Types of Anticancer Agents Isolated From Plants
Jonathan 1.Hartwell'.*
SUMMARY
The actire compounds which have been isolated from plants and tested in the
chemotherapy program of the Sational Cancer Institute since the inception of
t h e plant program (as part of t h e Cancer Chemotherapy Kational Service
Center) are listed, classified into types, and discussed in terms of their activitlin experimental tumor systems. The tumor systems include the most important
ones comprising the regular screen at different times and aIso t h e slow-growing
tumors, R16 melanoma and Lewis lung carcinoma (newr).The strueture-antitumor
activity relationships bring out the desirability for further investigation of
certain types of compounds as possibilities for clinical trial. S o t e s on the current
pharrnacologic and cIinical status of certain compounds are also presented.
[Cancer Treat Rep 60:10:31-1067, 19761
From t h e earliest days of t h e Cancer Chemotherapy National Service Center (1956) it was realized
t h a t a comprehensive program for t e s t i n g compounds for antitumor activity m u s t include those of
n a t u r a l as well as synthetic origin. I t w a s also
known t h a t n a t u r e is able to produce a wide variety
of chemical entities of novel structure. Many of t h e
new and novel compounds i s d a t e d from n a t u r a l
sources might otherwise have never been discovered, especially those of considerable complexity
requiring t h e development of methods for t h e creation of new ring systems. N a t u r a l products appeared to be a promising source for new types of
colnpounds t o t e s t for antitumor activity. Consequently, a fermentation program was initiated in
1956 and in 1957 t h e plant program followed alt h o u g h a few p l a n t e x t r a c t s w e r e received and
tested in 1956. Procurement of animals and their
extracts began In 1962.
Before t h e establishment of t h e experimental n a t ural products program, 1 had conducted a survey of
t h e l ~ t e r a t u r eand folklore of plants with reputed
efficacy in cancer (1) and found > 3000 different
species of such plants reported from all over t h e
world. Previously, I had isolated podophyllotoxin
and two other lignans from t h e mayapple root (Po'Drug Research and Development Program (DR&DP), Dlvislon
of Cancer Treatment (DCT), National Cancer Institute (NCI).
Bethesda, Bld.
*Reprint requests to: Natural Products Branch, DR&DP, DCT,
NCI, Blair Bldg, R m 4A17,8300Colesville Bd, National Inst~tutes
of Health, Silver Spring, Md 20910.
d o p h y I l ~ r ~peltaturn
n
L.)(2),all of which were powerfully active against Sarcoma 37 in t h e mouse; I
undertook t h i s s u r v e y when I learned t h a t t h i s
plant w a s used by t h e Penobscot Indians of Maine
as a t r e a t m e n t for what was believed t o be cancer
(3) a n d t h a t the root of t h i s plant w a s recommended
for cancerous tumors in a book on materia medica
and therapeutics published in 1849 (4). I t is interesting t o observe t h a t several derivatives of podophyllotoxin a r e now in clinical trial in cancer. illthoug;t~
t h e literature and folklore c a n provide leads for
plant coIlecting, it was realized t h a t selective collecting is expensive a n d t h a t , besides, this kind of
input would be insufficient t o m a i n t a i n a large
program for a long time. Therefore, a world-wide
random collection program was initiated with t h e
expectation not only of uncovering new leads for t h e
isolation of novel compounds but also of ultimately
revealing correlations between anticancer act~l-ity
a n d botanical classification t h a t would make collection more efficient in terms of finding active agents.
The success of these considerations can be judged
from t h i s and other papers in this Symposium, as
well as by t h e multitude of publisI~edpapers already
in the literature which arose from our program.
METHODS
The efficient isolation of active compounds from
plants in a large p r o p a m is
dependent
upon t h e effectiveness of t h e extraction procedure
Cancer Treatment Reports Vol. 60, No. 8, August 1976
1031
a n d t h e bioassay methods used to detect active
plants and to guide the fra~t~ionations.
I believe i t is
worth a short discussion of t h e s e points before
taking u p t h e compounds themselves, because variations in the methods have a profound effect on t h e
types of compounds isolated. Beginning with necessarily arbitrary methods, some improved methods
have evolved over the years based on feedback from
t h e results obtained (these are outlined in other
papers in this Symposium). For example, the original antitumor screen consisted of t h e three mouse
tumors {Sarcoma 180, Carcinoma 755, and L1210
leukemia) deemed most able to select most of t h e
compounds considered in 1956 to be clinically useful
in man. KB cell culture was added in t h e latter part
of 1960. Plant extracts were prepared using different methods and solvents recommended by the suppliers. After i t was determined t h a t all t h e active
crudeextracts obtained by t h e different methods
could also be uncovered by the use of 50% aqueous
ethanol, a standard procedure using this solvent
was adopted by all suppliers. In 1966, the Walker
256 r a t carcinoma was added to t h e screen to replace Sarcoma 180, Carcinoma 755, and certain
other tumors after an analysis of clinical results ( 5 )
showed that 33 of 45 drugs with definite clinical
activity could have been predicted by L1210 leukemia and nine of 45 by Walker 256 carcinoma. The
newly constituted screen had t h e disadvantage,
from the chemical standpoint, t h a t the ubiquitous
t a n n i n s and p h y t o s t e r o l s were very effective
against Walker 256 (as well as Sarcoma 180, Carcinoma 755, and the Lewls lung carcinoma) but not
against L1210 leukemia and KB cells; many plants
therefore showed activity against Walker 256 and
only a very few showed activity a g a i n s t L1210
leukemia and KB cells. Slnce the tannins and phytosterols could not be developed into useful anticancer drugs (6), a great deal of effort was required to
find Walker 256-active agents that were nontannin
in nature. The developn~entof a novel procedure for
t h e nondestructive elimination of t a n n i n s fro111
plant extracts ( 7 ) permitted fractionation of nontannin Walker 256 actives only; these and t h e KB
actives provided t h e only sources of antitumor
plants at this time. Walker 256 was later dropped
from the screen pending feedback from t h e clinic on
the usefulness of drugs active in Walker 256 only,
Table 1. - k t i v i t y of a?enLs me of t l . c r r plaxts of origin
Agent
-
Activitj.
l'lant of Origln
Act ivir:,
Acrr a e o n i n 1
WA
A c e r 7eguildo
54
brucemtln
31 ,L:,PS,U
*rucea ar,: l d y s e n t e r ~ c a
.S
Cancer Treatment Reports
,
and the more sensitive mouse P3XX le~tkemiawas
substituted for LlZlO leukemia. The present screen
consists of P3XX leukemia a n d KB cells and does not
react t o t h e unwanted tannins or. phgtosterols. In
fact. KB cell culture has emerged as t h e principal
predictor of activity fbx newly isolated compounds
against t h e in ~ i v otumors t h a t we consider ilnpurt a n t . T h i s is llrobably because most a n t i t u m o r
agents a17ealso cytotoxic, and since t h e KB t e s t is
more sensitive t h a n t h e in vivo tests (eg. P388 a n d
L1210 leukemias), it is able to detect cytotoxic cornpounds in a complex mixture such as a crude extract or fraction where in vivo activity would be
obscured. In practice, a KB-active plant is fractionated until t h e activity is concentrated into one or a
few fravtions. The concentrated fractions are t h e n
tested against P3X8 and L1210 leukemia, and activity in one or. both tumors is frequently found. A
majority of t h e plant-derived compounds of interest,
including those passing- t h e criteria (activity in P388
and L1210 leukemias, B16 melanoma, anti t h e new
Lewis lung tumor) for f u r t h e r phar~nacologic and
clinical study were isolated from plants originally
found to be active against KB cells (table 1). The
latest developn~entin t h e preparation of crude plant
extracts for testing. which h a s been described elsewhere in t h i s Synposium, is t h e preliminary fractionation to eliminate inactive materials and concentrate t h e active agents present prior to testing.
This procedure results in greatlg- increased yields of'
plants active in P388 leukemia and KB cells, a n d
produces many high priority plants for fractionation. This development, however. has not yet been
in operatior, long enough t o establish its value in
l
producing ~ i s e f ucompounds.
RESULTS
The results a r e summarized in t h e tables which
list t h e active compounds along wit11 t h e ~ n l p o r t a n t
tumors against which they have been tested. In
many cases, results a r e available in our files for
other less important tumors t h a n the ones listed.
T h e gaps m the data usually stem from a shortage
of compound.
T h e t u m o r systems considered, with their activity
criteria, are listed in table 2. Activity as shown in
the "active" c o l u n ~ n sof the tables does not always
reflect reproducible activity. Many materials were
tested as suspensions which frequently led to erratic- results u-ith compounds of marginal activity.
Also, t h e effort a n d expense required t o obtain
additional m a t e ~ i a lprecluded t h e extensive testlng
of compounds with initial borderlrne activity. These
compounds for which activity h a s not been "con-
Vot. 60,No. 8, August 1976
firmed" have nevertheIess been included since o u r
purpose is t o show t h e broad activity relationships
of groups of compounds, not t o provide the kind of
d a t a on individual compounds required for determining whether further pharmacologie testing will
be performed.
T s ~ l e2 . - Tumor s'ysfems
.Aooreviatxr
Nme; host
31
El6 r#lanocarcL~oma; cause
ILS
L/ ?&OX
GA
.Xenocarcinome 755; m ~ r e
37
it 2
HE
IjeLa h ~ m a r .carcinorca: c c l l c u l t u r c
EDSo
Z3
h u m cpiCcrmoid carcinoma o f t h e
~ 3 ~ ~ 2/
~ 1 . 0
A c t i v e response
58).
I/ 51 .D
nasopharyva: c e l l c u l t u r e
E:
> w h o i d 1eukco:a
IL
L
:,I (new)
1-1210; nouse
~LS'-ZSS
I 3 1 25s::
~ lung
U
cercinom: m u s e
.,
,#
iLS 5401
PS
L)npllocytic le<xbemia P36Y; acuae
ILI ' 2 %
54
Sarco3a 180: lrausc
rd t56:
YA
Aalker c ~ r c ~ n c s a r c o m2a5 8 ; rar
rh? * 5 6 %
1.
TWI (tuxor veigh:
~ f i h i b i t l o c l ; ILS (lccrrase
Ln life . ~ p - ) ;
21
3Djp
dcse i e v r l l n p g t m l at whltl: 5 3 l i n h i b i t i o n of growth of cells
y
2.
g is noted
A few coopounds
vs
ancreated controls.
in the I o l l w l n g t a b l e s
nave beco c o l s l d e r e d active
where the ED50 was <&,0.
3.
Lr- che L o l l o x l n ~ t e b l e s ,
ectivicr
p a r e n t n e s i r w h i c h % t t v I!C
% PS 1 s expressed
by e f i w r e in
o r r a c i o o f a.erags s v r v l v c l o f treatef
anrmals i n days t o tllat OF c o n t r o l l r 10C.
TIC
-
ILS
+
100.
