Cancer Chemother Pharmacol
DOI 10.1007/s00280-016-2976-z
REVIEW ARTICLE
Platinum‑based drugs: past, present and future
Shahana Dilruba1 · Ganna V. Kalayda1 
Received: 31 August 2015 / Accepted: 20 January 2016
© Springer-Verlag Berlin Heidelberg 2016
Abstract  Platinum-based drugs cisplatin, carboplatin and
oxaliplatin are widely used in the therapy of human neo-
plasms. Their clinical success is, however, limited due to
severe side effects and intrinsic or acquired resistance to the
treatment. Much effort has been put into the development
of new platinum anticancer complexes, but none of them
has reached worldwide clinical application so far. Neda-
platin, lobaplatin and heptaplatin received only regional
approval. Some new platinum complexes and platinum
drug formulations are undergoing clinical trials. Here, we
review the main classes of new platinum drug candidates,
such as sterically hindered complexes, monofunctional
platinum drugs, complexes with biologically active ligands,
trans-configured and polynuclear platinum complexes,
platinum(IV) prodrugs and platinum-based drug delivery
systems. For each class of compounds, a detailed over-
view of the mechanism of action is given, the cytotoxicity
is compared to that of the clinically used platinum drugs,
and the clinical perspectives are discussed. A critical analy-
sis of lessons to be learned is presented. Finally, a general
outlook regarding future directions in the field of new plati-
num drugs is given.
Keywords  Platinum drugs · Resistance · Toxicity ·
Clinical perspective · Future directions
* Ganna V. Kalayda
akalayda@uni‑bonn.de
1
Department of Clinical Pharmacy, Institute of Pharmacy,
University of Bonn, An der Immenburg 4, 53121 Bonn,
Germany
Cisplatin, the first platinum anticancer drug
Cisplatin, cis-diamminedichloroplatinum(II) (Fig. 1), is
known as Peyrone’s chloride since the end of nineteenth
century (named after Michele Peyrone, who synthesized
it first). The cytostatic property of cisplatin was discov-
ered by Barnett Rosenberg in the late 1960s, while he
was doing experiments to analyze the effect of electric
field on bacterial growth. He observed that bacterial pro-
liferation was ceased and pinned down the cause of this
phenomenon to the platinum electrode that was used.
Rosenberg and colleagues identified cisplatin as a key
compound responsible for the anti-proliferative effect.
Clinical trials were initiated in 1971, and after circum-
venting a number of obstacles, cisplatin was finally
approved for use in testicular and ovarian cancer by the
US Food and Drug Administration and in several Euro-
pean countries in 1979 [1].
Cisplatin is active against a wide spectrum of solid
neoplasms, including ovarian, testicular, bladder, colo-
rectal, lung and head and neck cancers [2, 3]. The drug
often leads to an initial therapeutic response associated
with complete disease remission, partial response or dis-
ease stabilization. However, cisplatin therapy requires
additional medication and is accompanied by severe side
effects including dose-limiting nephrotoxicity, cumula-
tive peripheral sensory neuropathy, ototoxicity due to
irreversible damage of the hair cells in Corti organ, as
well as nausea and vomiting. Furthermore, resistance
to cisplatin represents a major hurdle to the success of
the treatment. Many tumors are intrinsically resistant
to the platinum drug. Moreover, many originally sensi-
tive tumors develop resistance gradually after initial
response [4].
13
 Cancer Chemother Pharmacol

Fig. 1  Chemical structures of O H2
the clinically used platinum N O
H3N Cl H3N O O
drugs Pt Pt Pt
H3N Cl O O
H3N N O
O H2

cisplatin carboplatin oxaliplatin

O
O NH2 O O NH2 O
H3N O
Pt Pt
Pt
O NH2 O
H3N O NH2 O O
O

nedaplatin lobaplatin heptaplatin

Fig. 2  Schematic representa-
tion of the mechanism of action
of cisplatin and resistance to
the drug

Mechanism of action of cisplatin and resistance
mechanisms
Multiple cellular events appear to contribute to the cyto-
toxic effect of cisplatin, although DNA platination is seen
as a crucial step. Alterations in any of these events manifest
in drug resistance to the treatment (Fig. 2). The mecha-
nisms of cisplatin resistance have been classified into pre-
target (i.e., those interfering with cisplatin transport prior
to DNA binding), on-target (repair of Pt-DNA lesions),
post-target (cellular events taking place after DNA platina-
tion) and off-target (alterations in signaling pathways not

