Marine organisms and other novel natural sources of new cancer drugs

Gilberto Schwartsmann
South-American Office for Anticancer Drug Development (SOAD), Comprehensive Cancer Centre (CINCAN),
The Lutheran University (ULBRA) & Postgraduate Course in Medicine (UFRGS), Porto Alegre, Brazil

Introduction Anti-cancer agents derived from natural sources

Man has always relied on nature for survival. Since Several new anticancer agents that entered the mar-
ancient times, nature has been our main source of ket in the 1990s were obtained from natural sources

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food, protection, clothing, transportation and reme-
dies [1,2]. This can be illustrated by the number
of natural product derived agents currently in use
in routine medical practice (Table 1) [3-5]. In ad-
dition to plant-derived compounds, microorganisms
constitute a very important source of novel bioac-
tive agents. They have contributed to the medical
armamentarium with antibiotics such as penicillins,
aminoglycosides and cephalosporins, which repre-
sent landmarks in the history of human therapeutics
[6,7]. Although marine compounds are yet under-
represented in routine clinical practice, it can be
anticipated that aquatic environment may become a
potentially valuable source of novel compounds, as
the world's oceans cover about 70% of the earth's
surface and all except 2 of the 28 major animal phyla
are represented there [8-11].
(Table 2) [12,13]. There is also a significant number
of naturally derived new anticancer candidate com-
pounds that are currently undergoing preclinical and
early clinical development (Table 3) [3,14].
Plant-derived compounds, in particular, have .a
special place in the anticancer therapy (Table 4)
[15,16]. The Vinca alkaloid vincristine (isolated from
Catharanthus roseus) is part of various curative reg-
imens in patients with leukaemia and lymphoma
[17,18]. Similarly, the epipodophyllotoxin deriva-
tive, etoposide (extracted from the mandrake plant
Podophyllum peltatum and the wild chervill P. emodi)
is included in drug regimens that produce a signif-
icant number of cures in patients with germ-cell
tumours [19,20]. The taxoids (extracted from the
bark of the Taxaceae Taxus brevifolia, T. canadensis,
or T. baccata) and the camptothecins (derived from
the bark and wood of the Nyssacea Camptotheca
acuminata) have also significant anti-solid tumour

Table 1
Drugs developed from plant sources

Drug Medical use Plant source

Aspirin Analgpsir, antiinflammatnry Filipendula ulmaria
Atropine Pupil dilator Atropa belladonna
Benzoin Oral disinfectant Styrax tonkinensis
Caffeine Stimulant Camellia sinensis
Codeine Analgesic, antitussive Papaver somniferum
Digoxin For atrial fibrillation and CHF Digitalis purpura
Eugenol For toothache Syzigium aromaticum
Hygoscyamine Anticholinergic Hyoscyamus niger
Morphine Analgesic Papaver somniferum
Papaverine Antispasmodic Papaver somniferum
Pilocarpine For glaucoma Pilocarpus jaborandi
Quinine For malaria prophylaxis Cinchona pubescens
Reserpine Antihypertensive Rauwolfia serpentia
Scopolamine For motion sickness Datura stramonium
Toxiferine Relaxant in surgery Strychnos guianensis
Xanthotoxin For vitiligo Ammi majus

235
236 G. Schwartsmann

Table 2
Anticancer drugs developed from plant sources

Drug Medical use Plant source

Etoposide Testicular tumours, small cell lung cancer Podophyllum peltatum and P. emodi
Teniposide Paediatric acute lymphoblastic leukaemia Podophyllum pellatum and P. emodi
Vinblastine Hodgkin's disease, non-Hodgkin's lymphoma, carcinoma of the testis, Kaposi's Catharanthus roseus
sarcoma, choriocarcinoma, breast cancer
Vincristine Acute leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, Catharanthus roseus
rhabdomyosarcoma, Wilm's tumour
Vindesine Investigational; modest activity in Hodgkin's disease, non-Hodgkin's lymphoma, Catharanthus roseus
leukaemias, non-small cell lung cancer, and breast cancer
Vinorelbine Activity in breast and non-small cell lung cancer Catharanthus roseus
Paclitaxel Ovarian, breast, lung cancer and others Taxus brevifolia
Docetaxel Ovarian, breast, and lung cancers Taxus baccata
Topotecan Ovarian cancer Camptotheca acuminata
Irinotecan Colorectal cancer Camptotheca acuminata