No distinction is made between marginal and high
antitumor activity except against P388 leukemia. I n
this case, t h e figure in parentheses after "PS" is t h e
highest Tic obtained in any t e s t a n d does provide a
measure of t h e degree (marginal, high, or intermediate) of activity; this figure is prorided because in
practice so much depends on t h e interest generated
by the first in vir.0 tests. While a T i c of 125% is an
indication of activity, a figure of 175% is normally
required for a priority high enough t o w a r r a n t
advanced screening a n d preclinical evaluation.
I n the tables presented in this paper the source
(table 3) of t h e compounds is acknowledged after t h e
co~npoundname. The classification adopted for t h e
c o m p o u n d s listed t h e r e i n i s g i v e n in t a b l e 4.
Broadly, all of t h e classes are non-nitrogenous except for the ansa ~nacrolides,t h e proteins, a n d t h e
alkaloids; t h e miscellaneous group is mixed.
Table 3.
- AcknowledgPents
1.
m.
2.
Dr. Jack X. Cole
3.
Comonwedth S c t e ~ r i f i cand
4.
Dr.
5.
Dr. R. !;. Dosketch
J. L. seal
M. L. Dhar
6.
Dr. Pi. R. P s r n w o r t h
7.
ilr. .%rtJn Jacobson
8.
Dr. G. J. Kapadia
9.
Dr.
L. B. Riel
Dr. 0 . G . I. Uflgston
L1. Dr.
12.
S . ?lorric,
No formal attempts were made to prepare pure
compounds from this heterogeneous group of widely
occurring polymeric materials after i t was shown
Melbourne, h l s r r a l l e
that the tannin fractions were generally inactive
Ccnrrol. Drug x e s e a r o h s r l r u c e .
against t h e predictive tutilors (L1210 and P388 leuIndia
kernias and KB cells), were active against uninterOhio S t a r e University
esting tumors (Carcinoma 755, Lewis lung, Sarcoma
Universirg o f I l l l n o l s
180, and Walker 256), a n d were quite toxic. MoreC . S . DepeFtMCt of Q P ~ C U ~ F U T over,
~
t h e y were g e n e r a l l y chemically u n s t a b l e ,
being susceptible to air oxidation and further 110Howard Univcrsiry
lymerization.
w s a c h u s e c t s College cf ?l~amac?
In 1969 (61,82 different active plant species were
v i r g i n l a Po1)rechnic I n s t i t ~ c e
listed
as owing their activity solely to tannins. Since
Unix-rsity of V i r p c l e
t
h
a
t
time,
another 82 species have been similarly
4rizona s t a r e 3 n l u e r s l t g
identified. Fortunately, t h e makeup of t h e current
M a w ~ d ,:! .J.
screen precludes t h e appearance of more plants
U.S. 3cpartmenc of A e r i c u l t u r e
whose activity is due t o tannins.
U n i v e r s i t y of Arizona
Industrial Resoarch Organization
10.
Kupchm
D r . G. R. P e t t i t
13.
Charlss P f i a e r and Co.. Lnc.
14.
M r . R. G. Powell
15.
Dr. B.
16.
Dr. 14. S i l v a
Lhiverricy o i Conception, Cnilc
17.
Dr. W r o e E. ' ; d l
Reseerch T r i a n t l e 1.1s tituce
1B.
Dr. K . Gellerr
~ ~ : l o n g o n gVniverhirg i o l l ~ ~ a
19.
Dr. J . M. Cassady
3urdue u n i v e r s i t y
20.
~ r .Xing-iu
21.
~ rA.. C. Case?
s ~ a u f f e rCr,elrical C~m?an,,
22.
~ r .D.
:Lgslssippi i t a t c Univerrlty
23.
Dr. P. C. Chms
U n i w r s L t y of Tsnnessee
24.
k.6. J . Persinus
ncrpstrm. T o r i c o l o g j Laboratory
1;ationaI I n s t ~ ~ u of
t e Allergy
PICSCDF~
and I n f e c c i o u r Diseases
Kine
Watlonal k f e n s e f l e d ~ c e lCenter,
Taiwan
)i.
Tannins
Ohio scare b i u c r s i c y
mles
Teble 4 . - C l a s ~ L F i c a t i ~ n
Tannins
S c s r o l s ( i n c l . zimgle glycorjudas; e x c l . saponinsl
Quinones [ i n c l . qulnoids and q u l n o l s )
Terpenes
rridoids
Sterols (Including Simple G lycosides but
Excluding Saponins)
The phytosterols a n d their glycosides are widely
distributed in plants. The ones t h a t have shown
antitumor activity a r e g i r e n in table 5. Only daucosterol showed marginal activity in P388 leukemia.
Other phytosterols such as cholesterol (NSC-87981,
ergosterol (NSC-627911,a n d stigmasterol (NSC-8095)
have been tested in a variety of tumors (6), including- Carcinoma 755, LIZ10 leukemia, Sarcoma 180,
and Walker 256, without showing activity; in addition, stigmasterol was inactive in P388 leukemia and
ergosterol w a s inactive in KB cells.
In 1969 (B), 20 different active plants were listed
as owing t h e i r activity t o sterols (mostly {i-sitosterol), and since then, a n o t h e r 42 species have
appeared. Again, t h e antitumor screen eliminates
most of t h e plants whose activity is due to sterols.
sesquitlrpenf s
Diterpenes
Quinones (Including Quinoids and Quinols)
Triprepenes ( i n c l , c u c u r b l t a c i n s ; e x c l . s a p w i n s )
Liplans
Plavonoids
Table 6 lists t h e quinones t h a t have shown antitumor activity. Although some activity h a s been ob-
saponins and t h e i r aglgcooes
Sternidal
Table i. - s t s r o l s
Tritepenold
s c e r o i d l a c t o n e s ( I n c l , cardenolidee, b u f a d i e n c l i d e r , xi:hmolides
and t h e i r agl?oones)
W a s s t n o i d s (simarmrboLides)
Ansa mcrolideb
18:13
Proteins
.go83
flkalDid5
ftiscellsneous
i
Sk, :2
Cancer Treatment Reports
A c t iw
Inactive
\<A
LH,PS,SA,i(B
PS(136) ,SA
Emodin ( a l e e - d i n ) * 1 6 /
Jacaranone
38628
i/
Lapachol 1
3
JacAra~lone
NSC 251682
FIGCRE
1
TERPENES
#yH3
0
Elephantopin
NSC-100046
0
CH3
R
\
0-
H
0
Triptolide
NSC-163062
= l4
tained against P388 leukemia (the best is jacaranone): no activity has heen found against L1210
leukemia, B16 melanoma, or Lewis Iung carcinoma,
and this class of compounds cannot presently be
considered very promising. Lapachol (fig 11, originally obtained from Stereospermum suaueolens
(Roxb.) DC., h a s been carried into clinical trial
=Farnsworth NR. Personal communication.
Vol. 60,No. 8,August 1976
mostly on t h e basis of i t s high Walker 256 activity
even when given orally (8). Lack of toxicity permitted Iarge oral doses b u t sufficiently high blood levels
could n o t be obtained to show a therapeutic effect.
I t is perhaps of passing interest t h a t Tabebuia
and Tecoma species, containing lapachol, have long
been popularly used in Brazil for cancer a n d t h a t a
Jacaranda species, called cancer bush, i s popularly
used in the Bahamas for skin cancer (1).
1035
Terpenes
certain chemically reactive functional groups besides t h e lactone group ((I, &unsaturated carbonyl,
This large a n d complex group of natural products
epoxy) a r e important for in vivo antitumor activity
h a s moved t o be of substantial interest to us. The
and t h a t polyfunctionality seems t o increase t h e
natural, breakdown into chemical subgroups reveals
chances for activity. However, physico-chemical and
t h a t only t h e iridoids, sesquiterpenes, diterpenes,
steric factors are undoubtedly important also, and
and triterpenes have antitumor activity. No activity
t h e whole question of structure-activity relationhas been found among t h e rnonoterpenes, sesterterships is in need of clarification.
penes. and carotenoids. Figure 2 g-ir-es representac. Dite?-penes.-This subgroup (table 9) h a s yielded
tive examples of the cllemical structures of these
two compounds of high activity in P388 leukemia.
active classes, namely, an iridoid (allamandin), a
Tu-o others, tl-iptol~dea n d tripdiolide, a r e also active
sesquiterpene (elepliantopin), two diterpenes (triptoin L1210, a n d tripdiolide is active against t h e Lewis
lide and tripdiohde), a n d a triterpene (cucurbitacin
l u n g carcinoma. A d d i t ~ o n a ls t u d i e s will be per13). Allamandln was obtalned froin Allrr tna tlda caformed on t h e l a t t e r two compounds as more plant
fharfica L. (9), elephantopin frorn Elephuri.topus elamaterial becomes available.
t u s gertol. (lo),triptolide and tnpdiolide from Tripd. Triterpenes ( e ~ c l t ~ d i nsaponins).-This
g
group
t e q g i l r j n u:ilforrlii Hook. fil. (11),a n d cucurbitacin B
so far h a s not been promising. The cucurbitacins as
from several sources not all C u c u r b i t a c e a ~ u e u ~ - a class (table 10) show general cytotoxicity and
bita rligitata Gray,' Llcffa g m v e o l e ~ l sRoxb.,' Begotzia
negative o r marginal i n vivo a n t i t u m o r activity
X fuberhybricia Voss (12), a n d Datisca glomerata
against P388 leukemia, L1210 leukemia, B16 mela(Presl) Baill.'
noma, a n d Lewis lung t u m o r (new). O u r present
(1. Iridoids.-Table
7 lists t h e active iridoids (all of
screen will continue to identify plants containing
wlllcl~ a r e lactones) which have been isolated to
Table 8. - Sesquiterpenes a1
date. Lack of material has prevented testing in a
KSC
bctiue
Inactive
wider variety of tumors but it is encouraging t h a t at
.*rosin
/
65235
PS(1W) .KB
SA,LE
least some P3SX leukemia activity h a s been shown
ArcriopicrLne 21
177853
PS(1AOJ ,KB
by two of tlie four substances.
Artemhlifolin
Bailcyin
?ISC
Active
Inactive
u!
Costunolide
w i n
L/
12/
I/
g/
Elephantin
Elephant-in
10-Epieupatoroxtn
:pitulipLnolide
b. S e s q ~iterpelzes.-Table
r
8 shows t h e active sesquiterpenes t,hat have been isolated in t h e fractionation program. All but one are lactones. Many more
have been received a n d tested in the "synthetic"
program b u t t h e results obtained do not generally
alter t h e comments made liere. A majority (38 of 47)
of the coinpounds have cytotoxic a c t i ~ i t y(KB or
P388 leukemia in vitro), a few (eight of 47) have
activity against Walker 256, and a large number (23
of 4,3sllowed activity a r a i n s t in viva P388 leukemia.
A sufficient number of P388 leukemia actives have
relatively high T!Cs for some interest t o be maintained in this subgroup. Although none Eias shown
activity a3 yet in LIZ10 leukemia or in either of the
two slow-growing tumors, B16 melanoma a n d Lewis
lung (nem-), hope renlains t h a t additional testing will
reveal sue11 activity. There is some evidence t h a t
Erioflorin
GI
177852
~ ~ ( 1 3 ,KB
01
L79192
PS i n v i t r o
106404
KB
85249
W
tE
102817
WA,Fg
LE
100046
WA,PS(160)
LE,U,SP.
