865

Review
ISSN 1462-2416 Pharmacogenomics (2010) 11(6), 865878 10.2217/PGS.10.69 2010 Future Medicine Ltd
Wide-spectrum characterization of trabectedin:
biology, clinical activity and future perspectives
After World War II, the US National Cancer
Institute (MD, USA) carried out a wide-ranging
program of screening marine plant and animals
in order to nd new and promising antineoplas-
tic agents. Among several agents tested in clinical
trials (TABLE 1), extracts from the Caribbean tuni-
cate Ecteinascidia turbinata, later named ectein-
ascidins (ETs), were shown to exert antitumor
activity [1,2]. The small amount of ETs in E. tur-
binata prevented their isolation for over a decade.
The structure of one of these, ET-743, was
nally determined in 1984 and chemically syn-
thesized in 1996 [3,4]. Later, ET-743, or trabect-
edin (Yondelis

, PharmaMar, Madrid, Spain),

was the rst representative of a marine natural
product to receive marketing authorization [5].
Trabectedin has raised a growing interest
in the last few years because of its proven ef-
cacy in the treatment of advanced soft tissue
sarcoma (STS). Given the recent introduction
of this new compound into clinical use, a com-
plete revision of its mechanisms of action (still
not completely understood), the preclinical and
clinical evidences that brought it to its approval
in Europe, and its main side effects and their best
management is needed.
Drug purication, biosynthesis
& structure
As extensively reviewed by Cuevas and
Francesch [5], the diff iculties faced when
develop ing sufcient supplies of trabectedin
have represented a severe limitation on its use
for a long time.
The tunicate normally lives in coastal shal-
low waters (015 m depth) and in lagoons. It
is distributed throughout the Caribbean and
in the temperate regions of the Atlantic and
the Mediterranean.
Before 1997, PharmaMar started both a
wide aquaculture program and a chemical syn-
thesis program, in order to produce enough
ET-743 for preclinical and clinical use.
For the aquaculture program, two main
methodological approaches were developed: sea
farms and inland facilities. In 2004, all of the
Mediterranean aqua farms collectively produced
approximately 100 metric tons of tunicate bio-
mass. However, as a consequence of the isolation
and purication procedures, the nal yields of
ET-743 were of very low concentrations. Thus,
in order to achieve the future commercialization
of the drug, it was necessary to develop a syn-
thetic process to produce ET-743, so as to avoid
the dependence on the natural source.
Since 1996, when the Corey group published
the complete synthesis of ET-743 [4], several
groups have improved the synthesis process,
but the manufacture of ET-743 on an indus-
trial scale was still not possible. Nevertheless,
in 2003, PharmaMar successfully developed a
short and straightforward semisynthetic process
starting from cyanosafracin B, an anti biotic
obtained by fermentation from the bacteria
Pseudomonas uorescens [6,7]. In addition, other
synthetic or semisynthetic approaches have
been reported from a large number of research
groups [816].
Ecteinascidin-743 (trabectedin, Yondelis

; PharmaMar, Madrid, Spain), a 25-year-old antineoplastic

alkylating agent, has recently shown unexpected and interesting mechanisms of action. Trabectedin causes
perturbation in the transcription of inducible genes (e.g., the multidrug resistance gene MDR1) and
interaction with DNA repair mechanisms (e.g., the nucleotide excision repair pathway) owing to drug-
related DNA double strand breaks and adduct formation. Trabectedin was the rst antineoplastic agent
from a marine source (namely, the Caribbean tunicate Ecteinascidia turbinata) to receive marketing
authorization. This article summarizes the mechanisms of action, the complex metabolism, the main
toxicities, the preclinical and clinical evidences of its antineoplastic effects in different types of cancer
and, nally, the future perspectives of this promising drug.
KEYWORDS: adducts n cancer n double strand breaks n ET-743 n MDR1 n NER
n ovarian n sarcomas n therapy n trabectedin
Bruno Vincenzi
1
,
Andrea Napolitano
1
,
Anna Maria Frezza
1
,
Gaia Schiavon
1
,
Daniele Santni
1
&
Giuseppe Tonini
1
1
University Campus Bio-Medico,
Medical Oncology, Via Alvaro del
Portllo 200, 00128 Rome, Italy

Author for correspondence:

Tel.: +39 339 319 9912
b.vincenzi@unicampus.it
For reprint orders, please contact: reprints@futuremedicine.com
Pharmacogenomics (2010) 11(6)
866 future science group
Review Vincenzi, Napolitano, Frezza, Schiavon, Santini & Tonini
Ecteinascidin-743 is composed of three
fused tetrahydroisoquinoline rings (FIGURE 1) [17]:
two of the rings (units A and B) recognize
and bind covalently to the minor groove of
the DNA double helix; the third ring (unit C)
protrudes out of the minor groove and inter-
acts directly with transcription factors, nota-
bly the nucleotide excision repair (NER)
endo nuclease, XPG [18]. Contrasting evidence
currently exists regarding the necessity of this
subunit for the specic biological responses
induced by ET-743 [19,20].
Trabectedin mechanisms of action
n Trabectedin alkylating mechanisms
The antitumor mechanisms of action of ET-743
are various and not entirely understood. One
of ET-743s most studied properties is its abil-
ity to interact with DNA. This property has
been proposed on the basis of biochemistry,
NMR spectro scopy, x-ray crystallography and
molecular modeling data indicating structural
similarities with other antibiotics containing
tetrahydroisoquinoline [2124].
Ecteinascidin-743 contains a carbinolamine
center at the N2 position. The elimination of
the adjacent 21-OH group results in a Schiff
base that is vulnerable to nucleophilic attack.