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Table 3 Table 4
Examples of natural product derived agents approved for market- NCI-sponsored experimental agents whose pharmacophores are
ing (1990-1999) obtained from natural sources

Bisantrene Fludarabine phosphate Source Agent Status

Interferon y-lA Pentostatin
Animal Hydroxydopamine derivative Preclinical
Cytarabine ocphosphate Formes tane
Animal Tributyrin PrecUnical
Miltefosine Paclitaxel
Animal 2-Methoxyestradiol derivative Preclinical
Porfimer sodium Sobuzoxane
Marine Halichondrin B Preclinical
Pegaspargase Bicalutamide
Marine Dolastatin 10 * Clinical
Zinostatin stimalamer Raltitrexed
Microbial COL 3 Preclinical
Gemcitabine Docetaxel
Microbial Cordycepin/deoxycoformycin Preclinical
Topotecan Lyposomal doxorubicin
Microbial Geldanamycin derivative Preclinical
Irinotecan Lyposomal daunomycin
Microbial Iododoxorubicin Clinical
Etoposide phosphate
Microbial Rapamycin derivative Preclinical
The agents are either natural products, semisynthetic analogues Microbial Vicenistatin Preclinical
or the pharmacophore is from a natural product. From Cragg and Microbial Bizelesin Clinical
Newman, 1999 [3]. Microbial Depsipeptide Clinical
Microbial KRN55O0 Clinical
Microbial 9-cir-Retinoic acid Clinical
activity [21]. Paclitaxel was approved by the FDA Microbial Quinocarmycin derivative Clinical
Microbial Rebeccamycin derivative Clinical
for the treatment of ovarian and breast carcinoma,
Microbial Rhizoxin Clinical
and has also important activity against other tumours Microbial UCN-01 Clinical
such as non-small cell lung cancer [22]. Irinote- Plant Neriifolin PrecUnical
can and topotecan are more water-soluble semi-syn- Plant Flavopiridol Clinical
thetic camptothecin derivatives which were approved Plant Perllyl alcohol Clinical
Pyrimidine base 5-Ethynyluracyl Clinical
for the treament of advanced colorectal [23,24],
and ovarian carcinoma [25-27], respectively. These From Cragg and Newman, 1999 [3].
agents have also shown clinical antitumour activity
in other malignancies of the adult and children [27].
Antitumour antibiotics such as doxorubicin, dauno- also attention in the laboratory, because of the similar-
mycin, bleomycin, mitomycin, streptozocin and deo- ity of their mechanism of action to the taxoids [32].
xycoformycin are clinically active agents against sev- Cytosine arabinoside, a synthetic analogue of the
eral types of cancers [28,29]. They were all isolated C-nuclesides initially isolated from the Caribbean
from Streptomyces species. Other microbe-derived sponge, Cryptotheca cripta, was the first and, so
metabolites under current development are rhizoxin, far, only, marine-derived compound routinely used in
deoxyspergualin, UCN-01 (7-hydroxystaurosporin), cancer therapy. It has significant antitumour activity
spicamycin (KRN5500), CC-1065 (bizelesin), and in leukaemias and lymphomas [33,34]. The system-
the rebeccamycin analogues [3,30,31]. The epithilone atic exploration of marine organisms as sources of
derivatives obtained from myxobacteria have gained novel bioactive agents initiated in the 1970s and
 Marine organisms and other novel natural sources of new cancer drugs
expanded markedly since the mid-1980s. Presently,
more than 2500 new metabolites were described
from a variety of marine sources, anticipating its
future role as a valuable source of novel chemical
classes not usually found in the terrestrial environ-
ment [35-37].
Several potentially interesting marine compounds
are in preclinical development. Discodermolide, a
metabolite of the deep-sea sponge Discodermia dis-
solute, was collected in the waters of the Bahamas,
and it was shown to induce microtubule stabilisation
[35]. Halichondrin B, first isolated from the sponge
Halichondria okadai in Japan has shown in vivo
activity against melanoma and leukaemia. It is being
currently obtained from the New Zealand deep-water
sponge Lissodendoryx. Isogranulatimide, an aromatic
alkaloid extracted from the Brazilian tunicate, ascid-
ian Didemnum granulation, acts as a G2 checkpoint
inhibitor. Its synthesis has been fully accomplished