LE .w
135068
j/
II/
E r i o f l o r i n acetate
161
142844
KE
lkbl51
PS(127),ka
251667
PS(l5lJ , X I
LE
251866
KB
PS
Briolangin El
182855
PSI128)
k3
3
144152
PS(152) ,IQ
erioflorin methacnlate
Esiolanin
Eupachlortn
II/
Eupachlorin a c e t a t e
lL/
116567
W
111568
WA,?S(1533,
6A
K3
116570
S
135520
YA,PS<135),
I
s
Eupacunoxin
II/
135021
?3
104942
KE
104943
WA, W
135023
i
3
135023
PS ( 1 5 0 ) , I
S
"Cole JR. Personal communication.
114569
KE
'Dhar ML.Persona! communication.
'Kupehan SM.Personal communication.
'11566
P5 (153). I
Z LL. =E, Srl.
Euparotfn
Euparotin a c e t a t e
2
PS
WA
Cancer Treatment Reports
able B.
- seeguiterpenes
95C
Pastigilin 8
GI
176503
(continued)
IIFtiYe
PS (137)
Table 9.
Wm),
Fa8tigilin C
121
176507
Caillardin
106394
85236
PS ( 1 3 7 )
KE
PlS C
iictive
mldicin
gJ
238941
Ps ( 1 7 3 )
mididin
&/
238942
PS (1271
~ i d i t r h
238913
PS (168)
239073
Ps (131)
135037
PS (14S), k3 B1, LB, LL,
111
239072
PS (200)
B1, LLCnem)
Pcdolide &&I
238378
l
3
PS
T a x o d b e ( a l s o mder p l L n o n e s ) g /
122419
UA,
taactive
~ 1 LE,
,
KB
II/
12-liydrwdaphnetoxin
LE
P5 (220), KE Bl, LE, LL,
- PltergeMs
Jatrophono g I
Inactive
iL(new)
LLlneul, S 4 .
YrterCin
Ilelenalh acetate
Isogaillardin
Liacrin
El
166UC
c/
106395
11/
L i p i f a r o l i d e 21
PS (165)
D
1350%
PS (163)
251676
[3
"
"
11/ I22420
-
Imodone
"
Tripdiolide
V/
163063
111
L630b2
L E , PS
kg
KE
LE, PS (1581, B1, tL(new)
KB
Triptolide
LE, L L ( n w ) ,
BL
PS (1311, YB
Paucfn 5 2 1
136722
Tulipinolide
PS (138)
Triptwide
a l . LE
LE,
106405
KB
124659
MA, KE
106398
WA, PS (155).
12L46I)
V3
Wh, LE,
KB
165677
WA
r&lt
PS (141)
- Cueurbitacins
10.
Active
Inacciw
hsrsl
PS (135) , KB
a l , CA, LB,
521776
PS (131), W
LE, W4
LL, KE
E l , LE, PS,
ElSC
Zduzmin C
3
from Acanthospemum
lr607a
PS (1361
135072
kg
177851
PS i n v l t r o
--
PS I l 4 7 ) , W
--
PS t150), Ka
b/
@ntaurea
21
-
"
a/ All
-
l a c t o n e s except the
K
CucurbLtacin B 2,1,5,Ll1
LL, S 4 , WA
PS
A
piyccsue.
been isolated a r e generally not cytotoxic but show
activity in Walker 256. Negative or marginal in vivo
a n t i t u m o r activity a g a i n s t t h e P388 a n d L1210
leukmias, and against the slow-growing tumors, has
made t h i s group of little interest for our program.
D
'"
E
"
one n o t c d .
these cotnpounds because of t h e i r K B cell activity.
The remaining triterpenes (table 11) which have
"
m
1
u
3
l
106399
521775
b / A o t a lactone.
C/
F
--
':A,
"
IG /
521777
I
3
L
112167
PS h v i t r o ,
"
Pll/
US074
KB
"
Q
GI
135075
KB
11/
--
W
I
3
a CueurbPlac3n g l y c o s i d e
.. ..
..
"
111
--
'
-
--
,,
"
>>
??
111
q
Datiscacfn (Cucurbitacin R)
111
-
LE, PS
XB
"
LE, PS, WA
K3
PS, Wd
YB
-
146154
Y
B
I
3
D a t i s ~ o s i d e(Cucurbitacin D
d e b y d r o e p i r h m o s i d e ) 111 164L53
Val. 60,No. 8 , August 1976
S A , WA
&/
Lignans
These are a g r o u p or r a t h e r uncommon plant
c o n s t i t u e ~ ~ which
ts
a r e found In some plants with
activity against KB cells. The chemical skeletons of
t h e g-roup are shown in figure 3. The bisbenzocyclodctadiene skeleton on t h e right is a type recently
added to t h e classic lignan family. Although podophyllot&xin (fig 3) never passed o u r criteria for
pharmacologic and clinical study, several semisynthetic relatives have been in clinical trial here and
elsewl~erein the world (13). Two df thetn, VM-26 a n d
VP-16-213, h a r e produced responses in brain tumors, lyrnphosarcomas, and (in Europe) Bodgkin's
LE
kg
--
I r m Jacropha
U, PS (1501,
UP.,
Dih?drocucurbltacin
B
a/
Isocwurbitacin B
LOB401
W
106400
13
KB
B l , LE,
~L(nex)
WA
(2-Epicucurbitacin B)
disease. These compounds differ from podophyllotoxin in that they are demethylated at the 4' position, are epimerized at the 1 position, have a glucoside on the 1-hydroxyl group, and are acetals by
reaction with aldehydes. The original 4'-demethylpodophyllotoxin came f r o m Podopkyllum hexandrum Royle [P. ewwdi Wall. ex Royle]. Table 12 lists
t h e active lignans isolated d u r i n g fractionation.
While several of the compounds have shown high
activity in P388 leukemia, they have not met the
other criteria required to justify further study.
Table 11.
- Tricerpenes
d-wrin
ISG
Active
Inactive
114787
h'4
Bl. LL(newl
4644
KA
Flavonoids
This very common class of plant constituents is
generally inactive in our antitumor screen. Many
have been submitted as "synthetics." Table 13 lists
those showing activity during fractionation. Only
one showed marginal activity in P388 leukemia.
PS, YB
Berulin
i/
B1,
CA,
LE,
T a b l e 13.
LL, SA. CIA
betulinit acld
2,221
113090
L u p ~ o l=/
90487
PS ( 1 4 0 ) . CIA
K3
LH, PS ,
VA
Centaureidin &I
SA,
Taxifolin
liQ
Ursolic acid
-/
4060
ASC
Active
mac t i v e
106969
XB
FS
PS ( 1 4 2 )
LE.
KE
PS
IISC
Attiire
Inactive
123126
WA
36398
SA
3',5,7-Trihydr--3.b'-
El, L E ,
PS (125)
161
- Flavmoids
dicxthoxyflavone 111
LL (new),
106970
WA, KE
Uvaol
g
159627
--
frw Bureera 2 1
"
Jatyopha
9/
"
Haytenus
/
"
hbibi. 21
--
---
--
L/
FS 0 5 8 )
T e b k 14.
PS (166), b 3
Steroidal
WA
NSC
ACtiuB
123428
WA, w
--
khydmanhydr~lcmpodophyllin
3'-aemethylpodophylloroxin
UA
- Lignans
Table 12.
Burseran
PS (125)
6/
Deorjpodophyllotsxin 2,6,11,17,23/
PS
Inactive
dtro
251681
PS I130J, KII
403148
LE,
PS ( 1 5 4 ) ,
B1, LL,
- Saganiw
--
VIA
137660
V.4
--
:iA
--
h'b
--
h'4
---
HC
Wi,
LLlnew) ,
KB
SA, CI'A
a l , t ~ LL
,
5'-Desrwthwq
P-
peltatlv A
methyl ether
i/ 126727
LL(new),
PS ( t 8 P ) ,
MA,
81, LE
PS, XE
KB
"
"
(+)-Dlaethylisolariciresinol-
+q.loaide
gl
--
KB
PS
Celsioside C
, CIA
from
256665
2 4 6 3
XZ
P l { I b O ) , KB
-/
?/
IE, E
a
~ c e g/
r
LI, PS. B1
"
Entada l 3 /
"
Ipomopsis
"
!lachaeranrhera
from Agave
2/
"
El, <A,
LE,
LL, LL(TLe"J
SA
.
..
f r o m Aga*
--
-
--
Allium lL1
--
"
*ter
-"
6l
171
-
from Chrysopsia
It
SA
----
171
11/
LE, PS
"
cyc1&.=n ;
l/
PS
"
Saponaria
PS
W4
II/
"
'
tE
g/
Undetermined
tL(new). Sh
PodophyIlotoxin
h' A
Bl, CA, LL,
81, LE.
p-Pelcatin A methyl ether
qlJ
l3/
NJ.
SA
144
PS
--
IIA, PS (135)
--
SA
135029
h'A
77672
VA,
M
SA
CA, LL.
IE, ?S
Cancer Treatment Reports
tumor activity is attributable t o saponins will probably not be detected wit11 our current screen. Y everThis widely disseminated class of plant constitu- theIess, since they are so widespread. in t h e plant
ents generally possesses activity against Walker 256
kingdom, and since many were active in Walker 256,
and Sarcoma 180, but lacks activity in K 3 cells. it was decided t o continue studies on the best one,
Twenty-three new active saponins have been added Acer saponin P, in order to obtain feedback. Figure
to t h e t e n t h a t were listed in 1969 (6); altl~ougli 4 gives the carbon skeletons of the two main types
isolated in some state of purity, in many cases the
of saponins, steroidal and triterpenoid, and t h e parn a t u r e of the aglycone is undetermined (table 14). tial formula for Acer saponin P. This substance was
They- have shown marginal activity against P38g obtained from Acer negu~idoL. (14) a n d is now being
leukemia, and no activity against LIZ10 leukemia o r
prepared in quantities sufficient for pharmacologic
t h e slow-growing tumors. Thus, plants whose antiand clinical trials.
Saponins
Vol. 60,No. 8 , August 1976
--
Steroidal
Triterpenoid
R = Mixture of -CO(CH=CH)2CH(CH
3)CH2CH3 and
-CO(CH=CH:CH~CH)CH(CH3)CHZCH3
c
Acer saponin P
NSC.100045
Cancer Treatment Reports
Steroid Lactones (Including Cardenolides,
Withanolides, Bufodienolides, and Their
Aglycones)
Quassinoids (Sirnaroubolides)
The carbon skeletons of tllese t \ ~ r e etypes ot lactones are given in figure 5. T h e cartienolirles, especially, are widely distnbuterl in nature. Table 15
lists tile active steroid lactones isolateci during fractionation: t i l e type of lactone is indicated in the first
column. I t i s apparent tllat t h e y are generally cytotoxic with v e r y little activity in any in r 1x.o tumors.
Plants contain in^ these oornpountis will s l ~ o uI ~I In
~
our screen b u t 1~111 be ruleri out, for t \ ~ emost part,
wllen KB-active concentrates are subjected to P3X8
and L1210 leukemia testing.