Therefore, the binding of ET-743 to the exo-
cyclic 2-amino group of guanine in the DNA
minor groove leads to DNA alkylation.
Some important characteristics differenti-
ate ET-743 from other minor groove mono-
alkylating agents: a unique ability to bend
DNA towards the major groove by alkylating
the minor groove, duplex stabilization and
extrahelical protrusion of the C-subunit [25].
Interestingly, the alkylation reaction is not
random but DNA sequence specic (5-PuGC,
5-PyGG) [26]. This specicity seems to be
mainly related to slower rates of the reverse
dealkylation reaction in favored bonding
sequences rather than in nonfavored ones
(5-AGT), probably owing to more stable
conformational changes [27].
A very important point is the specicity
of cellular proteins able to bind to ET-743-
alkylated DNA sequences. Remarkably, the
minor groove alkylation causes an interference
in the DNA-topoisomerase I cleavage sites. At
high concentrations (i.e., micromolar levels),
ET-743 causes a topoisomerase I-induced for-
mation of cleavage complexes enzyme-linked
and -mediated DNA strand breaks which
are the catalytic intermediates of topoisomer-
ization reactions. On the other hand, it traps
and stabilizes these complexes [28], functionally
resembling topo isomerase poisons [29]. Using
pharmacologically reasonable concentrations
of ET-743 (i.e., nanomolar levels) in sensitive
cells, no DNA breakage or DNA/protein cross-
links are seen [30], suggesting only an ancillary
role of topoisomerase I poisoning in ET-743
cytotoxicity [31].
In a similar manner, the DNA binding of
several transcription factors, notably SRF/TCF
and NF-Y, is impaired at concentrations in the
50-M range, which is still much higher than
the concentrations that cause cellular cyto-
toxicity. Nevertheless, the specicity of alkyl-
ated DNAprotein interactions is conrmed by
the evidence that other transcriptional factors
(e.g., MYB and MYC) can bind to the DNA
even at very high concentrations of ET-743
(300 M), as alkylation does not involve the
binding sequences of those specic transcription
factors [32].
The main pharmacological activity of ET-743
is thus mostly independent of an alkylation-
dependent inhibition of the DNA binding of
proteins or transcription factors. In fact, on the
basis of DNAprotein molecular modeling, it
has been shown that ET-743 can target DNA
with two or more molecules simultaneously and
that the DNAET-743 covalent complex are
virtually superimposable to the minor grooves
of DNA when bound to the zinc ngers of
transcription factors [33]. This structure is also
strongly reminiscent of an RNADNA hybrid,
and these striking similarities raise the inter-
esting hypothesis that ET-743 preferentially
targets the minor groove of DNA when bound
to a zinc-nger-containing transcription factor
by the exposition of a more readily accessible
2-amino group of guanine [34].
n Trabectedin & perturbation of
transcription & cell activities
Preincubation of ET-743 with the transcription
factor NF-Y causes inhibition of DNA bind-
ing at lower concentrations compared with the
Table 1. Some Phase II marine natural products.
Compound Source organism Chemical class
Ecteinascidin-743 Ecteinascidia turbinata Tetrahydroisoquinolone alkaloid
Dolastatin 10 Dolabella auricularia
Symploca sp.
Linear peptide
Bryostatin 1 Bugula neritina Macrocyclic lactone
Kahalalide F Elysia rufescens/Bryopsis sp. Cyclic depsipeptide
Squalamine Squalus acanthias Aminosteroid
Dehydrodidemnin B Trididemnum solidum Cyclic depsipeptide
www.futuremedicine.com 867 future science group
Wide-spectrum characterization of trabectedin Review
pre incubation with DNA, suggesting that the
protein rather than the minor groove is the
target [31].
Furthermore, since the inhibition is extremely
rapid (1 min) and the effect is observed at
pharmaco logical concentrations, it is probably
due to the C-subunit or the DNA bending to
the major groove. Transcriptional activation of
NF-Y-dependent genes is likely to be one of the
main cytotoxic mechanisms of ET-743 action [35].
Among the inhibited genes, the most prom-
ising targets code for MDR1 (P-glycoprotein
[P-gp]), HSP79 and collagen I. ET-743 is the
rst pharmacologically relevant agent to prevent
the activation of both MDR1 [36] and HSP79 [34]
transcription by multiple stress inducers (i.e., his-
tone deacetylase inhibitors and UV irradiation),
without affecting their constitutive expression.
ET-743 may thus selectively inhibit activation of
MDR1 expression in tumor cells without affect-
ing constitutive expression in normal cells, but
acting as a specic antitumoral transcriptional
regulator. Preclinical studies have also conrmed
that ET-743 is an effective agent in MDR1-
overexpressing cells [37], despite the hypothesis
that P-gp overexpression contributes to ET-743
resistance in an ovarian cell line [38].
In a similar manner, ET-743 is responsible for
a dose-dependent downregulation of COL1A1
(the gene coding for pro-a1 chain of collagen I)
expression [39]. These data were conrmed by the
particular ET-743 cytotoxicity in mesenchimal
tumors (i.e., sarcomas) and by the ana lysis of a
ET-743-resistant sarcoma cell line, in which pro-
longed exposure to ET-743 caused changes in cell
function through cytoskeleton rearrangement
and/or modulation of collagen levels [40].
Moreover, it has been reported that ET-743
is responsible for a unique microtubule
disorganization in vitro [41].