13
Cancer Chemother Pharmacol
directly engaged by cisplatin but interfering with cisplatin-
induced proapoptotic events) [4].
Cisplatin had been long presumed to enter the cells by
passive diffusion as its uptake is concentration-depend-
ent and non-saturable. However, copper transporter 1
(CTR1), which is a transmembrane protein involved in
copper homeostasis, was found to play an important role
in the uptake of cisplatin as well [5, 6]. Ctr1−/− (CTR1-
deficient) mouse embryonic fibroblasts accumulated
much less cisplatin than their wild-type variants and were
several times more resistant to the drug [7]. Downregula-
tion of CTR1 is often observed in cisplatin-resistant cells
[8]. In non-small cell lung cancer patients, low levels of
CTR1 correlated with poor therapeutic response [9]. On
the other hand, copper-extruding P-type ATPases, ATP7A
and ATP7B, were found to participate in cisplatin trans-
port as well. Detailed studies showed that ATP7A seques-
ters cisplatin in vesicular structures preventing further
distribution of the drug, while ATP7B is responsible for
cisplatin efflux [6, 10]. These transporters were reported
to be upregulated in cisplatin-resistant cancer cells [11],
and patients with high levels of ATP7A and ATP7B had
significantly poorer overall survival [9, 12]. Other trans-
porters appear to be involved, too. For instance, inhibition
of Na+, K+-ATPase leads to a reduction in cisplatin accu-
mulation, and the transporter is downregulated in cispl-
atin-resistant ovarian carcinoma cells [13]. And although
defects in cellular accumulation represent the most fre-
quently and well-documented feature of cell lines selected
for cisplatin resistance [6], we are still far from having
a complete picture of transport mechanisms influencing
tumor cell sensitivity to the drug. Very recently, the loss
of LRRC8A and LRRC8D subunits of the heteromeric
volume-regulated anion channels (VRACs) was associ-
ated with resistance to cisplatin [14].
Once inside the cells, where the chloride concen-
tration is much lower (4–20 mM) than in the blood-
stream (100 mM), cisplatin is hydrolyzed yielding
monoaqua [Pt(NH3)2Cl(H2O)]+ and diaqua complexes
[Pt(NH3)2(H2O)2]2+ [15]. These reactive species bind
to cytoplasmic nucleophiles such as glutathione (GSH),
methionine, metallothioneins and other cysteine-rich pro-
teins. This leads to the depletion of cytoplasmic antioxi-
dant reserves resulting in the oxidative stress in cells. On
the other hand, these nucleophilic species act as scavengers
limiting the available reactive cisplatin and thus contribut-
ing to cisplatin resistance. Elevated levels of glutathione
or glutathione-S-transferase, an enzyme mediating cispl-
atin coupling to GSH, were observed in cisplatin-resistant
cells [4]. Platinum–glutathione conjugates were reported
to be readily excreted out of the cells by multidrug
resistance protein MRP2, a member of the ABC family
ATPases. Thus, MRP2 also mediates cisplatin resistance
by increasing the efflux of drug [16]. Furthermore, over-
expression of this transporter seems to correlate with poor
prognosis [17].
The activated platinum species also react with nucleo-
philic centers on purine bases of DNA, in particular, N7
positions of guanosine and adenosine residues. The two
reactive sites on the platinum center permit the formation
of a cross-link between two adjacent guanines. In addition,
platinum can coordinate to guanine bases of different DNA
strands to form interstrand cross-links. The intrastrand
1,2-d(GpG) cross-linking induces a significant distortion
in the DNA double helix [18]. This DNA lesion, which is
assumed to largely account for cisplatin cytotoxicity, is rec-
ognized by several cellular proteins leading to the repair,
replication bypass or initiation of apoptosis. Several protein
families are involved in the recognition of Pt-DNA adducts
including non-histone chromosomal high-mobility group
proteins 1 and 2 (HMG1 and HMG2), nucleotide exci-
sion repair (NER) proteins and mismatch repair (MMR)
proteins.
HMG proteins are mainly involved in gene regulation
and chromatin structure. HMG1 and HMG2 recognize
intrastrand DNA adducts between adjacent guanines chang-
ing cell cycle events and subsequently inducing apoptosis
[19]. HMG proteins also contribute to cisplatin cytotoxic-
ity by shielding platinum-DNA adducts from repair [20].
On the contrary, NER is the pathway employed by cancer
cells for removal of platinum-DNA adducts and for DNA
damage repair. A cellular defect in this pathway resulted
in hypersensitivity to cisplatin and the restoration of this
pathway reversed the process [21]. On the other hand,
enhanced NER activity is associated with cisplatin resist-
ance [4]. Mismatch repair (MMR) protein complex does
not actually repair cisplatin-DNA adducts, rather it tries to
repair DNA damage, but after failing to do so, it initiates
apoptosis. Downregulation or mutation of MMR genes is
consistently documented in context of cisplatin resistance
[22]. Another protein family, poly(ADP-ribosyl)ated pro-
teins (PARP), critically involved in base excision repair, is
getting attention, as PARP are highly expressed and consti-
tutively hyperactivated in cisplatin-resistant cells [23].
DNA damage activates the signal transduction path-
ways that eventually lead to apoptosis. Post-target resist-
ance results from defects in the signaling pathways as well
as from problems with the cell death execution machinery
itself. The inactivation of tumor suppressor p53 is one of
the most predominant mechanisms of post-target resist-
ance, as it is the case in half of the human neoplasms [24].
HMG1 and HMG2 facilitate the binding of p53 to DNA to
induce the transactivation of several target genes involved
in cell cycle progression (p21), DNA repair and apoptosis
(Bax). Ovarian cancer patients with a wild-type p53 have a
higher probability of recovering following cisplatin-based
13