This group of bitter plant principles lias proved to
be of great interest. Figure 6 presents tlie f o r m ~ ~ l a s
of t h e two most prornislng representat~ves.Bruceantin was isolated from Rrlrceu ntztidyseutsrica
J.F. $rill. (15), a plant used in Ethiopia and Eritrea
for cancer (I), anti Iiolacant~lonefrotn Holacanthu
ernorul Gray (16). Table 16 outlines data on the
actire compounds which have been isolated. In generaI, they are cytotoxic; a large proportion of t h e m
are highly active in P388 leukemia and several are
also active in L1210 leukemia o r Blfi melano~na.It
is evident t h a t plants contain in^ active quassinoids
will be readily detected hy o u r screen. Bruceantin is
Table 1 5 . - steroid l s c t m e s and cheir aglycones
T > ~ e21
Nark
5
C,G
~ c o b i o s l d ea
C,G
Acospectoslde
NSC
Active
116768
E[B
Table 1 5 . - Steroid lactones dnd their e g l y c o s e s (continuec)
luactiue
Type
a/
N
I
a 8/
113569
1-acetate
]iB
dccvenoside A
6,10/
116757
33
~
111
BSC
A:rive
z35080
KB
135079
KR
lnac~iue
LZ
3,4
C,G
E
16
-Eydror?bersa?deger.:n
81, LE, PS
5 - a c e ~ a t c 111
.A
Bl, LLrnev)
PS
g YE
LE, P S ,
B,b
SA,
Bersaldepenin
3-acctete
2 1
aer$~lCe&enin
1.3,s-orthoacetate
111
Bersamagenin
1,3,j-orrhoacc tate GI
B e r s c i l l o g c n i n 111
Bcrsenoeecln 111
Ca?ctropin
g1
F,B
CA, LC. LL
!:.A
PS, SP. 'n'h
'a
LE, PS
:iIi
C h , LE, PS,
C,G
Sb, XA
Vol. 60,No. 8 , August 1976
from 4rrcle?los
I
--
PS ( l j O ) , !i6
1
s
1CB
C ( ? ) ,G
"
C ~ o s s o s m2 t
.
-
--
--
"
Elacodendro~;
l/
--
-2
LE
STEROID LACTONES
Bufadienolides
Cardenolides
Withanolides
QUASSINOIDS
Bruceantin
NSC-I65563
now being prepared in quantities sufficient for toxicologic and pharmacolog4c studies.
Ansa Macrolides
Holacanthone
MSC-126765
t e x e n s i s (Torr. & Gray) Gray (18). The group is
generally cytotoxic and is unusually actil-e in P388
leukemia at remarkably low doses. Maytansine, t h e
most readily available member of t h e group, is also
active in L1210 leukemia and B16 melanoma and is
now in clinical trial. I t is interesting to note t h a t
one of the Maytenus species, many of which are
known to contain maytansine, has been in popular
use f o r 30 years i n South Africa in an herbal
mixture for carcinoma and sarcoma.
This is a relatively new class of compounds characterized chemically by t h e presence of a large
macrocyclic lactone ring, frequently W-heterocyclic,
and incorporating within it a n m- o r p-bridged aromatic moiety. The class was originally found among
microbial products 'and the current findings represent their first appearance in higher plants. Figure
Proteins
7 gives the formula for two representative members
Over t h e years, proteinaceous materials have
and table 17 lists the ones isolated so far in fractionation. Maytansine was isolated from several ;Way- been isolated a s t h e active agents in several plants
tenus species (17) and eolubrinol from Colubrina (table 18). Some were thought to be simple proteins
1042
Cancer Treatment Reports
ANSA MACROLIDES
CL
CH3
I
Maytansine
=
R,
=
NSC-153858
Colubrinol
NSC-196519
H
\
= CH3;
R o= OH
0
I
Toblc 16. - Quersinoidr
2'-ketyl~iaccarubinone
Bllantainonc
nruceactin
11/
z/
G/
?eble li.
!lLC
~ctivs
Icactive
194251
PS (lSi), M
Colubrlnol 171
238157
PS (1481, :;o
Colubrinol e c c t a t e
165563
31. LE,
LL(ncw)
?~+fiac
+L!
+i/
- ,use zacroli~es
ivr
SSC
AC t
195514
F S (1131, i3
1F652C
P5 (206). 1 2
21797?
1
s
laactlvc
TnXe 1 s . - Proteins
)
'
I
and others were thought to be glycoproteins but,
with one exception, they were never purified. T h e
one with t h e highest activity in Walker 256, obtained from Caesalpinia gilliesii (Hook.) D. Dietr. in
good yield (19), was selected, for further development. Purification yielded a product (named cesalin}, highly active'in Walker 256 but inactive in the
leukemias and slow-growing tumors, El6 melanoma
and Lewis lung carcinoma (new). As a representative of a large class of natural products, it will be
interesting to follow i t s progress in preclinical pharmacologic and possible clinical trials.
Vol. 60,No. 8,August 1976
--
56
"-
LL. W R
.-
SA
--
SB
110135
LL, SA,
81, PS,
VA> 3
JK, I L < o c x l
--
L L , S A , YA
--
W
Si
Alkaloids
More members of t h i s class of compounds have
come out of t h e plant fractionation program t h a n of
any other class. They a r e widely distributed in t h e
plant kingdom and many a r e active against KB cells
or Walker 256 carcinoma. After isolation, activity in
other in vivo t u m o r systems h a s frequently been
found. T h e g r e a t diversity o f chemical types in this
group of compounds is illustrated in table 19 which
lists t h e classes into which t h e 80 isolated alkaloids
(table 20) fall. No attempt u-ill be made t o d r a w a n y
structure-activity relationships since t h e number of
compounds is too small and t h e d a t a a r e too scanty.
Rather. a few of t h e alkaloids t h a t have proved to be
most i n t e r e s t i n g will be discussed. Figures 8-12
represent ?nost of t h e interesting alkaloids in o u r
pyograln and typify t h e variety of t h e cllemical
structures encountered, some of which are novel.
l a ~ l c19 - U ~ a l o i d r
Class
-
.'1
1.
Cipoatics
2.
C c l c o i c l c + croup
i5.
.w.arylTidacesc a l k s l o ~ h s
irmtliine group
3.
P}rrolieitices
:6.
~ h u v o ~ f iazl k a l o i d s
4.
Tecrahydrolsoquic~lioc.
n.
Iroquinuclldines
j,
3 :, h., d c n n ~ l i ~ ~ q u i n o l i n c 5
IB.
D i r e r i c indoles
6.
.\?orptincs
9.
C l l i p t i c i c e grou)
7.
Dibenzopyrrocolincs
20,
Texanes
E,
r ~ r p h l n a n el r o u ~
21.
C a ~ p t o t n c c he r D G p
9.
Yro:oberberiues
22,
F~roquLncllncs
:D.
2eilzo?tacns~tt~ridlcc.
23.
S t e r o l alkaloids
11.
tce:ice
2A.
Ccphslotsxus a l k s l o ~ d l
12.
. L L a l k a l o l d r
25.
hnoptcrus n l l e l o i c s
13.
P h e n e n t h r o q u i c o l i m i d i m and
16.
A l b l o i d s of 'msn'cccun
srou?
phccmthroindollzidine5
str~~tkre
a. Thalicarpine (,fig #).-This
is t h e first dimeric
alkaloid recognized to contain both t h e aporphine
and benzyIisoquinoline moieties (20). I t entered clinical trial primarily on t h e basis of its Walker 256
antitumor activity. .Major organ toxicity is consistently manageable. While it is still under study in t h e
clinic, however, its prospects do not look promising.
b. I n d i c i n e W-oxide (f'ig 81.-Many pyrrolizidine
alkaloids have been tested besides t h e four reported
liere (6), b u t indicine .XT-oxide,from Heliotropiu m
ij~dic-u
m E., is t h e only one possessing significant
activity in P388 leukemia. Since it is also active
against t h e E l 6 melanoma, L1210 leukemia, and
Walker 256, it was entered into clinical trials. Although pharmacoiogic testing is as yet incomplete,
negative histopathologic findings indicate t h a t t h e
hepatotoxicity commonly associated with this class
1044
of alkaloids may not be a clinical problem with this
compound.
Heliotropiutn indict4 I)I iias been used since ancient tirnes against w a r t s a n d its close relative, H.
elcrvlpaeuln L., has been recommended for cancer
t r e a t m e n t (I).
c. Catnptothecin ( f ' i y g).--TIlis novel s t r u c t u r e ,
isolated in minute quantity from t h e wood of Camptotheca aclcrninata Decne. (21), is highly actire in
P38X and LIZ10 leukemias b u t causes gastrointestinal t r a c t toxicity i n t h e mouse. Results from ~ t s
first clinical trlal in patients with gastrointestinal
cancer looked very promising (22), but subsequent
work did not uphold t h e earlier f i n d ~ n p .
Camptothecin is present in the plants along with
smaller quantities of t h e 10-hydroxy and 10-methoxy
derivatives (23). Since these also have hlgh activity
in P388 andlor L1210 leukemias it is possible t h a t one
t
better clinical results. Accordof them m i ~ h yield
ingly, a comparative adranced bioassay is belng carried o u t on carnptothecin, the two derivatives, and
9-methoxyc.amptothecin in order to provlde a basls
on which t o select one for further development.
I t 1s interesting t h a t a plant not closely
.Ilagpiu foetida, (Wight) Miers, h a s yielded both
calnptothecin a n d 9-methoxpcamptothecin (24); preliminary tests with t h e l a t t e r compound reveal activity similar t o t h e 10-methoxy derivative.
d. Taxol (fig D).-This novel compound was isolated from Taxus brev{foLia Nutt. and other T, species (25). Because of its high activity in t h e tumors
of interest, suitably large quantities a r e being prepared for further study.
e . Elltpticiw (fig lo).-Ellipticine
and ~ t 9-rneths
oxy derirative were isolated from Exeavatia coecirlea (Teysm. & Binnend.) Markgraf a n d Ochrosta
tnoorei (F. Muell.) F. Muell. (26). Their high activity
in t h e leukemias indicated t h e f u r t h e r development
of one of them. Ellipticine w a s selected because of
better activity by t h e oral route and better avallabilitp by large-scale synthesis. Phar~nacologicstudies of t h ~ scompound a r e in progress, and chnical
studies of t h e 9-methoxy derivative have been carried o u t in France (27).
,f: Tylocrebrine (,fi'g 1O).-Th1s alkaloid, obtained
from Tylophol-a crebriflora S.T. Blake (28),has been
through limited cIinical trial. Irreversible and unmanageable centraI nervous system effects, not a n ticipated from preclinical work, precluded f u r t h e r
clinical studies.
g. . l T i t i d i n e and fi-tga~*o)lit>e
(fig lo).--Tliese closely
related alkaloids, isolated from Fagara tnucrophylla
(Oliv.) Engl. (29) and F. nanthocyloirles Lam. (30),
respectively, showed activity in t h e Lewis Iung
Cancer Treatment Reports
berbtrine sulfate 1,4,11.17,20/
Cmptotnecln
4/L7/
ASC
yclve
Io.lct2~e
179172
'3
IIA, LC
9
5344
21
;i/
Colchiclnc
C o ~ q o u n df r o n
2
, g ~ n 131
a
b/
25
Ciass
,z2i/
MOpierillc
f6
94h0O
7 7
92071
LC, IT;,
31, PS (131).