Further links between transcriptional
inhibition and ET-743 action have not been
investigated. ET-743 has been proved to also
inhibit NF-Y-independent transcription (Sp1-
mediated [42] or SXR-mediated transcription).
SXR inhibition is particularly interesting because
SXR regulates both drug efux (by activating the
expression of the MDR1 gene [43]) and metabo-
lism (by activating the cytochrome P450 (CYP)
CYP3A4 gene [44]). Moreover, gene-expression
ana lysis through microarray technology has
identied selected groups of genes inhibited by
low doses of the drug in different cell lines [45,46].
Remarkably, another important indication of
the unusual antiproliferative effect of ET-743 is
its predominant activity in the G1 phase of the
cell cycle, eventually resulting in a G2/M block,
a different mode of action to other alkylating
agents, [24]. This effect has been conrmed by the
ana lysis of differential ET-743 activity on G1/S
promoters and nucleosomes [47].
The complex antiproliferative activity of
ET-743 involves other mechanisms: an high-
dose transcription-independent effect leading
to rapid apoptosis involving mitochondria, JNK
and caspase-3 [48], and a low-dose transcription-
coupled block of the cell cycle involving the NER
pathway [49].
n Trabectedin & DNA
repair mechanisms
Since mammalian cell lines lacking NER gene
products are resistant to ET-743, a novel mech-
anism of cell-cycle block based on the NER
pathway was recently hypothesized [48,50].
The mechanism of action is probably very
similar to that of the topoisomerase I poison-
ing: ET-743 traps an intermediate in the NER
processing of DNA adducts. This trapped inter-
mediate proteinET-743DNA adduct complex
could be responsible for ET-743 cell toxicity [51].
In particular, the NER protein Rad13 seems to
be crucial for ET-743 cytotoxic effect by the for-
mation of a Rad13DNAET-743 ternary com-
plex, resulting in cell death [22]. The crucial role
of this pathway is demonstrated by the evidence
that restoration of NER function sensitizes cells
to ET-743 treatment [52].
Investigating cell-cycle phase perturbation, the
cells with functional NER appear to overcome
the G1 block more easily, but are then blocked
in the G2/M phase, suggesting that the NER
mechanism itself leads to some sort of persistent
DNA damage [53]. Unrepaired adducts probably
mediate the damage by arresting and degrading
O
O
N
N
O
NH
O H
O
O
O
S
OH
O H
O
Subunit B
Subunit C
Subunit A
Figure 1. Ecteinascidin-743 and its three fused tetrahydroisoquinoline rings.
Pharmacogenomics (2010) 11(6)
868 future science group
Review Vincenzi, Napolitano, Frezza, Schiavon, Santini & Tonini
DNA polymerase II [54] and by forming DNA
double strand breaks (DSBs), monitored by the
activation of g-H2AX and Rad51 foci [55], even
though several other studies showed no DNA
breaks unless at micromolar concentrations of
ET-743 [23,24].
In 2008, a owchart of molecular pathways
involved in ER-743 cytotoxicity was proposed.
According to the authors, there are two types
of DSBs produced by ET-743: trascription-
coupled DSB involving the NER pathways and
replication-coupled DSB involving the ATM
pathway independently from trascription-cou-
pled DSB [56]. Moreover, it has been recently
shown that Von HippelLindau tumor suppres-
sor protein deciency made the cells resistant to
ET-743-induced cell death with a similar effect to
NER deciency. The Von HippelLindau com-
plex could act in promoting DNA polymerase II
degradation in DNA damaged cells [53].
Finally, recent evidence suggests that the
homologous recombination pathway respon-
sible for DNA break repair is essential for
ET-743 cytotoxicity, at least as much as the other
previously mentioned pathways. In fact, cells
lacking the homologous recombination path-
way were extremely sensitive to the drug with
an approximately 100-fold decrease in IC50 [57].
In a similar way, the Fanconi anemia pathway
seems to be very important in the DNA repair
of ET-743 DNA adducts that might functionally
mimic an interstrand DNA crosslink (ICL) [33,58].
Indeed, cells with mutations in any of the tested
Fanconi anemia genes are extremely sensitive to
ET-743 [59], whose behavior mimics that of the
ICL-forming drugs (e.g., mitomycin C) [60].
As previously described, ET-743 has a very
complex mechanism of action via DNA alkyla-
tion and protein interactions. Nevertheless,
ET-743 is an alkylating agent, and its main
pharmacological action seems to be due to both
transcriptional regulation of inducible genes and
to DNA DSB and ICL-like adducts (FIGURE 2).
Myxoid liposarcoma and could lead to the
association of ET743 with compounds acting
on lipogenic pathways.
n Trabectedin & differentiation in
myxoid liposarcoma tumors
Among the different mechanisms of action
ascribed to ET-743, one of the most fascinating
is its potential ability to induce differentiation
in specic histotypes of STS, such as myxoid
liposarcoma. Myxoid liposarcoma is character-
ized by a fusion between the cyclophosphamide,
hydroxydaunorubicin (doxorubicin), Oncovin

(vincristine; Genus Pharmaceuticals, Newbury,
UK) and prednisone/prednisolone (CHOP)
transcription factors and the FUS or EWS genes,
which is probably one of the key points to its
pathogenesis; ET743 has been proven to be par-
ticularly effective in this subtype of sarcoma.
One hypothesis is that the activity of trabectedin
is related to the inactivation of the FUSCHOP
oncogene: Forni et al. reported that trabectedin
causes detachment of the FUSCHOP chimera
from targeted promoters. Reverse transcription
PCR and chromatin immunoprecipitation ana-
lysis in a myxoid liposarcoma line and surgi-
cal specimens of myxoid liposarcoma patients
in vivo show activation of the CAAT/enhancer
binding protein-mediated transcriptional pro-
gram that leads to morphologic changes of
terminal adipogenesis.