therapy than the patients with mutations in this protein
[25]. Moreover, testicular neoplasms are particularly sensi-
tive to cisplatin since they almost lack mutated p53 [26].
The contribution of the off-target mechanisms to cisplatin
resistance is increasingly recognized. For example, over-
expression of the ERBB2 protooncogene (also known as
HER-2) encoding a member of epidermal growth factor
receptor (EGFR) family was associated with resistance to
cisplatin in non-small cell lung cancer patients [4].
Carboplatin and other second‑generation drugs
The second-generation platinum drug carboplatin (cis-
diammine(1,1-cyclobutane dicarboxylato)platinum(II),
Fig. 1) was developed in order to reduce the dose-limiting
toxicity of cisplatin. Carboplatin’s mechanism of action is
similar to that of cisplatin. However, the second-generation
drug has a lower aquation rate due to the bidentate cyclobu-
tane dicarboxylate ligand [27]. As a result of reduced reac-
tivity, the neurotoxicity and ototoxicity after carboplatin
treatment are much less pronounced. Due to its reduced
toxicity profile, carboplatin is suitable for more aggressive
high-dose chemotherapy. This drug is accepted worldwide
and almost replaced cisplatin in combination regimens with
paclitaxel for treatment of ovarian cancer [28]. But the dose
is limited by myelosuppression, with thrombocytopenia
being more severe than neutropenia and anemia. Carbopl-
atin has limited efficacy against testicular germ-cell can-
cers, squamous cell carcinoma of the head and neck and
bladder cancer. As a consequence, cisplatin still remains
the drug of choice for treating these diseases. As in the case
of cisplatin, tumor resistance to carboplatin poses a major
clinical problem. The mechanisms underlying carboplatin
resistance are generally similar to the mechanisms of cispl-
atin resistance [29].
Nedaplatin (cis-diammineglycolatoplatinum(II), Fig. 1)
has improved toxicity profile compared to cisplatin and
pharmacokinetic properties similar to cisplatin [30]. It has
limited regional approval (Japan) for treatment of small cell
lung cancer (SCLC), non-small cell lung cancer (NSCLC),
head and neck and esophageal cancer [15].
Oxaliplatin and other third‑generation drugs
The third-generation platinum drug oxaliplatin (Fig. 1) was
developed to overcome resistance against cisplatin and car-
boplatin. In combination with 5-fluorouracil and folinate,
this drug is used as an efficient treatment of adjuvant and
metastatic colorectal cancer intrinsically insensitive to cis-
platin [15]. Oxaliplatin is a platinum complex with (1R,2R)-
1,2-diaminocyclohexane (DACH) ligand and oxalate as a
13
Cancer Chemother Pharmacol
leaving group. The bidentate oxalate significantly reduces
reactivity of oxaliplatin and thereby limits the toxic side
effects to peripheral sensory neuropathy [15]. The DACH
ligand is more lipophilic increasing passive uptake of oxali-
platin compared to cisplatin and carboplatin. Higher lipo-
philicity may also be a reason why oxaliplatin also employs
some other routes of cellular entry than first- and second-
generation drugs. Organic cation transporters OCT1 and
OCT2 have been implicated to mediate oxaliplatin uptake,
as their overexpression significantly increases the cellular
accumulation of oxaliplatin, but not cisplatin or carbopl-
atin. Colorectal cancer cells overexpress organic cation
transporters, which may explain the efficacy of the oxali-
platin in this particular type of cancer [31]. The clinical
relevance of these transporters remains, however, unclear.
In some clinical studies, increased expression of OCT2 cor-
related with prolonged progression-free survival of patients
with metastatic colorectal cancer [32]. On the other hand,
OCT2 mRNA was barely expressed in nine colorectal can-
cer cell lines and in ovarian cancer patients [33]. Regarding
CTR1, evidence that the transporter is involved in oxalipl-
atin uptake is not that strong as in the case of cisplatin; nev-
ertheless, acquisition of oxaliplatin resistance was reported
to be accompanied by CTR1 downregulation. Also reduced
expression of the β1-subunit of Na+, K+-ATPase was found
in some oxaliplatin-resistant cells. Copper efflux transport-
ers appear to play an important role in oxaliplatin sensitiv-
ity, too. Low levels of ATP7B in colorectal cancer patients
were associated with a favorable outcome [33].
Similar to cisplatin, oxaliplatin mainly forms cross-
links on the adjacent guanine bases or between guanine
and adenine, however, to a lower extent. Nevertheless,
oxaliplatin-DNA adducts are more efficient in inhibition of
DNA synthesis. Due to the bulkier DACH ligand, oxalipl-
atin induces different conformational distortion on DNA.
The bulkiness and lipophilicity of DACH are considered
responsible for differential processing of oxaliplatin-DNA
adducts. The latter are not recognized by MMR proteins.
Interestingly, it does not lead to decreased cytotoxicity but
makes oxaliplatin antitumor activity MMR independent.
Besides, increase in replicative bypass, i.e., DNA synthesis
bypassing platinum-DNA adducts, was reported not to cor-
relate with cytotoxicity of oxaliplatin [34]. All these factors
result in different activity spectrum of the drug compared
to cisplatin or carboplatin. At present, oxaliplatin is being