SA,
Z5
CA, LL, LL(nm>
LE, PS (2501.
5
I
,
A .
D l , Cb: LL
LE, :?a
i L ( r c w ) , SA
CA, iOA,
CA,
LE
PS (126)
#<
w
"
"
"
171
26
-
l7/
.Dichroa
-
26
.Tlophors
13
Compou~dS from
--
C A , P3
SA, GA.
:3/
--crcbriflora -'8
0
88
8,
13/13
"
13/13
-
8,
13/13
-
Coryound O from
T~lllophora
1:1
-
65701
L C , PS <177!
Cb, L C , 5.1
13
LE
131
-iildica
8,
Conzssinc
L
"
"
i:ySroc;7loride
61
13
1S0057
ili
23
32989
>'A=
119754
Li
:s
CA, LE, SA
r3
r;,
CP.,
LL(ce'a).
LLkLlevI
vol. 60, No. 8, August 1976
LL
SA
Table 2 0 . - h l b l o i d s (contmucd)
la1636
L E , PS (209)
:
a
LE, :%
PS. S A
iH, '5, Xb,
21, LLCncnj
S A - Ch
LE,
LL, ' : A
( l a - ) , r-;
5 1 , =(am)
69X7
5: C2GOI, Sh,
!'A
98928
:A
;.:,
l86F3
?S (133). !ih
T.L, L C , .S
ni,
l463Vi
$
!:,
sn, cn
P5 (26C,J. LC.
: , I j LLCnfw)
LH, SP. !:A
PS
Cancer Treatment Reports
Table 20. - A l k a l o i d s (continued)
CA-
Ll, WA,
Sb, PS
LE, ,:B
PS, 13
I,'-, PS, %A
'
LC, PS. A
:
75, LE, El
CA, L B , P S .
5ab-c
:A,
a
,!B
LL, I L ( r e %
172260
base
Lolasodi.?r ri~aa:osidc
;:c:>bav~siv.e
Tzxul
.
I;/
JL!
23
--
iIn
6
135326
LL
20
l?j373
:;A.
Lt, 01
S h , !ih
m.
:A
CA, LE, U
PS, 31,
LE, 56
?!
Supcrscripta i n si':
llc
Vol. 60,No. 8,August t 976
coluw refer c o supplier 3udcrr in C a S k 3 .
classes zrc n ~ q b e r z daccordinn io Cable 15.
ALKALOIDS
0 OH
I1 I
I L3
HO
CH2-0-LC-C-CH-CH
' J - - - ~ . .C\
J8
HO-CH
I
0
0
C'43
Indicine N-oxide
Thalicarpine
NSC-68075
NSC-132329
ALKALOIDS
Taxol
MSG-125973
Camptothecin
NSC.94600
FIGURE 9
Cancer Treatment Reports
ALKALOIDS
OCH3
I
Ellipticine
NSC-71795
Nitidine chloride
NSC-146397
Fagaronine
NSC-157995
Vol. 60,No. 8,August 1976
Tylocrebrine
NSC-60387
R R ' = CH,
R = H; R ' = CH,
there w a s some evidence of activity at hig;t~doses in
lung carcinoma ( 2 50% reduction of t u m o r size in
t w o cases) and in one case each of carcinoma of t h e
trachea a n d of t h e thyroid gland (31), no response
was demonstrated in several o t h e r malignancies
ALKALOIDS
(321.
Emetine hydrochloride
(new) tumor. A simple addition reaction product of
nitidine, methoxydihydronitidine, was o b t a i n e d
from the plant as an artifact (29) and showed similar
activity. Advanced comparative screening is under
way to determine which compound should be developed.
h. Emetine ( f i g Ill.--This alkaloid, isolated in our
program from Cephaelis acucninata Karst. (tables 3
and 201, but already a n old commercial d r u g used as
an arnebieide, was given a clinical trial on the basis
of its activity i n P388 and LIZ10 leukemias. While
i. Harrittgtonine and hoinoharringtonine {,fig
Il).-These alkaloids, together with isoharrinfftoni n e , i s o l a t e d from Cephalota.rus h a r r i n g t o n i a
(Knight ex Forb.) R. Sm. Tar. drllpacea (Sieb. &
Zucc.) Koidz. (33), form a newly discovered type of
active alkaloid which consists of complex esters of
t h e inactive alcohol cephalotaxine. Lack of activity
in the slow-growing tumors h a s lowered t h e priority
on f u r t h e r development of these alkaloids, but t h e
critical importance of t h e ester group for activity, a
situation frequently encountered elsewhere, has
stimulated efforts at synthesis designed to exploit
t h e inherent activity of the esters; such efforts will
hopefully provide compounds with broader activity.
j. 3-Desmethylcolchicine ( , f i g I ) . - - T h i s newly
tested representative of an old class of active alkaloids was isolated from Colch icn m speeiostr ~n Stev.
(34). Certain advantages over other colchicine derivatives, one of which (demecolcine o r V-deacetyl-.Vmethylcolchicine) h a s been declared ( 5 ) t o be an
established, clinically active antitumor agent, have
revived interest in t h i s group and sufficient quantities of this alkaloid a r e being obtained for further
study.
.Vl iscellansous (table ,Ill.-This table lists a small
group of compounds t h a t have antitumor activity
but do not fall into one of t h e previous groups. None
is particularly i n t e r e s t i n g except p e r h a p s as an
ALKALOIDS
Harringtonine
NSC-124147
Homoharringtonine
NSC-147 633
n=2
3-Desmethylcolchicine
NSC-I 72946
=
Cancer Treatment Reports
f a b l e 21.
- KLacullanawa
Mrim
9SC
h e c a r j i c acid (7)
hacerdol :?)
GI
3/
:06051
XA
106090
VA
11, LL,
h r i 8 ~ 0 ! 0 ~ h i cacid
90250
Zdthylchrome
SA
PS, LL, L I
106396
!,!A
LL,
FS, LB
t!A
?/
pi
1944
Gallic a c i d
2C103
Duleiro:
compounds mentioned in t h e tables h a s been prepared.
ZnCcFiM
U, LE, S A
PS (136)
CA,
LL, IZ
:?A, P I ,
SA
Geiparrarin
142227
PS ( 1 3 C ) . i a
BL,LE,LL
?_/
56817
LL(nm) , ilA
E l , Ch, LB,
?!:,
LE, FS
Gossypl
Lipin
9
Xnntanii acid
11577.6
,moooeiycctidc 6/
ere-I,
8-Pentadmcadicr.e
.
1-2tc:adccenc
7/
J/
-138626
Pb
77:25
W
(1271, .K!
PS (:55),
Rotcnonf
~05647
0
PS (125)
PS 1133)
LC, PS, 81
2
GA,
jib,
7 2 ,
:A
WI- x ,
LE
SA
3
ism3 .a
i
PS, TTA, S A
CA,
u, U.
43333
qg2794
L-Usnic
acid
>L/
5889
I?i (L351
WA, 2L, iZ,
Lt, LL(r.cu) ,
indicator of related compounds to acquire and test
in t h e hope of finding improved activity. For readier
reference, an alphahtical list (table 22) of all the
Vol. 60, No. 8,August 1976
COMMENTS AND CONCLUSIONS
The compounds which have been isolated from
plants in t h e NCI program with activity against
experimental tumors have been listed according to
chemical type, along with t h e tumors against which
they have shown activity and inactivity. Changes in
methods of extraction and in the composition of t h e
antitumor screen which have affected t h e identity
and type of the compounds isolated a r e discussed.
I t is evident t h a t antitumor activity is encountered in compounds encompassing a wide variety of
chemical classes. Many of these compounds are of
novel chemical structure. On t h e basis of activity
against experimental tumors thought to be most
predictive of clinical effectiveness, i t appears t h a t
certain chemical classes a r e of greater interest as a
source of antitumor agents t h a n others. Presently,
t h e most interesting ones are the diterpenes, lignans, quassinoids, ansa macrolides, and alkaloids.
Continued study of the plant kingdom will undoubtedly reveal other compounds in these classes t h a t
will be superior to existing ones, perhaps in possessing fewer toxic effects, and may also uncover other
classes of compounds t h a t will prove to be of high
interest. In addition, i t is expected t h a t better plant
sources of certain useful compounds will be found,
as has been the case with maytansine.
A critical review of t h e antitumor properties of
certain interesting compounds, as well as of some of
t h e less interesting ones, will reveal fruitful areas
for analog synthesis either from "scratch" o r using
existing compounds as templates. For example, a
number of completely inactive alcohols have been
converted into highly active esters simply by acylation.
Continued feedback of results from preclinical
pharmacologic studies and from the clinic should
result in modifications in t h e makeup of our bioassay screen and in t h e types of compounds t h a t we
are (and are not) seeking to test. Continued taxonomic analysis of plant sources of compounds should
result in more selective collections for these cornpounds.
Tablc 2 2 .
Cumulative indcx of co~=o'mdslisted i:
their plants of o r i g i n
(see
r i a c t tables aod
t s b l t 231
P l m t entry no.
Compound
cnrry ro.
Y-
1.SC
C1
Acer sapmtkn ?
100065
Cli
,%brasin
cn
#-+~yrim
KO.
T&ole 30.
( t z b l c 231
P3
14
8523s
a
116787
il
Pb9, P186
?L9
?127
C18
. h a c a r d i c acid ( ? )
106051
21
C?9
Anacardol [?1
10BOjO
21
P19
C20
{nemonin
94101
21
PZO, P11, 7 2 2
179172
20
P24
83216
15
P25
C21
hopterine
C22
h7ocannoside
C23
nrctiopic~int
0.4
Arirtoloct~ic a c i d
C31
BersciUogenin
C32
bersenogenl3
C33
Beculln
C36
BcCulinic a c i d
--
3uforalldln aeetzre
NO
Burscran
See :iellebrLgmln 3-acetate
123428
15
12
P47
Cancer Treatment Reports
Tabla 22. - Curnularive index of compounds l i s t e d in these t a b l e s and
their plants of origin (see t a b l t 23) (continutdl
Compound
Plant e n t r y n o .
t n t q no.
>I-
1lSC S O .
Table !lo.
W1
Calotropin
113925
15
P32
C42
Ca?ptothccin
C43
Calsioridc C
C44
Centaureldii
CP5
Cerberin
--
14
P13
11
P13
lk
PI1
14
Pi2
14
PlO
..
,,
8,
,,
8,
,,
8,
8,
C56
>.
c57
C58
C59
>>
E60
"
Bursera
P50
"
Cacsalpinie
PSZ
"
"
Contaurta
P63
"
"
Cerastiun
P67
"
"
Cercidium
Ph8
"
"
Chryaopsis
P70
croaso~m
780
=n
P86
"
CSZ
??
-
"
..
"
Capolmd from
C81
1
"
8,
CSO -
I/
Compound fron dgave
-----
(tab+
"
"
"
"
"
"
I
t
t
Elaeodendron
P91
W6
P99
Cutlcrreaia
P115
..