and several analogues are being developed [36].
Experimental anticancer agents in phase I—II
trials
Tunicate derivatives
Of the marine compounds that have entered clini-
cal evaluation, three — didemnin B (DB), aplidine
(DDB) and ecteinascidin 743 (ET 743) — are de-
rived from tunicates. DB is a cyclic depsipeptide
isolated from the tunicate Trididemnum solidum and
was the first to enter phase I and II studies. In
phase II trials sponsored by the NCI, partial and
complete tumour responses were documented in pa-
tients with non-Hodgkin's lymphoma. However, DB
caused cardiotoxicity and was stopped in its further
development. DB also produced significant nausea
and vomiting, and isolated cases of hypersensitivity
reactions [36-38].
Aplidine was obtained from a Mediterranean colo-
nial tunicate, Aplidium albicans. It has a pyruvyl
group replacing the lactyl group in DB and its syn-
thesis has been achieved. It appears more active than
DB in preclinical models and apparently not car-
diotoxic. Aplidine entered clinical trials in 1999 both
in Europe and in the US under the sponsorship of the
Spanish company Pharma Mar.
The ecteinascidins (Ets) are derived from the Carib-
bean tunicate Ecteinascidia turbinata. Following a
period of supply problems, enough amounts of this
compound could be obtained from aquaculture and
synthesis. The derivative Ecteinascidin 743 (ET 743)
showed promising activity in murine and human tu-
237
II
r,
• o
>= 0
«A/V\
II I I
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Fig. 1. Chemical structure ET743.
mour models, and is currently in early clinical devel-
opment (Fig. 1) [39,40]. It is a tetrahydroisoquinoline
alkaloid that alkylates selectively guanine N2 from
the DNA minor groove, and this alkylation is reversed
by DNA denaturation. Therefore, it differs from other
DNA alkylating agents so far used in the clinic [40].
Dolastatins
The dolastatins are cytotoxic peptides, which can be
cyclic or linear, derived from the sea hare, Dolabella
auricularia, a mollusc from the Indian Ocean. Dolas-
tatin 10 and 15 are small peptides that were shown
to interact with tubulin. Dolastatin 10 (NSC 376128)
was selected for initial clinical development because
of its more favourable preclinical profile (Fig. 2). It is
extremely potent in vitro and it was shown to inhibit
microtubule assembly, tubulin-dependent guanosine
triphosphate (GTP) binding and inhibit vincristine
and vinblastine binding to tubulin. It causes cells to
accumulate in metaphase arrest and is modulated by
the MDR gene product [41,42].
Dolastatin 10 has in vitro activity against several
human leukaemia, lymphoma and solid tumour cell
lines with IC50S between 0.1 to 10 nM. It has doc-
umented antitumour activity in various human solid
tumour models, such as LOX#IMVI melanoma, OV-
CAR-3 ovarian carcinoma and NCI-H522 NSCLC
O CH3 OCH3O
H3CO
Fig. 2. Structure of dolastatin 10 (NSC 376128).
238 G. Schwartsmann
Fig. 3. Structure of bryostatin-1 (NSC 339555).
cell lines. In animal toxicology studies, myelosup-
pression was the dose-limiting toxicity. This agent
is highly bound to plasma proteins and pharmacoki-
netic studies in animals showed a rapid degradation
probably by hepatic metabolism [43,44].
This agent entered phase I trials as an i.v. bolus
injection every 3 weeks. The maximum tolerated
dose (MTD) was 300 mg/m 2 for heavily preteated
patients, while 400 mg/m 2 appears to be the MTD
for minimally pre-treated patients. The dose-limiting
toxicity (DLT) was myelosuppression, and local irri-
tation and phlebitis, and mild peripheral neuropathy
were also observed. Phase II trials are being initiated
in breast, colon, lung, ovarian and prostate cancer, as
well as lymphomas and leukaemias [45,46].
Bryostatins
Bryostatin-1 (NSC 339555) is a macrocyclic natural
lactone isolated from the marine Bryozoan, Bugula
neritina (Fig. 3). It has shown both antitumour as
well as immunomodulatory effects [47,48]. It is a po-
tent activator of the protein kinase C (PKC) family,
lacking tumour-promoting activity and with antag-