evaluated in clinical trials for treatment of gastric, pancre-
atic, breast and non-small cell lung cancers [15].
Among other third-generation drugs, lobaplatin and
heptaplatin received only regional approval. Lobaplatin
(Fig. 1) is approved in China for the therapy of metastatic
breast cancer, chronic myelogenous leukemia and SCLC
[15]. Its dose-limiting toxicity is thrombocytopenia. Hepta-
platin (Fig. 1) has a bulkier amine ligand but is structurally
Cancer Chemother Pharmacol
similar to lobaplatin. The drug was demonstrated to be sta-
ble in solution, to have no remarkable toxicity and to retain
cytotoxic activity in cisplatin-resistant cell lines. Heptapl-
atin is currently applied in the Republic of Korea for the
treatment of gastric cancer. A Phase III study showed that
heptaplatin combination with 5-fluorouracil is comparable
to cisplatin/5-fluorouracil regimen with less severe hemato-
logical side effects [15].
New platinum‑based drugs
Given the toxic side effects and tumor cell resistance
against clinically used platinum drugs, much effort was
devoted to the development of platinum compounds, which
would overcome these disadvantages. Numerous com-
plexes have been synthesized, thoroughly investigated and
evaluated in cancer cell lines and xenograft models. Some
platinum drug candidates have reached clinical trials. Here,
we review the main classes of platinum anticancer com-
plexes in the context of their mechanism of action, cytotox-
icity and clinical perspective.
Sterically hindered platinum complexes
Since one of the resistance mechanisms is increased cyto-
solic deactivation of platinum drugs by sulfur-containing
peptides and proteins, researchers aimed at decreasing
reactivity through introduction of a bulky carrier ligand.
Decreased reactivity was also expected to improve the
toxicity profile, as was the case with carboplatin. The
most prominent compound of this group is picoplatin, cis-
[PtCl2(NH3)(2-methylpyridine)] (ZD0473, Fig. 3). This
complex was indeed shown to be less susceptible to deac-
tivation by intracellular thiols as compared to cisplatin
[35]. Picoplatin retains its cytotoxicity in cisplatin- and
oxaliplatin-resistant cell lines independently of the resist-
ance mechanisms prevailing [36]. An interesting feature
of the drug is that it was the first platinum(II) complex,
which could be administered orally. Applied either orally
or intravenously it exhibits antitumor activity in vivo. The
combination of picoplatin and paclitaxel was found to act
synergistically [36]. Toxicity profile of picoplatin is similar
Fig. 3  Chemical structures of
some sterically hindered plati-
num anticancer complexes N Cl
Pt
H3N Cl
picoplatin
to that of carboplatin, with thrombocytopenia being a dose-
limiting factor. The new platinum drug showed antitumor
activity against platinum-sensitive ovarian cancer in a
Phase II clinical trial [36]. In a Phase II study in SCLC,
the therapeutic effect of picoplatin in platinum-sensitive
and platinum-resistant tumors was evaluated [37]. The
observed overall response rates of 8.3 and 15.4 %, respec-
tively, were modest. The median overall survival was 35.7
and 27.3 weeks, respectively. Following these studies, a
larger Phase III SPEAR (Study of Picoplatin Efficacy After
Relapse) trial has been launched. Unfortunately, it has not
shown any advantage of the picoplatin arm over the con-
trol group (best supportive care) [38]. This disappoint-
ing outcome may have been caused, at least partly, by an
unbalanced proportion of patients in the control group who
received post-study chemotherapy. In addition, the subset
analysis of refractory patients, i.e., those who showed no
response or relapsed within 45 days after first line of plat-
inum-based regimen, has shown a significant advantage
of the picoplatin treatment in terms of progression-free
survival [38]. It is unclear why best supportive care was
chosen as control instead of drugs like topotecan known to
show activity in the second-line treatment. Apparently, the
choice of the control group has played a decisive role in the
outcome of the SPEAR trial seriously damaging the clini-
cal perspective of picoplatin.
Besides increasing steric hindrance of cisplatin, attempts
to modify oxaliplatin in order to improve its therapeu-
tic characteristics were made. For this purpose, a series of
oxaliplatin analogs with various alkyl substituents was devel-
oped. A comparative study showed that oxaliplatin deriva-
tives with higher lipophilicity had a potential to overcome
oxaliplatin resistance; however, their absolute cytotoxicity
was decreased [39]. Further evaluation revealed the methyl-
substituted analogs {(1R,2R,4R)-4-methyl-1,2-cyclohexan-
ediamine}oxalatoplatinum(II), KP1537, and {(1R,2R,4S)-
4-methyl-1,2-cyclohexanediamine}oxalatoplatinum(II),
KP1691 (Fig. 3), as the most promising candidates. Their
activity in vitro was better than that of oxaliplatin in plati-
num-sensitive and platinum-resistant cell lines, with KP1691
being more cytotoxic than its isomer [40, 41]. Interestingly,
of the two platinum complexes, KP1537 accumulated in
human colon carcinoma cells to a much higher extent than
KP1691. Even though KP1537 was susceptible to extensive
H2 H2
N O N O
O O
Pt Pt
O O
N O N O
H2 H2
KP1537 KP1691
13
 Cancer Chemother Pharmacol

