnin B
CVeral humancancers Telraplod plants
neritina,
ymphomas)and bry- and larger flowers than diploid ones.
ncluding prostate, lun
kinase C which med in folk
found to b: teproiein has a certain reputation
History. Although the plant
been
has i)is aVery potent inhibi-
:tatin I of
cancer

diabetes, modern investigators lav

growth is noW available cine for the treatment of workers. during
mediates a s s e m b i
matcrial Canadian
this property.
Instcad
ial trials. An NCDD Group t0 confirm
of the leaves produced leuK to
m i c r o t u b u l e

unable
of three compou
tor discovered that extracts
All derived from cultured and 1955-1960, at Eli Lilly
fortesting. led researchers
nis

new anticance: observations

rats. These with a
reported on u d e cancer cell growth inhibi- penic actions in of the plant
phytochemical investigation
these
d marine organisms: undertake an intensive
n llected.

invertebrates Sponges). selected

marine microalgae
constituents of
value in cancer chemotherapy
from marine al. (21 View to the isolation of available
fungi and bacleria (W. Fenical et
in this respect and two are n o w
marine active
proved 1990, 68.
nnflagellates), Six alkaloids CelI Biol.,
41(supplement). 6). Biochem.
Biol.. 2005, (see R. L. Noble,
Pharm. commercially
aunthors). intro-
1344-1351). which has been
is an example of a drug plant the isola-
Catharanthus
and it is used for
recent years,
PLANTS CONTAINING ANTICANCER duced into medicine during Indeed,
for galenical preparation.
substances rather than
CURRENT USE tion of pure material and
con-

AGENTS IN from the dried plant

Simple galenicals, prepared be quite useless thera-
of alkaloids, would is
wide spectrum material
CATHARANTHUS ROSEUS taininga
circumstances, the raw
in normal as
has been variously peutically. Hence, not reach the
pharmacist
CatharanthuS roseus, manufacturer and does
periWinkle, handled by the
It is indige-
The Madagascan and L o c h n e r a
rosea (Apocynaceae).
Vinca rosea such.
designated distributed throughout w a m
but is now widely in been isolated
from
Madagascar it grows profusely alkaloids have
now
nous to ornamental; About 150 and
as a n
culüvated Constituents.
lochnerine, serpentine
and is much obtained from both
regions supplies of the drug
are
roseus; some,
for example, ajmalicine, Of particular
Commercial C. the family.
southern Florida. various locations, including Africa, o c c u r in
other genera of
in contains those
wild and
cultivated plants produced USA and
Australia.
tetrahydroalstonine,
about 20 bisindole
alkaloids which
Spain, group of (vincristine) and
Taiwan, e a s t e n Europe, is
interest a leurocristine
India. Thailand, activity, including
high, having antineoplastic
Vinblastine is produced by coupling
subshrub, 40-80
cm
(vinblastine).
herbaceous vincaleukoblastine

C. is a
oppositely arranged,
roseus
Characters.
leaves are
at the base. The
becoming woody

OH
CH,O2C
OH
CH,O2C
OH
MeO H HNOC OPH

MeO
ocoCH
CHO
Vindesine

Vinblastine, R = CHa

CHO
Vincristine,
R =

CHOC

O c o C H ,

MeO H
CH,OC

Vinorelbine
OF the indole alkaloids catharanthine and vindoline, both of which occur

Tee in the plant. Formation of 3'4-anhydrovinblastine from these

monomers has been effected with

peroxidase isozymes isolated from
POseus suspension cultures and with commercial horseradish peroxi-
dase (see J. P. Kutney. Nat. Prod. Rep., 1990, 7, 85-103). Vincristine is
structurally similar to vinblastine, but has a formyl group rather than a
methyl on the indole nitrogen in the vindoline-derived portion. Because
these alkaloids are
only minor constituents of the plant (vincristine is
obtained in about 0.0002% yield from the crude drug), large quantitic.
of raw material are required and chromatographic fractionations are
extensively employed in the isolation procedures. In addition, there is a
growing demand for vincristine rather than vinblastine, but the plant
produces a much higher proportion of vinblastine. Fortunately, it is now
possible to convert vinblastine into vincristine either chemically, or via
microbiological N-demethylation using Streptomyces albogriseolus.
Cell cultures. In efforts to improve the production of alkaloids, cell
cultures of C. roseus have received considerable attention (Chapter
13). Success has been achieved in obtaining total alkaloid yields cor-
responding to 0.1-1.5% dry weight cultured cells, but cultures pro-
duced catharanthine and tabersonine, and not vindoline, so lacked one
of the essential precursors for formation of the bisindole alkaloids.
A similar problem arises with transformed root cultures although the
feeding of loganin alone at the early stationary phase has been shown
to increase the ajmalicine production 2.3-fold and the serpentine 1.8-
fold when compared with control cultures; catharanthine levels are
unaffected by a single feed of the precursor. Research is still necessary
to find means of inducing the production of the useful alkaloids.

Uses. Vinblastine is used mainly for the treatment of generalized

Hodgkin's disease, and non-Hodgkin's lymphomas. Vincristine is
used principally in the treatment of acute lymphocytie leukaemia in
children. It has other applications for lymphomas, small-cell lung
cancer, cervical and breast cancers. The semi-synthetic vindesine is
also used in the treatment of acute lymphoid leukaemia in children.
Vincristine has a superior antitumour activity compared to vinblas-
tine, but is more neurotoxic. Vinorelbine is a newer, orally active,
semi-synthetic anhydro derivative of 8'-norvinblastine with a
broader anticancer activity and lower neurotoxic side-effects than
the other Catharanthus alkaloids.

Other species. A number of other Catharanthus species have been

investigated and found to contain vindoline-type alkaloids; some (e.g.
C. longifolius, C. trichophyllus and C. lanceus) contain dimeric
alkaloids similar to vineristine and vinblastine.

PODOPHYLLUM AND PODOPHYLLUM RESIN

DJ Ma D t :LJ