onistic effects on tumour-promoting phorbol esters.
This effect is probably related to down-regulation of
PKC or by specific isoform activation. It also stim-
ulates cytokine production, bone marrow progenitor
cells and neutrophils [49-51].
In vitro, bryostatin-1 has cytotoxic activity against
various leukaemia and solid tumour cell lines [50]. It
has also in vivo antitumour activity in various murine
models, including leukemia, lymphoma, ovarian can-
cer and melanoma. It was shown to enhance the
antitumour effects of various anticancer agents, such
as vincristine, cytosine arabinoside, cisplatin, mel-
phalan, paclitaxel and others. These effects may be
schedule-dependent [47,48,52].
This agent was studied in phase I trials at differ-
ent infusion schedules. The recommended doses for
phase II trials were 25-35 M-g/m2 when administered
over one hour for three of every four weeks; 25
u.g/m 2 given as a weekly 24 hour infusion. Myal-
gia was the DLT in all trials. Other toxicities were
joint aches and a transient decrease in platelet counts
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[53,54]. Notably, partial responses were reported in
patients with melanoma, ovarian cancer and NHL.
Phase II trials of bryostatin-1 are being conducted
at various infusion regimens in a large number of
tumour types in both solid and haematological ma-
lignancies. In addition, phase I trials of brystatin-1
in combination with other agents, such as cisplatin,
paclitaxel, fludarabine, vincristine, cytosine arabi-
noside and 2-CDA are also being conducted under
the sponsorship of the US NCI [51,53,54].
MGI-114
MGI-114 (6-hydroxymethylacylfulvene; HMAF;
NSC 683863) is a semisynthetic derivative of illudin
S, a naturally occurring sesquiterpene obtained from
the mushroom Omphalotus olearius, which exerts
its cytotoxic effect following its rapid intracellular
uptake, covalent binding to DNA, inhibition of DNA
synthesis and induction of apoptosis (Fig. 4). Bind-
ing to non-DNA cellular components appears also
important for cytotoxicity [55,56].
In preclinical models, this form of DNA damage is
more difficult to be repaired and requires functional
DNA helicase activity. MGI-114 has shown in vitro
cytotoxic activity in various human tumours and also
in paediatric tumours. In vivo studies in animals bear-
ing human tumour xenografts have shown antitumour
activity in MX-1 breast carcinoma, MV522 lung
CHjOH
HO"
Fig. 4. Structure of MGI-114 (NSC 683863).
 Marine organisms and other novel natural sources of new cancer drugs
adenocarcinoma, DU145 and PC-3 prostate, HT-29
colon carcinoma and HL60/MRI myeloid leukaemia.
It is also active in mdrl/gpl70 and other chemother-
apy-resistant tumours. In preclinical models, includ-
ing paediatric tumour cell lines, its antitumour effects
were shown to be synergistic with paclitaxel, topote-
can, irinotecan and 5-fluorouracil [55,56].
In a phase I study of MGI-114 given as a 5-minute
infusion daily for 5 days every 28 days, grade 3
thrombocytopenia and neutropenia, and reversible
renal damage were documented at a dose of 14
mg/m 2 /day. Other toxicities were nausea and vomit-
ing, fatigue, asthenia, local phlebitis, facial flushing,
alopecia and mucositis. Maximum plasma concen-
trations of MGI-114 in the range of levels required
for in vitro cytotoxicity were obtained in the patients
[57]. Therefore, the recommended dose for phase II
trials was 10.6 mg/m 2 /day for 5 consecutive days
every 4 weeks. The US NCI is currently sponsor-
ing trials in various solid rumours. A phase I trial
widi the above mentioned schedule is also being
performed in solid paediatric malignancies.
Flavopiridol
Havopiridol (NSC 649890) is the first cytotoxic
agent in clinical trials that targets cell cycle progres-
sion at either Gl or G2 via the inhibition of cyclin-
dependent kinases (CDKs). It is a synthetic flavone
derived from the plant alkaloid rohitukine isolated
from Amoora rohituka, and later from Dysoxylum
binectariferum (Fig. 5) [58]. It blocks cell growth
and causes apoptosis in various rumour cell lines.
It binds ATP competitively at the nucleotide-binding