efflux in contrast to oxaliplatin and KP1691, it induced sig-
nificantly higher amount of early apoptosis and more late
apoptosis as compared to KP1691 [41]. These features of
KP1537 are likely to account for its superior antitumor activ-
ity in vivo. In L1210 leukemia-bearing mice, KP1537 led to
an increase in life span of more than 200 % with five out of
six animals being long-term survivors, as compared to 152
and 122 % increase in life span for oxaliplatin and KP1691,
respectively, and two out of six long-term survivors in each
case. In another study, oxaliplatin derivatives were evalu-
ated in colon cancer xenograft models [41]. Since the neces-
sity of active immune response for oxaliplatin activity was
recently shown [42], immunocompetent BALB/c mice have
been compared with immunodeficient SCID/BALB/c ani-
mals. All three drugs have been active in immunocompetent
mice and retarded tumor growth significantly, with KP1537
being the most potent compound. Oxaliplatin has shown no
activity in immunodeficient mice; in contrast, tumor growth
retardation has been significant for both oxaliplatin analogs
with minor difference between them [41]. Both isomers have
shown lower systemic toxicity, which allowed to increase the
maximum tolerated dose [40, 41]. In spite of these promis-
ing findings, more detailed studies are needed to find out
whether the methyl-substituted oxaliplatin derivatives are
worth further clinical evaluation.
Platinum(II) complexes with biologically active
ligands
Introduction of bulky ligands got a new twist with biologi-
cally active carriers. It was shown, for instance, that estro-
gen enhances cisplatin cytotoxicity by increasing the levels
of HMG1 protein, which shields platinum-DNA adducts
from repair [43]. As a number of human tumors have estro-
gen receptors, various platinum(II) complexes with recep-
tors substrates were synthesized. The most interesting
compound of this group is VP-128 (Fig. 4), an estradiol-
tethered platinum complex with excellent receptor binding
affinity [44]. In ovarian cancer cells, the complex induced
caspase-independent apoptosis and autophagy due to the
formation of acidic vesicular organelles [45]. Without an
increase in systemic toxicity, VP-128 showed markedly
improved in vitro and in vivo activity in ERα (+) breast
cancer (MCF-7), which has weak sensitivity toward cis-
platin. In ERα (−) breast carcinoma (MDA-MB-468),
VP-128, and not cisplatin, resulted in nuclear accumulation
of apoptosis-inducing factor. However, its in vivo activity
was comparable to that of cisplatin [46].
A recent report has introduced a glucose-conjugated
oxaliplatin-based complex Glu-Pt (Fig. 4) designed to