<,
:iespcraloa
p122
"
"
fpomopis
p131
"
Jatropha
p134
0,
.,
..
p134
p149
P156
P158
Vol. 60, No. 8, August 1976
23)
Table 22. - Cumulative index of compounds l i s t e d i n these t a b l e s and
=heir ~ l a n c so f o r i g i n (see t a b l e 2 3 ) (continued)
Cmpound
encry ;lo.
Plant entrv no.
Namc
:qSC 90.
"
"
C86
"
"
CBT
"
"
hteomcles
C38
"
"
-
ca9
"
"
~a~onarii
CY1
C52
c9 3
(cable 23)
Mirabilis
ca5
C90
Tsble No.
-it
Rubla
Cocpound from
"
"
Trillium
coopound B from q i o p h o r a
''
C ''
m4
C9S
C96
C17
c96
cg9
Coptisine chloride
ci00
ClDl
CI02
C103
Crotcpoxide
C104
Cryptopleurine
CLOj
C r j p t w o l l i n e lodide
ClO6
Cucurhrtacln 3
52177d
See D a t i s c o c t d e
1963g
j21775
c;10
Clll
Clll
Ci13
Clld
C115
C116
Cl17
CllS
C119
C120
a21
El22
C123
Cancer Treatment Repbrts
Table 2 2 . - Cumvl.?civc index ol comporm.is l i s t e d I n t h e s e t a b l e s end
t h e i r plants
o!
o r i g i n (see t a b l e 231 I c o n t i n u e d l
Planr entry r.o.
Compound
e n ~ r yno.
Its C o:
Bamc
Emodin
(aloe-caod f n j
3-Zpibereclliogenln
2-tplcucurbiractn
B
10-Hpleupat~rnxin
E?icul~pinolidc
Eriofhrin
E x l o f l o r i n acetate
Zrlofiorin methacrylate
Eriolsngin
Zrlolanin
Iu?achl~rio
3x?ecnlorln acetate
Lugacblorox~n
Eupacunin
Zupncunoxi;l
c~?ar0tl3
:uparotln
ccetate
Eucatocunin
Vo!. 40,No. 8, August 1976
.
T 3 b k 'To.
( t a j l e 131
Table 22.
- Cumulative index uf
compounds listed i n rheae t a b l e e and
thelr p l a n ~ sof origin (See r a b l t 23) { c u n c l n r ~ d )
PlanL entry no.
Compound
encry nb.
!Tarn
?lSC No.
Table No.
-68
Eupatofolin
135023
3
<table 23)
PlOl
C174
L-Po~~ldcsacecyl~nlehicinc
A03142
20
774
Cl7S
Gaillardtn
LO5391
8
Plll
Cl76
Callit acid
20103
21
P:66,
C177
Geiparvarin
142227
21
FLlla
'
C187
IIelenaLin acetate
CLS6
liellebrigtaie 3-acetate
el36
(Eufotalidin a c e t a t e )
C189
t:ailcbriecnin 3.5-diacetart
C195
16 P-~ydraryber$amagenin I,J ,5-
109330
15
PA1
251695
15
PL1
orthoacetate
Cancer Treatment Repofis
Table 22.
- Cumqlative
l n d e x of compounds lisred 1"
rtleir p l o n t a of 0rip:n
(see
t h e s e tables and
t a b l e 2 3 ) (cocttnuedJ
Compound
Plant entry ao.
C238
;<onocrotaline
C239
Flont.nn=c acid q--nosoglyccr~dc
C210
?lyrsine s a p o c i n
ClLj
F l t i d ine chlor:de
Vol. 60,No. 8,August 1976
90187
11
Pli. P18, P50. P198
&dl353
1C
P79, P126
28893
2'1
P8;
--
21
Plllb
123126
14
P162. F228
Table 2 2 .
- Curnularive
index of compounds 11sLed i n these t a b l e s and
t h e i r plants of origln
(see t a b l e
231 (continuedl
Plant snrry n o .
compound
entry no.
NIvx
ISC T o .
T a h l e :to.
I t a b l c 231
Oleanddr.
opposlde
Ovatifolin acetat e
wacanthine
Oxyni t i d i n e
Orjtylozrrbrinc
Parthmolidc
Paucin
ql-pcltatm
Podophyllotoxin ducosldc
16-PropionylpicoxLgcnin
Reserpine
Rhmlexin I
RoCtnme
P - ~ l t o s t e r o l glucoside
See Daucosterol
5
$-~olmarinc
Soiapalmaronine
Solapalmarine
Solaplunbin
Solaaodin~basc
Solasodrne hydrochloride
"
rhsmaside
Somalin
Steganacin
Stewangin
Cancer Treatment Reports
Iable 22.
- Curnularive indcn u f
compounds
1is:ed
ic these rablcs and
cheir p l a n t s oC o r l g i n (see t a b l e 2 3 ) (continued1
Compound
Plant e n t r y
no.
e n t w 20.
C285
s Tetraol
Thalicarpine
fi.alidasmc
F-Tkojapllcin
3 ' , i ,?-Tiijlydro~{-3 , d a d i e t h o h ~lsvonc
f
Tripiiolido
Triptoilde
iripconioe
P9, Pol. P163,
PZ13, P224
1-usnic acid
e72
Waol
9224
uvarctin
P223
Uzarigcnin
PI13. P138
Vernodalin
P12j
PlZb
P225
P226
P225
~ 1 9 9 , PLao, ~ 2 2 7
P227
P?
Pi, PL73
P230
Vol. 60, No. 8,August 1976
Table 23.
- Inccv of
p l a n r s mf a c t i ~ eagents i s o l a t e d therefrom
l'lmr:
entry no.
Conpound e n t r y no.
( t a b l e 22j
Kame
h i e s c o n c o l o r (Gord. G Glend.) L i n d l , cx B i l d e b r .
C298
Acanthorpem>m g l a b r a t u n (DC.) Ytld
C52
accr n e g u n d o L.
C I , CZ
A. pensglvanicrar L.
C53
Dunalia arborestens (I.) Slem-r
U 2 0 , C321
[ h c n ~ s c u sarborescenz ( L . 1 S c h l c c h t . 1
t,cokantilera l o n c i f l o r a Stapf
C5, C 1 , CZL8
a . cb1on:lfoLia
CA,
( 3 ~ c h s t . i Codd
ndefiium ojezuic (Foraka11 Reem. h S c h u i t .
C282
G i n a n d r a dumosa J a c k
C308
npve brandegtei T w l .
C60
A . c a c c i l i a n a 3erger
C58
l c c b e g u l l l a Torr.
C59
A.
A. s c h o t t i x dngelm.
A;ar.:iux
C h A , c 5 5 , C56,
.
s a l v i i f o L i u n {L. f l l ) :;znzer.
Clb, C15, Cia6
A I l i u o d r u m o n d i i Regel
C63
A1n.s i l m f o l l a ?em.
C33, C2i8
A . =bra
Emg
[A. o r e g m a buct.]
[ ~ e m o
paten=
~
[Memone p m t e n s i s
L.]
L.1
[Anemm l u l s a r i l l a L.1
C20
C20
CZO
Cll6
.Lulona g l a b r a L.
Anoptems m;lclca,.aus
F.
:uell.
C? 1
cZ2, C L 2 3
Asocynue cannabbum L .
4rgemone r x i c a n a L
U61
CIS, C19
~ v l s a t i l l ap a t e n s (L.) i ~ i l l .
F, vulgaris Iiill.
,
C33, C218
hqacardium o c c i d a n t d t 5 .
P. >raranais ( L . j ;!ill.
c57
C61, C62, C303
c s t b a r t i c ; L.
.?Jlaomd~
C 6 , C7, CB
.
C2i
. I n s t o l o & i i a lndlcn L .
WI
?.r.mebia D o b i l i s R e c l ~f. 5.1.
C11. C12, C13
Arnica c n m i z s o n i s Less. suosp. f a l i v z a (Nc:t.)
C~87
!!aguire Tar. m e a n 3 (G:e.y).J
:!ult.
Asarum cansdcnsc L.
45clepLas a l b i c m s Ilatl.
A . curassauica L.
& t e r d i v a r l c a t u s I.
A.
: l a u c o d ~ s :lOc
3 x c h a r l s ssrocllroides Gray
Zalleya m u l t i r a d i a t a liar#. & Gray ex Torr.
k . pauclradlaca B a r . &
Gray
51
Gra?
Ealduina l i n g u s t l f o l i a (Pursh) R o b i z .
aegonia
:
cubcrl~)*bridsVns5 cv. " G b a "
Berbcris a s l n t k a Raxb, cir UC.
Persama a L y s s i n i c a Resen.
Cancer Treatment Reports
Table 23. - Index of p l a n t s and actrve a g e n t s i s o l a t e d thorefxom (coacinucdl
Campound entry no.
Plat
( ~ s b l e22)
entryno.
Name
Family
P42
boehmeria c y l i n d r l c a (L.) Sr.
Ur tlcaceae
C104
PSB
Buraera fagaroidcs (B.B.X.)
P67
3. d c r o p h y l l a Gray
P49
U. s c h l c c h t e n d a l i i Engl
PSO
b. s i r a r u b s (L.) Sarg.
Xy=qaceae
C42, C196, a 2 9
atl.
.
.
P58
Camptocheca acuminata m c n t
F5 9
Cassia o b t u s a CLos
Fataceat
ci50
h 0
Catharantbus lanceus (Zoj. ex A.DC.1 Pichon
mocynaceae
CZ12
P61
C
P62
Verb-cum
P63
Centaurea = l i t e n s i s
kteraceze
c13, C 2 j , C69
P64
Capheelis acmLna2a Karst.
Rubiactac
ClL9
P6S
cephalotavus h a r r i a g r o i l i s ( Y a l g b t *a Forb .) B.Sn.
CephaLoCasaceae
ClBj. U91, CZ05
PG9
Pi0
Chclidonium mfus L.
firysopsis vlllosa (Purshl !Tutt . c x DC.
Papawrace~e
Mtcraceae
C47, C99, C269
P71
C l f r u l l u s c o l o c y n t h i s (I.) Schrad.
Cucurbicac&ac
Cl09
P7Z
CLadonla l e p t o c l a d a d a s h b .
Cladoniaceae
C309
P75
Colchlcum speciosila S t c u
Liliaceac
C A B , U 3 3 , C138,
P75
Celubrina t u r e n s i s (Torr. 6 Gray) Grey
K~amaceas
P76
Coptis t e e c a Wall.
bnuncdaceae
C27
P77
C o r e n i l l a v a r l a L.
haryllidaceac
C103, C219
Lauraceae
C105
. prrsillur
.
(Mvrr. ) C Don
chinensc [I.) Santapau
L.
.
C7Z
Clf?, C234
Crinodendmn bwkerianum C . G q
P78
P79
GS1. C223
-
Crinum m a c ~ a n t h e r mEngl.
P9(1
Crossosoms, porviflorum Robins. 6 Fern.
P81
C r o t s l a r i a s p t e r a b i l i s Rnth
P83
Cryptocerya l a t v i g e t a 31. Tar. bowiei Rook.)