Trabectedin metabolism & toxicities
n Trabectedin metabolism
Data regarding ET-743 metabolism are still
limited. In vitro experiments consisting of drug
incubation with a human lymphoblast-expressed
CYP3A4 isoform suggested the presence of at
least three metabolites [301].
With an initial in vivo evaluation, no metab-
olites were observed in urine, serum or bile
samples from patients treated with intravenous
ET-743, whereas deacetylated ET-743 was found
after plasma incubation [61]. Recent evidence
obtained by using [
14
C] ET-743 proved that the
drug is quickly metabolically converted by the
liver to a large number of compounds excreted
in both urine (510% of total) and feces (major
excretory pathway) [62,63].
The presence of O-glucuronidated and
glutat hione-conjugated metabol ites i s
likely [64], although the inhibition of phase II
enzy mes, such as UDP-glucuronosyltransferase,
N-acetyltransferase, sulfotransferase and gluta-
thione S-transferase, did not show any signicant
inuence on the cytotoxicity of ET-743 [65].
The most important ET-743 biotransforma-
tion pathway is the enzymatic conversion by liver
microsomal proteins (~50% of the total conver-
sion). Two main chemical products are formed
during the microsomal breakdown: ET-743S1
and ET-743S2. Two other molecules, ET-743M5
and ET-743M6, are undoubtedly metabolites
of ET-743S2 [301]. ET-743 biotransformation at
the microsomal level is mainly due to CYP3A4,
2C9, 2C19, 2D6 and, to a minor extent, 2E1 [66].
These data have been conrmed in vitro by the
increased cytotoxicity of ET-743 (measured as
IC50 decrease) observed in a HepG2 cell line after
www.futuremedicine.com 869 future science group
Wide-spectrum characterization of trabectedin Review
incubation with CYP inhibitors [63]. Interestingly,
male microsomes showed a signicantly lower
ET-743 biotransformation rate, probably owing
to the different amounts of CYP3A4 and other
CYPs in the microsomal preparations. Typically,
higher quantities of CYP3A4 and faster conver-
sion of ET-743 were observed for female micro-
somes compared with male microsomes, with
CYP3A4 as the major isozyme involved in ET-743
biotransformation (~95%) [64].
Therefore, since CYP3A4 has an important
role in ET-743 metabolism, the risk of in vivo
drugdrug interactions must be considered
when the agent is combined with other CYP3A4
substrates [67].
Finally, given the complexities of ET-743
metabolism, it is unlikely that a single poly-
morphism or the inhibition of a single metabolic
pathway can change its metabolic prole.
n Trabectedin toxicities
The liver is a key organ not only for ET-743
metabolism but also for its collateral effects.
Preclinical studies in animals demonstrated liver
toxicity as an important side effect of ET-743. In
these studies, the female rat was identied as the
species with the highest risk of hepatotoxicity
from ET-743 [68]. Repeated treatment cycles were
able to increase the extent of clinical chemistry
changes, suggesting cumulative toxicity [69].
The unusual form of ET-743 hepatotoxicity in
female rats consists of damaged biliary duct epi-
thelia accompanied by inammation followed by
peribiliary brosis. The pathological alterations
were accompanied by defects of liver function,
such as dramatic elevation of plasma bilirubin lev-
els, moderate increases in plasma levels of alkaline
phosphatase (ALP) and aspartate transaminase
(AST) and a decrease in hepatic CYP activity [70].
In fact, together with dose-limiting myelo-
suppression (i.e., neutropenia and thrombo-
cytopenia), the main ET-743 toxicities registered
during clinical trials were acute (but revers-
ible) transaminitis and subclinical cholangitis,
characterized by increases in ALP and/or
bilirubin [71].
Interestingly, it has been shown that high-
dose dexamethasone administered 24 h before
ET-743 protects rats from hepatotoxicity with-
out compromising antitumor activity. This effect
has been rstly assigned to the dramatic dexa-
methasone-induced reduction of ET-743 hepatic
levels via the induction of the CYP enzyme
CYP3A [72]. Considering the side effects of high-
dose dexamethasone [73,74], the hepatoprotective
effect of other CYP3A inducers have been tested
for a potential use in humans. Indole-3-carbinole
(I3C), a potent inducer of CYP enzymes [75], is
the hydrolysis product of glucosinolates present
in cruciferous vegetables, such as broccoli and
Brussels sprouts. As expected, the food intake of
I3C protected against the detrimental hepatic
effects of ET-743 without interfering with its
antitumor activity in a model of mammary
carci noma. Surprisingly, ingestion of I3C did not
decrease hepatic levels of ET-743 in comparison
with animals who received ET-743 alone, sug-
gesting that CYP induction is not the main hepa-
toprotective event. Thus, the interference with
NF-kB transcriptional activity is the most attrac-
tive candidate mechanism to explain hepatopro-
tection, as it is common to ET-743 antidotes, I3C
and dexamethasone [76]. These data were con-
rmed by the evidence that the protection pro-
vided by a pretreatment with b-naphthoavone
and phenobarbitone, two other CYP inducers,
was not as effective in vivo as dexamethasone.
Pretreatment with N-acetylcysteine, a non-CYP-
inducing hepatoprotective drug, did not protect,
from ET-743-induced liver changes [77]. Recent
studies assessed the capability of sandwich-
cultured primary rat hepatocytes to predict the
hepatoprotective effect of dexamethasone, attrib-
uted, at least in part, to enhanced multidrug
resistance-associated proteins biliary excretion
and increased metabolism by CYP3A1/2 [78].