Fig. 4  Chemical structures of OH
some platinum complexes with
biologically active ligands HN
H Cl Pt N
HO Cl
VP-128

H2 O
N O
O O
OH
Pt
F
N O HO OH
H2 O
OH

Glu-Pt

N NH2
N + N

N
(CH2)n
O N
Cl HN H
HN NH2
Pt Pt
Cl N Cl Cl
H2

cis-[Pt{AO(CH2)6en}Cl2]+ 9-aminoac-PtenCl2 (n=2-5)

13
Cancer Chemother Pharmacol
specifically target glucose transporters (GLUTs). The com-
pound shares the mechanistic principles with oxaliplatin
but exhibits improved cytotoxicity. In DBA/2 mice bear-
ing L1210 leukemia xenografts, maximum tolerated dose
has been sixfold higher resulting in improved efficacy. The
complex has also shown superior synergistic interaction
with 5-fluorouracil and folinate making it interesting for
further evaluation [47].
A widely studied group of biologically active ligands
are intercalators. Combination of platinum with interca-
lators enables binding to DNA via two different sites—
through covalent bonds of the platinum moiety and by
intercalation of the ligand between DNA base pairs. It
was expected that such bifunctional complexes would
form DNA adducts, which would not be susceptible to
the repair mechanisms. One of the first complexes was
prepared by Lippard and co-workers and contained
acridine orange (cis-[Pt{AO(CH2)6en}Cl2]+, Fig. 4). It
showed the same sequence selectivity in cross-linking
DNA as cisplatin, and the ligand was found to interca-
late into DNA in the distance of one or two base pairs
from the Pt-DNA adduct [48]. Subsequently developed
acridine-containing platinum complexes (9-aminoac-
PtenCl2, Fig. 4) had different sequence specificity [49]
but failed to show an advantage over cisplatin in terms
of biological activity. The acridine–platinum compounds
were more active than cisplatin or than the correspond-
ing free ligands in CH1 ovarian carcinoma cell lines.
However, in contrast to the free acridines platinum com-
plexes exhibited much lower activity in the cisplatin-
resistant variant [50].
Fig. 5  Chemical structures of
some monofunctional platinum
complexes
H2
N S
Pt
N Cl HN
H2
PT-ACRAMTU
H2 H
N N
Pt
N Cl
H2
amidine analogue of PT-ACRAMTU
Monofunctional platinum complexes
Later on, researchers turned to monofunctional platinum
complexes, i.e., those featuring only one chloride as a
leaving group. Such complexes had for a long time been
considered inactive as the parent compound [Pt(dien)Cl]
Cl (dien = diethylenetriamine) is not cytotoxic. However,
when complexes with intercalators were concerned, it was
presumed that a platinum moiety would be covalently
linked to a nucleobase and an intercalator would addition-
ally interact with DNA forming stable and structurally
different adducts than cisplatin. This approach appeared
to be fruitful and has produced many interesting com-
pounds such as PT-ACRAMTU and its amidine derivative
(Fig.  5). These complexes rapidly intercalate into DNA
followed by platination of a nucleobase at the intercala-
tion pocket. This mechanism efficiently drives platinum
away from the classical binding sites [51]. Such mono-
functional-intercalative adducts induced much less dis-
tortion on DNA than cisplatin-d(GpG)-cross-link result-
ing in a decreased or negligible affinity of HMG domain
proteins to recognize the adduct [52], which implies
differences in adduct processing compared to cisplatin.
The amidine derivative formed DNA adducts faster than
PT-ACRAMTU. Moreover, these adducts were repaired
less efficiently. Rapid and irreversible DNA adduct for-
mation correlated with higher cytotoxicity. In general,
PT-ACRAMTU and especially its amidine analog were
more active in vitro than cisplatin and the free ligands
with the most prominent results obtained in non-small cell
lung cancer cell line NCI-H460. Antitumor activity of the
2+
+
H3N Cl
NH Pt
N
N H3N N
H
pyriplatin
2+ +
H3N Cl
NH Pt
N H3N N
N
H
phenathriplatin
13