Ibstem. [C. b m i c i (tlwk.) rnucel
Vol. 60, No. 8: August 1976
T a b l e 23. - h d e i : o f p l a n t s and active agenrs l ~ o l a t e dt h e r c f r o m ( c o a t ~ n u e d )
Plant
Compound s n t r y no.
P65
CucurSica d i g l t a t s Gray
Cucurbitaceae
C106
PS6
Cycleoen p t r s i c r r n ' l i l l .
PrL~ulaccac
C74
pH7
C i c l e a p e l t a t a (Lam.) ~ : o o k . f ~ l4. T h m s .
.bnispersaccae
C119, C120. ClZ1,
c202
*:v~rla=aceee
397,
Datiscaceae
C106, C110, C115,
CZ3i
~ 1 1 6 ,cin, c i i a ,
C119, C125, C126
P? 0
Derris t r i f o l i a t a Lour.
P? 1
Dichrea F e b r i i u g a Lour.
PY2
Digitalis purpurea 2 .
P93
D i p h y l l c i ? c)nosa :iicnx.
P94
Wrlnys winrcr:
Scro~l~ulariaceae
Forst, s B o r s r . f i l .
usr. c h i l e n s i h ( D C . )
P95
P35a
Clll
Cra?
Ecballium elarrriur. (L.) A . k c n
E c l ~ i l a c e aa : g u s t l f o l l s DC.
Pj1
Elephancopus e l a t a s 3cr:ol.
F96
E. scaber L.
P99
Lztada p h a a s o l o i d e r
(1.1 i l e r r .
pi00
a r ~ o p h y l l u m;macum
(Furshl
PlOl
Hupatori-
P102
E , rotuildlfoLiui~ L.
for^.
cueifolium silld.
C168
Ci53, CIGD, C161,
ClbZ, C165, C166,
~ 1 6 9 ,cno
I Z v c a v a t ~ ac ~ c c i n e a( T e y s r . G ;mneili.)
P104
Fapara c h a l y b e z (3.121.)
PLOS
E.
PI06
F. macmphylla ( O l i v . ) :n$l.
PIG7
Fzgcra x u b r c s c e a s (F:alci~.> C n z l .
Plilb
Gnidio iraussiane > k i s s n .
Pa2
G. l a ~ ~ n r a n t hGa l l ~
PI15
ell6
i e p r l e u r f i (Cuillcn..:
::arkgraE
Zngi.
Rucaceae
Pcrr. & .\.Ric!>.) 2ilei.
C243
C231. C243
C231, C 2 L 3 , C251
Rucaceae
C263
G u t i e r r e m i s s a r o t h r a e ( ~ u r s h jB r l t c . S Rugby
Asc?raceae
C77a
?laytenus v i $ h t I m r dabu
Celas traceac
W 2 3 . C224, C225
Cancer Treatment Reports
Table 1 3 . - Index of p l a n t s and a c t i v e agents l s o l a c e d thereirom [continued)
Cowound e n t r y no.
P
i
g
lt
entw n o .
:(me
P%ily
Pllg
1:eliecta p s r r l f o l i a ( G r a ~ex i?eosi.) Denth.
kraccae
CZ71
( t a b l e 22)
~120
l l e l i o r r o p i m l n d i s m L.
aoraglnaccse
El99
P121.
Kernandla a v l g c r a L.
::ernandiaceee
C135
Pi22
lie4peraloe parviflora (Torr.) Couir.
A~auaceae
~ 7 2
P123
!3olacantha = w r y < Gzay
SimaroLLbacea~
C190
PI24
iiolsrrhma a n t i d y s c n t e r l c a (L.1
Qocynaccat
C98
P125
k y d r a s t i s c a n a d t n s l s L.
PlZ6
n y e e n o s a l l i s l a c i f o l i a (W11.J
P127
*i:)venoclea
XelI. e x A.DC.
$1.
J.Rocn.
s a l s o l s Torr. b Gray ex Gray
hnunculaceae
Q7
k.aryll~daceae
c219
Astcraccse
C16
PI28
i l y p t b emoryi Torr.
P129
IF-a
P'-30
I, purpurea (t.) uorh
Pi31
X p o w p s k aggragara (Pursh) I'.Crant
Polcmonieceac
C79
PI32
Jacaranda caucma P i t t i e r
Bignon~zceae
C207
7133
J a t r o p h a z o % % y p i i f o l i aL.
iuphorbiaceae
i%O9
F136
J a t r o p h a macrorhiaa 3onch.
Zuphorbiaceac
C80, C81, U O B
P135
Juniperus c h i n e c s i a L.
Cupressaceac
PI36
J. c-rmir
acuminata ( V a h l )
Roen. & Schult.
Ldaceae
C 3 4 . C27L
Convolvulaceat
c290
[ I . l e a r i i Paxt.1
G74
ti63
I. var. > e p r e s s a Pursh
c?35
c263
P137
J. v i r g i n i a n a L.
PL38
F m a h i a l a i f o l i a IForalial) R.Er.
mclepiadaccae
C100, C 3 1 ?
P139
L i a t t i s c h s p m i i Torr. b Gray
uterac-ae
C213
P140
Caloctdrus tecurrens (Torr.) Plorfn
Cryressacea-
C!35
[ L i b o c e d r u s decurrens T o n .
1
L i n m album h t s c h y ex 3014s.
Liriodsndron t u l i p i f e r a L.
.ooci~ocarpus utucu K i l l i p & a . C . 5 ~ .
Fabacaaa
Lophocereus s c h o t t i i (Engclm.)
Caccaceat
3 r i t t . & Rose
Cucurbitaceac
i u f f a e c h i n a t a Roxb.
,,
t. p a v e o l e n s Roxb.
.
Lunasia amara B l m c o
Lunasia q u e r c i f o l i a (Uarb.1 6.Schum. h LauLerb
.iacnaeranthera L i n e a r i s trcmc
CSZ
llagnolia ~ r a n d i f l o r ai.
3:.
v i r g l n i a n a L.
t l q p i a f o e t i d a (Wight) aiers
Urah oreganus (Torr. d Glay) T.J.Hwel1
M, h e t e r e p h y l l a (Hckl. 6 Ze)-h.) ;I.Rebson
ti. % m e g a l e n s i s (tam.) E x 1 1
n.
s t r r a t a (Hochst. ex A.RLch.)
R.Yilczek
k r t e n s i a francircana B e l l e r
t4irabiLis m l t i f l o r a (Torr .) Gray
Momtezuma s n e c i o e i s s i w Sesse h )lo=.
Vol. 60, No. 8, August 1976
Tsble 23.
- Index of
planrs anc active agents isolaced therefrom (continued)
Conpound e n t r y m.
Plant
cntrg n o .
( t a b l e 22)
.;axe
Tamils
iluscari cmosu= !till.
tillaccae
CS6
Solanaceae
CZ79, C?B0. C181
Apocyneceae
U 4 8 , C232
Myrrina ~fricanaL.
Nardastachys jatamansi M.
:Uerium oleander L.
Rorsceae
ce7
Parquetlna n i p r e s t e n s (Mzel.) Bulloca
hsclepiadaceee
C123, C293
Psrthenocissus i a s e r c a (A.J.t'ern.)
Vicaceae
C274
Scro?l8l;larisceae
~27:
Pentaceras a u s t r a l i s (t.:i~ll.) i : w i . f i l ex X n t I l .
Autaceae
U30, C i 3 6
Phrdurn t e e m Forsr.
Cgavaceat
Clll
Fhyllantbus b r a s i l t e n s i s (Aubl.) P o i r .
Luphorbiaceae
c2lO
Plumria a c u t i f o l i a Pair.
.+oc;naceae
C: 74
Ntcracese
C3b,
Poa~car?aceae
C16?
Ogteor,(eleg
~chwerinae Sclln-id.
? ' e n s ~ m o xdeuscus Doupl. e x
&
Ritsfh
Llndl.
Forrc.fi1
C157, C 2 4 9
Sccecar?us anacardium L. f l i .
Siaarouba
.dqlauca
DC.
Solanruc dulcamara I.
S . aarginatum I.f i l .
5 . t r i p a r t i t u t Pun.
5, l a p m i c a (Tllmb. ex 21urr.) Z;iers v a r . o i l c o l o r
( B l u e c l Forman LS. llcmand!ifoLia
(Wild.) lid?.
C28B
I
Candr Treatment Reports
T s t l c 2 3 . - indcn ui plancs e*d e f t i v e
agents l r o l a t e d
t h e r s f r o r (colrinucdj
PianC
Compound ertry ao.
e n t r y do.
:I&
P199
Tabernaexoncana jouns c o n i i (6 rap!)
P200
T. ven:cicosa 1;ochsc.
(cable 2 2 )
Pzmlly
Pichon
Qocynaceae
C316
C318
ex a.3C.
iT. usamberenrls X.Schm ex Z"51.
I
P201
Talauma ovata Sc.--1iil.
Elagnoliaccac
CiOl
P202
' i ~ ~ . o d % u d181-1~hl~7
m
[L ,) M,RLc~.
TzxoCiaceae
C292, '293
PZ03
Tal-s baccota
Tzxaceae
C?F4
PiOr
T. brevifolia :iuCc.
C?Fb, a 9 5
P205
7 . canadens16 ?[zrsh.
C294
L. c v . " F a s t i g i a t a "
P?06
T. cuspibata Sieb. d Zucc.
C294
P207
T. :: r e d l a ~ e l t d .
C294
?208
l e c l e a wrdoomiana a x e l 1 4 ?endonca
Rutaceae
CZ18, C27L
P.%=unc~?ace+e
C296. C297
11'. x a n d i f o l i a 3 c g l . l
.,
P204
Thallct~umd a s y c a r ? ~ Pisch
P210
T , f l a w 2 i. bubsp, glaucun (&sf .) a a c t .
Eey. G l u e - < d l .
CZ i
[T. rugosuv A i t . ]
P211
Clevecr.
P212
T. ovacs (Cav.1 P.DC.
F213
T. peruvlans (PETS.) ;.Schu3.
P211
Klula o c c i d m t a l i s L.
iinouai (I.) 6.3C.
sS.ocynacezc
C262
C?d2
Sj, i 2 4 2 , C308
cUPre6SBCCile
CiZ5
P215
Toddalie a s i n c i c a (L.)
Ktt~ceae
C2$3
?216
i r i l l i m ertctur L .
Liliace-c
C9 1
PZ17
Tripterygcum x i l f o r d i i 5 0 o k . f l l .
Celas craceae
cjoo, c j a i , ~ 3 0 2
P218
Pjlopbora crebrifLora S.I.3:ake
Asclepiodrceae
C92, C93, C94,
i.2m.
C45, C252, C3U5
C306, C307
YZi9
I. t a l z e l l i i iiooX.iU.
C:3<
P220
T. lhirruta M a l l . ) k'igkt
C9?, C93, CPb,
P221
T. i r d i c a (Eunn.Fi1.) :<err.
C252, C305, C306
C76,
C97, C?39,
C 3 6 . C307
p22?
Urpiaca a I t l s s i 3 a ( L . f i 1 . ) 3 k e r
Lllinceae
C270
P223
k a r i a scurmlate OlL?.