ET-743 RAD13 NF-Y
DNA breaks
DNA alkylation
and bending
Transcriptional
regulation
Figure 2. Ecteinascidin-743 mechanism of action.
ET-743: Ecteinascidin-743.
Pharmacogenomics (2010) 11(6)
870 future science group
Review Vincenzi, Napolitano, Frezza, Schiavon, Santini & Tonini
There are poor data regarding the mechanisms
of hepatoxicity and hepatoprotection in humans.
A recent meta-ana lysis showed that dexametha-
sone pretreatment increases ET-743 systemic
clearance by 19% by increasing bile ow [79]. A
recent pharmacokinetic/pharmacodynamic ana-
lysis predicted an enhancement of ET-743 safety
and efcacy after administration of dexametha-
sone and a dose-reduction strategy based on the
serum concentration of liver enzymes [80].
As mentioned earlier, the other important and
dose-limiting ET-743 toxicity is represented by
myelosuppression. Reversible dose-dependent
neutropenia was the most frequently reported
toxicity in Phase II studies, with median nadir
values observed at approximately 14 days [81].
ET-743-induced neutropenia is largely dependent
on the intensity of dose administered and inter-
dose intervals, but not the duration of intravenous
infusion [82].
A pharmacokinetic/pharmacodynamic meta-
ana lysis showed that the pharmacological effect
of ET-743 on absolute neutrophil count was
more closely related to drug concentrations in
a hypothetical effect compartment, representa-
tive of bone marrow, rather than from the central
plasma compartment, with ET-743 reducing the
proliferation rate and stimulating the killing rate
of progenitor cells [81]. In mice, ET-743 toxic-
ity was lower in stem cells than in committed
progenitors, suggesting an unlikely long-term
myelosuppression as a consequence of ET-743
treatment [83]. Other in vitro evidence suggests
a direct immuno modulatory effect of ET-743
through inhibited differentiation of monocytes to
macrophages and reduced production of CCL2
and IL-6 [84].
Interestingly, advanced sarcoma patients
receiving dexamethasone before starting ET-743
experienced lower liver and bone marrow toxici-
ties than patients not receiving dexamethasone,
even though any relationship between the two
toxicities remains to be elucidated [85].
Moreover, several case reports described another
rare toxicity of ET-743 treatment: rhabdo myolysis.
In a Phase I trial, one patient experienced grade
4 rhabdomyolysis, renal failure requiring dialy-
sis, grade 4 neutropenia and grade 3 thrombo-
cytopenia. Hepatic toxicity in this patient was not
reported [86]. Two cases of rhabdomyolysis were
reported in a subsequent French Phase II trial [87],
as well as in another European Phase II study [88].
It has been shown that elevated intercycle peaks
of ALP and AST, as well as increased baseline bili-
rubin, are independent predictors of multiorgan
toxicities [89]. For this reason, the differences in
toxicities between European and American trials
may be due to a greater degree of dose adjustment
in the USA based on liver enzymes. However, a
fatal rhabdomyolysis case has been reported by a
US group [90].
Finally, skin and soft tissue damage have been
reported after ET-743 extravasation from a central
venous access device [91].
Preclinical & clinical evidences
The rst preclinical evidence of ET-743 antitu-
mor activity is relatively recent. Approximately
10 years ago, the effect of ET-743 was dem-
onstrated in human tumors explanted from
patients [92], ovarian carcinoma [93,94], melanoma
and non-small-cell lung cancer [93] xenografts. In
human STS cell lines explanted from chemonaive
patients, gene-expression prole ana lysis revealed
the upregulation of 86 genes and the down-
regulation of 244 genes in response to ET-743,
suggesting an important impact in tumor cell
biology [95]. Interestingly, ET-743 promoted dif-
ferentiation in myxoid liposarcoma tumors by
detachment of the pathogenic FUSCHOP
chimera protein from its promoters [96].
Ecteinascidin-743 also showed sequence-
dependent synergistic cytotoxicity with pacli-
taxel (administered before ET-743) in human
breast cancer cell lines in vitro and in vivo [97],
and with paclitaxel (administered before ET-743)
or doxorubicin (administered after ET-743) in
STS cells [98].
An additive or additive-to-synergistic effect
was seen in vitro with ET-743 simultaneously
or after cisplatin [99], irinotecan [100] or doxo-
rubicin [101] in human rabdomyosarcoma or
ovarian cancer cell lines and in a range of
human tumor xenografts, including rhabdo-
myosarcoma, brosarcoma, non-small-cell lung
cancer and ovarian cancer. Relevant effects have
been also seen both in drug-sensitive and drug-
resistant bone tumor cells [102]. Moreover, com-
bination therapy with ET-743 and plasminogen-
related protein B caused increase in human
chondro sarcoma necrosis by antagonizing
tumor-associated microvessel formation [103].
Finally, ET-743 exerts cell line-dependent
radiosensitizing properties. Initial evidence sug-
gested a moderate effect only with cytotoxic con-
centrations of ET-743 [104], but more recent nd-
ings showed a signicant in vitro radiosensitizing
effect and the induction of cell-cycle changes and
apoptosis in several human cancer cell lines in
the presence of pharmacologically appropriate
(within the nanomolar range) concentrations of
the drug [105].
www.futuremedicine.com 871 future science group
Wide-spectrum characterization of trabectedin Review
Several in vitro studies attempted to elucidate
the mechanisms of cellular resistance to ET-743.