hybrid compounds was attributed to higher cellular accu-
mulation, faster formation and less efficient removal of
DNA adducts as compared to cisplatin [51]. The mono-
functional-intercalative adducts were capable of induc-
ing cell cycle arrest in the S phase, while cisplatin causes
cells to accumulate in G2/M phase [53]. Unfortunately,
these advantages were not reflected in in vivo activity. PT-
ACRAMTU failed to slow tumor growth in mice. Moreo-
ver, the compounds were quite toxic to animals with max-
imum tolerated doses an order of magnitude lower than in
the case of cisplatin. Such lack of cancer cell selectivity
makes these complexes unattractive for further clinical
development. Specific delivery to cancer cells may sig-
nificantly improve the therapeutic profile of the amidine
analog of PT-ACRAMTU and lead to a promising antitu-
mor drug candidate.
Another group of monofunctional compounds has been
developed in the Lippard’s laboratory. They focused on
complexes with a general formula cis-[Pt(NH3)2AmCl]+,
where Am was a planar aromatic base like pyridine,
purine, pyrimidine or an intercalator. The complexes
with the latter (9-aminoacridine or chloroquine) were
found highly toxic in preliminary animal studies and
were not considered further [54]. Of these complexes,
[Pt(NH3)2(pyridine)Cl]+, later referred to as pyriplatin
(Fig. 5), had a remarkable affinity for organic cation trans-
porters OCT1 and OCT2, which are believed to contribute
to oxaliplatin influx. Interestingly, pyriplatin displayed
higher cytotoxicity in the cells overexpressing OCT1 than
in cells with low levels of the transporter [55]. The com-
plex forms monofunctional adducts, which induce only
little distortion on the DNA double helix [56]. Pyriplatin-
DNA adducts are mainly repaired by NER and not by
MMR or double-strand break repair. NER of the mono-
functional adducts is, however, less efficient than in the
case of cisplatin [54]. As a result, pyriplatin demonstrated
a different in vitro activity spectrum as compared to the
clinically used platinum drugs. But its cytotoxicity was
much lower than that of cisplatin in all cell lines tested
[57]. Since the studies with RNA polymerase II suggested
the relevance of steric hindrance of the amine ligand for
enzyme inhibition, the structure of the monofunctional
complexes was varied to introduce a bulkier ligand. The
platinum complex with phenanthridine, later called phen-
anthriplatin, turned out to be the most potent of the series
(Fig. 5) [56]. Its cellular uptake is higher than that of cis-
platin and pyriplatin, and the steric hindrance provides
protection from thiol deactivation similar to that found
for picoplatin [54]. Phenathriplatin’s spectrum of antitu-
mor activity on NCI panel of cell lines was different from
other anticancer agents [56]. However, its activity in vivo
has not been reported.
13
Cancer Chemother Pharmacol
Platinum(II) complexes with trans‑geometry
For a long time, cis-geometry was believed to be a neces-
sary feature for platinum complexes to exhibit antitumor
activity. However, increased repair of platinum-induced
DNA damage by resistant cells turned researchers’ atten-
tion to platinum complexes able to build structurally dif-
ferent DNA adducts. Such unprecedented adducts were
supposed to be processed by the cellular machinery in the
other way compared to the cross-links formed by the con-
ventional platinum drugs. Due to their geometry, trans-
platinum complexes are predestined to interact differently
with DNA than their cis-counterparts.
Transplatin (trans-[Pt(NH3)2Cl2]) is known to lack anti-
tumor activity, which has been attributed to the fast deacti-
vation by sulfur proteins [58]. Interestingly, if transplatin
is applied to the cells irradiated with UVA light, it forms
interstrand cross-links and protein–DNA adducts and
exerts cytotoxic effects comparable to those of cisplatin
[59]. Introduction of the bulky ligands instead of ammonia
decreased the rate of chloride exchange positively affecting
the kinetics of DNA adduct formation and antitumor activ-
ity [58].
Trans-configured platinum anticancer complexes, apart
from Pt(IV) and polynuclear platinum complexes, can be
roughly divided into three groups: complexes with planar
aromatic bases, with iminoethers and with aliphatic amines
(Fig.  6). All three groups of compounds feature highly
cytotoxic representatives, many of them retaining their
activity in resistant cell lines [60–62]. A special subgroup
of the complexes with planar aromatic bases was developed
substituting chloride leaving groups by carboxylates, e.g.,
trans-[Pt(OAc)2(NH3)(3-pic)] (Fig. 6) [58]. The water-
soluble carboxylate analogs were found to be slower in
DNA binding than their chloride counterparts [61], which
did not necessarily result in decreased antitumor activity
[63]. Slower interaction with DNA may be compensated by
enhanced cellular accumulation of these compounds [63].
As expected, trans-platinum complexes formed different
DNA adducts than cisplatin, carboplatin and oxaliplatin.
Most of them first build monofunctional adducts, which
tend to persist for a longer period of time. Trans-platinum
complexes with planar aromatic bases later form inter-
strand cross-links to a higher degree than cisplatin. As com-
pared to transplatin, the rate of monofunctional to bifunc-
tional adduct conversion is much lower (trans-[PtCl2(NH3)
(quin)] adducts persist for 48 h as monofunctional, whereas
the conversion rate for transplatin reaches 70 %) [58]. In
contrast, platinum complexes with iminoethers barely form
interstrand cross-links, they build relatively stable mono-
functional adducts first [60] later converting to protein–
DNA cross-links [64]. The recognition and the processing
Cancer Chemother Pharmacol