site of CDKs. The G2 arrest is caused by both direct
inhibition of CDK1 and changes in the regulatory
phosphorylation of CDK1. The Gl arrest appears to
depend on the inhibition of CDK2 and CDK4. At
higher doses, flavopiridol also inhibits protein kinase
A and C [58,59].
It has in vitro antiproliferative activity with IC 50 s
between 50-200 nmol/1, and has been shown to be
synergistic with various anticancer drugs, such as cis-
Fig. 5. Structure of flavopiridol (NSC 649890).
239
platin, paclitaxel, 5-fluorouracil, cytosine arabinoside
and topotecan. For some agents, this effect was
schedule dependent (paclitaxel and 5-fluorouracil)
while not for others (cisplatin). In vivo antitumour
activity was demonstrated in colon, prostate, lung,
breast, ovary, gastric and renal carcinomas as well as
glioma, melanoma and lymphoma [58,59].
Phase I trials of flavopiridol given as a 3-day
continuous i.v. infusion every 14 days have been
performed [60]. The DLT was a secretory-type diar-
rhoea, and fatigue, asthenia, anorexia, local tumour
pain, and transient rise in bilirubin was also ob-
served. Objective responses were documented in pa-
tients with renal, gastric and colon cancer, and with
NHL. The recommended dose for phase II trials was
50 mg/m 2 /day x 3. The initial phase II trials will
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be conducted in patients with colorectal, prostate,
NSCLC, and renal cell carcinoma, and in patients
with non-Hodgkin's lymphoma and chronic lympho-
cytic leukaemia. Combination studies with cisplatin
or paclitaxel are also being initiated in patients with
advanced solid tumours.
CCI-779
CCI-779 [sirolimus 42-{3-hydroxy-2-(hydroxyme-
thyl)-2-methylpropanoate}; NSC 683864] is a sol-
uble structural analogue of rapamycin (sirolimus), a
macrolide antibiotic isolated from Streptomyces hy-
groscopicus. It causes cell cycle arrest at Gl through
the inhibition of signalling pathways that produce
inhibition of RNA translation. It has marked im-
munosuppressive effects by interacting with signal
transduction pathways that are critical for normal T
cell function as well as for tumour cells. CCI-779
binds to immunophilins, inhibiting their function
[61,62].
Being more water soluble and more stable than
rapamycin, CCI-779 was selected for preclinical and
potential future clinical development. It inhibits key
signal transduction pathways, such as those regu-
lated by p70s6 kinase and phosphorylated heat- and
acid-stable protein (PHAS-I). The above mentioned
inhibitory effect interferes with cell-cycle progres-
sion through Gl [63]. Preclinical studies suggested
that tumours with deletion of the p l 5 / p l 6 family of
CDK inhibitors, such as melanoma, may be espe-
cially susceptible to CCI-779 [62,63].
Two schedules of CCI-779 administration are being
evaluated in phase I trials, weekly and daily times five
every 2 weeks. Phase II trials are being planned for
breast, pancreas, colon, glioma, lymphoma, small-cell
lung cancer and melanoma [64].
240
H3C N
D-V4I
J
^CH-C 1
NH
•Cv O CH3
Fig. 6. Structure of depsipeptide (NSC 630176).
Depsipeptide
Depsipeptide (NSC 630176) is a biclyclic peptide
isolated from a strain of Chromobacterium vio-
laceum by Fujisawa Pharmaceutical Co. (Fig. 6).
It decreases mRNA expression of the c-myc onco-
gene and inhibits the growth of Hd-ras-transformed
NIH3T3 clonal cell line, Ras-1. It did not affect
DNA synthesis but causes cell cycle arrest at G0/G1.
More recently, it was demonstrated that it acts as an
inhibitor of a histone deacetylase [65,66].
It possesses potent preclinical antitumour activ-
ity both in vitro and in vivo. In vitro, depsipeptide
showed cytotoxic activity in various human solid
tumour cell lines, such as NSCLC, stomach, breast
and colon adenocarcinomas, with IC5Os of 0.3-3.2
ng/ml, and was less potent against cultured nor-
mal cells. This agent appears to be also a substrate
for MDR P-glycoprotein. In vivo, it showed anti-
tumour activity against various murine and human
solid tumours (such as stomach, colon, breast and