MDR1 seems not to be crucial, since ET-743 is
clearly a P-gp substrate, but it makes the cells
resistant to ET-743 only when expressed at very
high levels [106]. Conversely, other pathways
seem to be important, for example IGF-1 recep-
tor for Ewings sarcoma cell line TC-71 [107], and
collagen I for chondrosarcoma cell line CS-1 [39].
A further conrmation of this hypothesis is
that resistance to ET-743 did not correlate with
resistance to doxorubicin [108], indicating that
the two drugs may act through different mecha-
nisms. For example, p53 mutations and deletions
in sarcoma cells correlate with extreme sensitivity
to ET-743 [109], whereas wild-type p53 sensitizes
cells to doxorubicin by downregulating MDR1
expression [110]. Moreover, in vitro ET-743 pre-
vented MDR1 gene expression, showing a syn-
ergistic cytotoxic effect with doxorubicin (a
well-known MDR1 substrate) [98].
Finally, a human chondrosarcoma cell line
resistant to ET-743 exhibited crossresistance to
cisplatin and methotrexate but not to doxoru-
bicin. Zinc nger proteins, especially ZNF93,
are thought to be involved in mechanisms of
resistance, probably because of their role in DNA
damage repair [111].
Following the preclinical studies, a large
number of clinical trials have been carried out
in order to evaluate the in vivo effect of ET-743.
A large number of Phase I trials included patients
with any solid malignancies, without focusing
on specific diseases, who were preclinically
more sensitive to ET-743. TABLE 2 shows maxi-
mum tolerated doses, dose-limiting toxicities
and synergies data.
These results suggested that maximum tol-
erated dose slightly changes with the sched-
ule (11001800 g/m
2
) and the dose-limiting
toxicities are mainly hematological toxicities
(i.e., neutro penia and thrombocytopenia) and
asthenia rather than transient transaminase ele-
vation. It should be highlighted that ET-743 does
not interact with other common chemotherapeu-
tic agents (e.g., doxorubicin, gemcitabine and
cisplatin) from a pharmacodynamic/pharmaco-
kinetic point of view. Therefore, combination
therapies could be suitable and useful in the
management of advanced diseases.
Several Phase II trials have been carried out
and are currently ongoing in patients with cer-
tain tumors, leading to more specic and clini-
cally useful results. ET-743 seems to be a very
promising drug indeed for the treatment of a
wide spectrum of tumors.
Nevertheless, ET-743 failed to show signi-
cant cytotoxicity against gastrointestinal stromal
tumors [112,113] and pretreated advanced colorectal
cancer [114].
However, several studies reported interesting
rates of responses or disease stabilization during
ET-743 therapies with Phase II toxicities over-
lapping Phase I ones, thus conrming the clinical
impact of the drug. The most promising results
have been achieved against STS (especially leio-
myosarcomas and myxoid liposarcoma) and ovar-
ian cancers (TABLE 3). Retrospective studies con-
rmed ET-743 efcacy in advanced pretreated
STSs [115] and advanced pretreated myxoid lipo-
sarcomas [116,117]. A case report showed a durable
objective response lasting at least 8 months in a
case of advanced, recurrent and refractory uter-
ine leiomyosarcoma treated with 1200 g/m
2
intravenous ET-743 over 24 h every 3 weeks [118].
In evaluating clinical trials results, it should
be noted that a recent report suggested the inad-
equacy of size-based response criteria (Response
Evaluation Criteria In Solid Tumors) to assess
the efcacy of ET-743 in metastatic sarcoma
patients [119].
More recent trials (recently completed, active
or recruiting) will give further information on
ET-743 cytotoxicity in several types of cancer
(advanced prostate cancer, STS, ovarian cancer,
breast cancer, mesothelioma, endometrial carci-
noma, primary peritoneal cavity cancer and fal-
lopian tube cancer) and on ET-743 potential heart
toxicity (altered ECG QT intervals)[201].
In Europe, ET-743 in monotherapy
(1.5 mg/m
2
as a 24-h continuous infusion every
3 weeks) is currently the only agent approved
as a second-line treatment in the treatment of
advanced STS after the failure of anthra cycline-
and ifosfamide-based regimens. The drug
received orphan drug status from the European
Commission for the treatment of ovarian can-
cer in October 2003. The US FDA granted
ET-743 orphan drug status for both STS and
ovarian cancer.
As for trabectedin hepatic effects, plasma liver
enzymes level (transaminases, bilirubin, alkalin
phosphatases and 5-nucleotidase) should be
checked before each course, because patients
with any baseline alterations have a signicantly
higher probability of developing severe liver tox-
icity. The risk of developing grade 34 toxicities
seems to be strongly reduced through premedi-
cation with dexamethasone (4 mg orally twice
daily 24 h before therapy). A study by Grosso
et al. showed how elevation of transaminases,
neutropenia and thrombocytopenia incidence
Pharmacogenomics (2010) 11(6)
872 future science group
Review Vincenzi, Napolitano, Frezza, Schiavon, Santini & Tonini
are signicantly lower in patients pretreated
with dexamethasone (2%, 2% and 0) then in
not premedicated patients (34, 24 and 25%,
respectively) [84].
Putative predictive factors of activity
As soon as the rst promising effects of ET-743
appeared, strong efforts were made to identify
putative predictive factors of activity and to reli-
ably select subpopulations of patients who may
benet from ET-743 therapy.
The complex ET-743 metabolism seems to
exclude CYP genes as potential candidates.
NER protein levels rather than mRNA levels
seem to be more promising [142]. Moreover, it
has been recently proposed that screening for
mutations in Fanconi anemia genes may facili-
tate the identication of tumors displaying
enhanced sensitivity to ET-743 [59].