2xonace;ue
C311
P?Lb
Irauqaclinla c o r y h o s a Lorrea e x iunb. & 3onpl.
Roooceae
C 3 4 , C3G8, C310
PZi5
Irernonie amygdsline k l i ; e
Mtelace.+e
C313, C315, 3 1 7
P226
V . h y ~ n o l e p ~A.s Rich.
P227
Voacacga africana Stapf cx G . i l l .
A?ocynaceac
C315, C319
P228
W d l e n i a yunquensis {Urogn) Hez
Yy~sinaceae
C240
7229
a n t h o r r h i z a s h ? l i c i s s i x ~Iarsh.
Panuzcuizceae
C215, C 5 D
7230
Zeluzmla parcilecioides (DC.1 k e i .
Asteraccke
C??b.
hcaeeae
C27. C2$3
C31$, C316
Cj22
I Z . r o b i n s o n i l Sha-I
P231
Vol. 60, No. 8,,August 1976
Zanchoxyluo monopl~yllun (izc.) P. ,.'=ls.
Table 24.
- Plant
Lamlli~sand gencre
See
hpve
Ptlonnldn
AL&:c:;,c:fl.
.uL=glun
~LY~RYLLIQ?CJPIF
Crinur
sIXImGKE$2
;.UiLnM
E,G
ilesperaloe
Scrrscento
::np?ia
hcer
!>C).tA
'
S,4 Z.C4CE!TIACL$E
IKAC:%ALTIL?
bCLR4CLk
'Lrip:er?$i'~m
CEPii4LWkACCAL
Ceph~locxds
zm:;u.c?h:
Cladonla
copori:u
See k t c r a c c a c
Cx:>'o;WLAC.?>\'-
LA-
Lz~ieceet
I?~~O*B
SCnOPl;mhR19CEAL
.:??ti$
D1:Italis
:AUmzx
3
LEG'MliW E
Sse P~.bec=ee
:ILI+C3h€
&:=an
'
r-IlC4E
A'
~33ssaso?d.=4xk-
DiChroa
acza
Cr,'?iccsr;
.:~scari
Trilliu,~
Orqines
:I:;hCz+E
Llr.U3
?UMOLI$.CEP~
Il:io:endron
:1.,po1:a
Talallra
::a':AcxhL
fi:nptelu~
Pens cemo.
'(erbnscwn
51:?PWU3ACLK
Druica
~mOlaLao~ha
Picrasza
Picrrcode~tron
S:3a~3ub2
S5L.khPCLM
3cr a i i a
..ice::-ca
,.:..1 1 1 5 8 i i l
Soiacun
TAUCE.C
1'<wu3
T~dYoDI:\~:z&
Tauodiw
nZ$,czhF.
Mlnancra
I:!TEe:cAcIC3AE
Pzpcl,!
hidia
LIBELLIFLW
See P,?i~ctac
:rIu.cI>:
BociLCr=e
>'IERIh\PCr.K
.:ardo.tzc:::-s
?':TIE C
Cancer Treatment Reports
REFERENCES
I. BARTWELLYL. Plants used against cancer. A survey. Lloydia
30:37U36, 1967, and t e n additional installments ending with
34:386337,1971.
2. HARTFELL JL, a n d SCHRECKERAW. The chemistry of
podophyllum. I n P r o g r e s s in t h e C h e m i s t r y of Organic
Natural Products (Zechmeister L, ed). Vienna, Springer Verlag, 1955. vol 15, pp 83-166.
8. MAINE WRITERS
RESEARCH CLL-B. Maine Indians i n History
and Legends. Portland, Me, Serern-Wylie-Jeu-ett Co, 1952, pp
9G102.
4. KosT J. The Elements of Materia Medica and Therapeutics.
Cincinnati, Kost and Pool, 1849, 572 pp.
5. GOLDIN A, SERPICK
AA, a n d MANTEL N. A commentary.
Experimental screening procedures a n d clinical predictability
value. Cancer Chemother Rep 50:173-218,1966.
6. HARTWELLJL, and ABBOTTkJ.Antineoplastic principles in
plants: recent developments in t h e field. In Advances in
Pharmacology a n d Chemotherapy (Garattini S, Goldin A,
flawking F, et al, eds). New York, Academic Press, Inc, 1969,
vol 7, pp 117-209 (see pp 154 and 194).
7. WALL ME, TAYLOR H, AMBROSIOL , ET ALL Plant antitumor
agents. 111. h convenient separation of tannins from other
plant constituents. J Pharm Sci 58:839-841,1969.
8. Bmcii JB, SERPICG AA, MILLER- W, ET A L Early clinical
studies with lapachol (NSC-11905). Cancer Chemother Rep
Part 2, vol 4(4):27-28, 1974.
9. K V P C SM,
~ ~DESSERTINE AL, BLAYLOCK
BT,ET AL. Isolation and structural elucidation of allamandin, a n antileukemic
iridoid lactone from Allamanda cathartics. J Org Chem 39:
2477-2482, 1974.
lo. KUPCHAN SM, AYNEHCHIY , CAYSADYJM, E T AL. The isolation and structural elucidation of two novel sesquiterpenoid
tumor inhibitors from Elephantopua elatus. J Am Chem Soc
88:36743676, 1966.
11. K r P C H A N SM,COURT WA, DAILEY RG, JR, ET A L Triptolide
a n d tripdiolide. Novel antileukemic diterpenoid triepoxides
from Triptemgium wilfordii. J Am Chem Soc 94:719&7195,
1972.
rr. DOSKOTCH RW, MALIKMY, and BEALJL. Cucurbitacin B, the
cytotoxic principle of Begonia tuherhybrida var. alba. Lloydia
32:115-122, 1969.
13. NISSEh' NI, LARSEN V, PEDERSENH, ET A L Phase I clinical
trial of a new antitumor agent, 4'-demethylepipodophyllotoxin
9-(4,6-0-ethylidene-BDglucopyranoside)
(NSClll540; VP-16213). Cancer Chemother Rep 56:769-777, 1972.
14. KrPCHAii SM, TAKASUGI:M,S~IITH
RM,ET AL Tumor inhibitors. LXII. The structures of acerotin and, acerocin, novel
tripterpene ester aglycones from t h e tumor inhibitory saponins of Aeer negundo. J Org Chem 36:1972-1976, 1971.
15. KCPCHAXSM,B R ~ O .RW,
U Z~EGLERMF,ET A L Bruceantin,
a new potent antileukemic simaroubolide from Erucea antidpenterica. J Org Chem 38:17€&179, 1973.
16. WALL ME, and WANI JI. The isolation and s t r u c t u r e of
holacanthone, a potent experimental antitumor agent. (Abstr)
In Proceedings of t h e 7th International Symposium on Chemical Natural Products, Riga, USSR, 1970, E138, p 72.
17. KCPCHAN SM, KOMODA Y , COURTWA, ET AL. hlaytansine, a
Vol. 60,NQ. 8,August 1976
novel antileukemic ansa macrolide from :lfaytenus o v a t u ~ 3.
Am chern Soc 95:135&1366, 1912.
18.
MC, TAYLORHL, and WALL ME. Plant a n t i t u m o r
agents: colubrinol acetate a n d coluhrinol, antileukaemic ansa
macrolides from C o l u h r i ? ~taxensis.
~
.
I
Chem Soc Chem Commun 470:390, 1973.
19. ULUBELEKA, MCCAUGHEYWF, and COLE JR. Proteinaceous
antitumor substances from plants. 111. CaasaEpinia gillieaii
(Leguminosae). J Pharm Sci 56:914-916, 1967.
20. KUPCHAN SM, and Y O t i O ~ a n ~N.
a The structure, configuration and synthesis of thalicarpine, a novel dimeric aporphinebenzylisoqvinoline alkaloid. J Am Chem Soc 85:X361-1362,
1963.
21. WALL ME, W n N I MC, C O O & C E , ET AL. Plant antitumor
agents. I. The isolation and structure of camptothecin, a
novel alkaloidal leukemia and tumor inhibitor from Camptotkeca acuminata. J Am Chem Soc 88:388&3890, 1966.
22. GOTTLIEB JA, GUARINOAM, CALL JB, ET A L Preliminary
pharmacologic and clinical evaluation of camptothecin sodium
(NSC-100880). Cancer Chemother Rep 54:461170,1970.
23. WAKI MC, a n d WALL ME. Plant antitumor agents. 11. The
structure of two new alkaloids from Curnptotheca acumi~ata.
J Org Chem 34:1364-1367,1969.
24. GO>mDACHABI TR, a n d VISWAKATHLY N. 9-Methoxycamptothecin. A new alkaloid from Mappia foetida Miers. Indian J
Chem 10:45,U54, 1972.
25. U'ANI MC, TAYLOR HL, WALL YE, ET AL Plant antitumor
agents. VI. The isolation a n d structure of taxol, a novel
antileukemic and antitumor agent from T u u a brecifolia. 3
.4m Chem S o t 93:2325-2327, 1971.
26. LODERYNr. The structure of methoxyellipticine. Aust J Chem
19:1947-1950,1966.
27. M a r m G, H A Y - T M, nE VASSAL F,ET A L Ilfethoxy-%ellipticine lactate. 111. Clinical screening: its action in acute myeloblastic leukaemia. Rev Eur E t u d Clin Biol 15:541-515, 1970.
28. GELLERT E, GOVINDACHARI TR,LAKSHMIKANTHAM
MV,ET
ALL The alkaloids of Tylophora crebrzflora; structure and
synthesis of tylocrebrine, a new phenanthroindolizidine alkaloid. J Chem Soc, pp 1008-1014, 1962.
29. WALL ME, Whnr MC, and T-YLOR HL: Plant anti-tumor
agents. VIIX. Isolation a n d S t r u c t u r e of Anti-tumor AIkaloids from Faaura naaeroph~lla.(Abstr) In Proceedings of
the 162nd National Meeting of t h e American Chemical Society, Washington, DC, Sept 12-17, 1971. MEDI 34.
so. MESSMER WM, TIN-W.4 M, FONG HHS,ET AL. Fagaronine, a
n e w tumor inhibitor isolated from Fagara 2anthozyloides
Lam.(Rutaceae). J P h a r m Sci 61:1858, 1972.
31. PAI~EITIEKE F, and COLT&JAVCA, JR. Phase 1 experience
with, emetine hydrochloride (NSC33669) a s a n antitumor
agent. Cancer 27:836441, 1971.
32. S m n I q U I S , FIRAT
D, a n d OLSHIN S. Phase 11 study of emetine
(NSC-33669) i n t h e t r e a t m e n t of solid t u m o r s . C a n c e r
Chemother Rep 57:423428,1973.
33. POWELLRG, WEISLE~ERD, SMITHCR, JR, ET AL Structure of
c e p h a l o t a x i n e a n d r e l a t e d alkaloids. T e t r a h e d r o n L e t t
46:40814084, 1969.
34. KUPCHAN SM,BRITTEN RN, CRIANG CK, ET A L Tumor inhibitors. 88. The antileukemic principles of Colchicum apeciosum. Lloydia 36:33%340, 1973.
>.-