melanoma models) [65-67]. Two phase I trials of
depsipeptide are being conducted using a 4 hour
i.v. infusion weekly and twice-weekly, respectively,
every 21 days.
NSC D655649 (rebeccamycin analogue)
The rebeccamycin analogue (l,ll-dichloro-6-[2-A'-
diethylamino]-12,13-dihydro-12-(4-0-methyl-D-glu-
copyranosyl)-5H-indolo[pyrrolo[3,4-c]carbazole-5,7-
(6H)-dione; NSC D655649) is a synthetic antibiotic
with the antitumour properties of its less water-sol-
uble parent compound, rebeccamycin, which was
isolated from the actinomycete strain Saccharothrix
aewcolingenes found in the soil in Panama (Fig. 7).
It causes an unwinding of supercoiled DNA with-
out inducing single-strand or double-strand breaks
and also inhibits topoisomerase II by limiting strand-
passing ability. This compound showed in vivo an-
titumour activity against various murine models as
G. Schwartsmann
..CHa
1 LAM
Fig. 7. Structure of rebeccamycin analog (NSC 655649).
well as in human tumour xenografts, such as ESC
LOX melanomas and in the ESC RXK-393 renal
tumour models [68].
Downloaded from annonc.oxfordjournals.org by guest on December 7, 2010
Currently, three phase I studies of NSC D655649
in adults and one phase I trial in children are being
conducted. Two adult and one paediatric trial use a
single i.v. infusion every 21 days. The MTD is 572
mg/m 2 and the recommended dose for phase II is
500 mg/m 2 in adults. In children, the recommended
dose for phase II is 585 mg/m 2 . The DLT was
local irritation and phlebitis at the injection site, but
it became nausea and vomiting, myelosuppression
(mainly neutropenia) after the use of a central i.v.
line. Hyponatremia and elevations of liver enzymes
were also documented (ALT/AST). Phase I trials of
a 5-daily i.v. dose every 21 days revealed similar
toxicity profile and produced partial responses in
ovarian, gastric and cholangiocarcinoma [69].
Conclusion
Nature has given a major contribution to cancer ther-
apy. It contributed with the introduction of several
active agents that dramatically changed the natural
history of many types of human cancers. This new
wave of natural product derived experimental agents
is offering us the opportunity to evaluate not only
totally new chemical classes of anticancer agents,
but also novel and potentially relevant mechanisms
of action [73-75]. Marine compounds, for instance,
can interfere with very relevant intracellular targets
such as signal transduction, microtubule stabilisation
or new forms of interaction with DNA. They can
be extremely potent in culture, with IC50S in tumour
cell lines in the nanogram range [76,77]. Probably
they need potency and rapid penetration in cellu-
lar membranes to protect themselves efficiently in
an aquatic environment that rapidly dilute their poi-
sons. However, these compounds can be very toxic
to normal tissues as well. We are witnessing that
 Marine organisms and other novel natural sources of new cancer drugs
phenomenon with marine compounds that entered
clinical evaluation. The same holds true for other
plant- and microbial-derived experimental agents.
Therefore, the challenge of finding more selective
anticancer agents with a more favourable therapeutic
index still remains.
The search for new natural product derived com-
pounds for cancer treatment will continue through an
active international collaboration among researchers
in investigating rainforests, coral reefs and deep
subsurface thermal vents [70-72]. These efforts are
being expanded by recent advances in microbial
cultivation technology and nucleic acid extraction
from environmental materials. A large number of
novel living organisms that provide a tremendously
rich reservoir of genetic and metabolic diversity are
being identified. Furthermore, manipulation of mi-
crobial biosynthetic pathways making use of genetic
. engineering has allowed the production of interest-
ing molecules not generated naturally [3,72,73,78].
These unique sources of novel compounds will cer-
tainly make anticancer drug discovery even more
challenging in the next years.
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