No clear putative predictive factors of
ET-743 activity have been identied so far.
Therefore, greater efforts are needed in studies
investigating such aspects.
Conclusion & future perspective
Ecteinascidin-743 is a novel natural anti-
cancer agent, now synthetically produced,
with unique mechanisms of action involving
DNA alkylation, transcriptional repression and
NER/homologous recombination-dependent
cell-cycle blocking. The metabolism of ET-743
is quite complex amd is mainly achieved
through liver microsomal CYPs.
Preclinical and clinical evidence has dem-
onstrated how trabectedin combines a favor-
able tolerability prole with proven efcacy
in the treatment of advanced STS and ovar-
ian cancer. Moreover, ET-743 does not seem
Table 2. Phase I concluded clinical trials.
Drug(s) Tumors Administration Results Ref.
ET-743 Resistant solid
tumors
24 h intravenous q21 MTD: 1800 g/m
2
1500 g/m
2
dose is clinically feasible
DLTs: severe thrombocytopenia and neutropenia
[121,122]
ET-743 STSs 24 h intravenous q21
1500 g/m
2
Risk of severe toxicity enhanced in patients with
hepatic dysfunction
Dexamethasone co-treatment decreased incidence of
severe toxicity and AUC
[123]
ET-743 Solid tumors 72 h intravenous q21 MTD: 1200 g/m
2
DLTs: neutropenia, thrombocytopenia and fatigue
[86]
ET-743 Solid tumors 1 h intravenous q21 vs 3 h
intravenous q21
1 h MTD: 1100 g/m
2
1 h DLTs: thrombocytopenia and fatigue
3 h MTD: 1800 g/m
2
3 h DLTs: pancytopenia and fatigue
1650 g/m
2
dose is clinically feasible
[124]
ET-743 Refractory solid
tumors in children
3 h intravenous q21 Premedication with dexamethasone followed by
1100 g/m
2
dose
[125]
ET-743 Advanced solid
tumors
1 h intravenous for 3 wks
q28 vs 3 h intravenous for
3 wks q28
1 h MTD: 610 g/m
2

3 h MTD: 580 g/m
2

DLTs: febrile neutropenia and fatigue
[126]
PLD plus ET-743 Advanced solid
tumors
1 h intravenous PLD
(30 mg/m
2
), then 3 h
intravenous ET-743 q21
MTD
ET-743
: 1100 g/m
2
ET-743 plus PLD generally well tolerated
[127]
Gemcitabine plus
ET-743
Advanced solid
tumors
Intravenous on days 18-15
of q28 cycle
Study closed for unacceptable frequency of adjustments
to the weekly dosing schedule for hepatic toxicity
No DLTs observed
[128]
Doxorubicin plus
ET-743
STSs 10/15 intravenous
doxorubicin (60 mg/m
2
)
followed by 3 h intravenous
on day 1 q21
MTD
ET-743
: 1100 g/m
2
DLT: neutropenia
[129]
Cisplatin plus
ET-743
Solid tumors Intravenous day 1 and 8 q21 MTD
ET-743
: 600 g/m
2
MTD
CDDP
: 40 mg/m
2
DLT: febrile neutropenia
[130]
Doxorubicin plus
ET-743
Advanced STS and
breast cancer
Intravenous q21 MTD
ET-743
: 800 g/m
2
MTD
DOXO
: 60 mg/m
2
DLTs: febrile neutropenia and asthenia
[131]
AUC: Area under curve; DLT: Dose-limiting toxicity; MTD: Maximum tolerated dose; PLD: Pegylated liposomal doxorubicin; STS: Soft tissue sarcoma; wk: Week.
www.futuremedicine.com 873 future science group
Wide-spectrum characterization of trabectedin Review
to pharmacologically interact with other anti-
neoplastic drugs, demonstrating additive or
additive-to-synergic effects with common
chemotherapeutic agents. Further studies are
needed to assess its activity in combination with
standard chemotherapeutic agents and with
new biological compounds (i.e., monoclonal
antibodies or small-molecule tyrosine kinase
inhibitors) in STS and also in other human
neoplasia of different histological origins.
Financial & competing interests disclosure
The authors have no relevant af liations or nancial
involvement with any organization or entity with a nan-
cial interest in or nancial conict with the subject matter
or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or
pending, or royalties.
No writing assistance was utilized in the production of
this manuscript.
Table 3. Conducted Phase II clinical trials.
Tumors Administration Results Toxicities Ref.
STS: 25
OS: 3
Ewings sarcoma: 1 PD
at accrual
24 h intravenous q2128
12001800 g/m
2
STS: 2 PRs
OS: 2 PRs
2 MRs, 10 SDs
Transient transaminitis G3 (24%) and G4
(5%), neutropenia G34 (32%) with
concomitant G34 thrombocytopenia
(5.1%), asthenia G23 (21%)
[132]
Advanced pretreated STS:
54 (41% leiomyosarcoma)
24 h intravenous q21
1500 g/m
2
2 PRs, 4 MRs,
9 SDs, 3 CRs
after surgery
Transient transaminitis G34 (50%),
neutropenia G34 (61%), nausea,
vomiting and asthenia
[88]
Advanced anthracycline-
pretreated STS: 54
24 h intravenous q21
1500 g/m
2
3 PRs, 4 MRs
22 SDs
Transient transaminitis G34 (~60%),
neutropenia G34 (~60%)
[87]
Progressive refractory
SFS: 36
24 h intravenous q21
1500 g/m
2
1 CR, 2 PRs,
2 MRs
Neutropenia G34 (34%),
transient transaminitis G34 (26%)
[133]
Advanced STS: 99 24 h intravenous q21
1500 g/m
2
8 PRs, 45 SDs Neutropenia G34 (52%),
transient transaminitis G34 (40%)
[134]
Unresectable advanced
chemonaive STS
24 h intravenous q21
1500 g/m
2
1 CR, 5 PRs, 1 MR Neutropenia G34 (33%),
transient transaminitis G34 (36%)
[135]
Liposarcoma and
leiomyosarcoma: 270
24 h intravenous q21
1500 g/m
2
vs
3 h intravenous every wk for 3
wks q28 580 g/m
2
Reduction in the relative
risk of progression for
patients treated in
the q21
Neutropenia G34 (21% in 24 h arm
vs 2% in 3 h arm), transient transaminitis
G34 (32% in 24 h arm vs 3% in
3 h arm)
[136]
Pretreated advanced
sarcoma: 21
24 h intravenous q21
9001500 g/m
2
3 PRs, 8 SDs Neutropenia G34 (3), transient
transaminitis G34 (8)
[137]
Ovarian carcinoma:
platinum/taxane resistant
(30) or sensitive (29)
3 h intravenous q21
16501300 g/m
2
Platinum sensitive:
1 CR, 9 PRs, 9 SDs
Platinum resistant:
2 PRs, 8 SDs
Transient transaminitis,
asthenia, neutropenia
[138]
Ovarian carcinoma:
platinum resistant (79) or
sensitive (62)
3 h intravenous q28
580 g/m
2
once weekly for
3 wks
Platinum sensitive:
4 CR, 14 PRs, 22 SDs
Platinum resistant:
5 PRs, 36 SDs
Neutropenia G34 (8%),
transient transaminitis G34 (12%)
[139]
Relapsed, platinum-sensitive,
advanced ovarian cancer:
107
Arm A: 24 h intravenous q21
1500 g/m
2
vs Arm B: 3h
intravenous q21 1300 g/m
2
Arm A: ORR 38.9%
Arm B: ORR 35.8%
Neutropenia 55% arm A and
37% arm B, transient transaminitis 55%
arm A and 59% arm B, nausea/vomiting
and asthenia
[140]
Persistent or recurrent
endometrial carcinoma: 50
3 h intravenous q21
1300 g/m
2
1 CR, 18 SDs Transient transaminitis G34 (40%),
neutropenia G34 (13%),
asthenia G34 (14%)
[141]
Pretreated advanced breast
cancer: 21
24 h intravenous q21
1500 g/m
2
4 PRs, 2 MRs, 6 SDs Transient transaminitis
[142]
GIST: 20 24 h intravenous q21
1500 g/m
2
No ORR, 2 SDs Transient transaminitis G3 (10 patients),
asthenia G3 (1 patient)
[113]
GIST: 27 24 h intravenous q21
1500 g/m
2
No ORR, 9 SDs Transient transaminitis G34 (47%),
neutropenia G34 (48%)
[114]
Pretreated advanced
colorectal cancer: 21
3 h intravenous q21
16501100 g/m
2
No ORR, 4 SDs Transient transaminitis G34 (62%),
neutropenia G34 (42.8%)
[115]
CR: Complete response; GIST: Gastrointestinal stromal tumor; MR: Minimal response; ORR: Overall response rate; OS: Overall survival; PD: Progressive disease;
PR: Partial response; SD: Stable disease; STS: Soft tissue sarcoma; wk: Week.
Pharmacogenomics (2010) 11(6)
874 future science group
Review Vincenzi, Napolitano, Frezza, Schiavon, Santini & Tonini
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Executive summary
Trabectedin in the past: from discovery to industrial synthesis
Since the late 1960s, extracts from the Caribbean tunicate Ecteinascidia turbinata have shown promising anticancer activity.
In 1984, the structure of Ecteinascidin (ET)-743 was nally determined.
Since 1996, several chemical processes for synthesis have been achieved.
Pleiotropic & complex mechanisms of action
ET-743 acts as a DNA-alkylating drug, but functionally resembling classical topoisomerase poisons.
ET-743 inhibits the transcription of inducible genes (notably MDR1) via different pathways (e.g., NF-Y mediated, Sp1 mediated and
SXR mediated).
ET-743 interacts with DNA-repairing pathways (notably nucleotide excision repair and homologous recombination) owing to its ability to
form adducts and induce DNA breaks.
Metabolism & toxicities
The liver is the key organ for both metabolism and specic (i.e., nonhematological) toxicities.
In vivo, dexamethasone reduces both liver and hematological toxicities, probably via interference with NF-kB transcriptional activity.
Preclinical/clinical evidences
ET-743 shows pronounced antineoplastic activity in very different cancer line cells, both alone and in combination with common
chemotherapeutic agents.
ET-743 in monotherapy (1.5 mg/m
2
as a 24-h continuous infusion every 3 weeks) is the only agent approved as a second-line therapy in
the treatment of advanced soft tissue sarcoma (Europe).
ET-743 has received the orphan drug status for the treatment of ovarian cancer (Europe and USA) and for soft tissue sarcoma (USA).
The risk of developing grade 34 toxicities seems to be strongly reduced after premedication with dexamethasone.
Trabectedin in the future
Further studies are needed to understand specic predictive factors of response to trabectedin.
Future studies are needed to study trabectedin-based schedules in combination with chemotherapeutic and biological agents
(i.e., monoclonal antibodies and small inhibitors).
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875 www.futuremedicine.com
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