Fig. 6  Chemical structures of trans complexes with planar amines

some platinum(II) complexes
with trans-geometry
S O
N N N O
Cl Cl
Pt Pt O Pt
H3N Cl H3N Cl O NH3

trans-[PtCl2(NH3)(quin)] trans-[PtCl2(NH3)(tz)] trans-[Pt(OAc)2(NH3)(3-pic)]

trans complexes with iminoethers

MeO H
N Cl
Me Pt Me
Cl N
H OMe

trans-EE

trans complexes with aliphatic amines

Cl NH3
Cl NH2
H2 Pt
H Pt
Cl N N Cl H
N Cl
Pt
H
N Cl N .HCl
N .HCl

trans-[PtCl2(ipa)(dma)] trans-[PtCl2(NH3)(pip-pip)] trans-[PtCl2(n-butylamine)(pip-pip)]

of the DNA adducts formed by trans-platinum complexes
are also different from that of the conventional platinum
drugs. Many of them are not recognized by HMG proteins
and are not repaired by nuclear excision repair system [58,
64]. This explains antitumor activity of trans-complexes in
platinum-resistant cell lines. Protein–DNA cross-links also
appear to be of major importance for the anticancer activity
of these compounds. The biological consequences of these
cross-links are yet to be clarified.
A distinguishing feature of the trans complexes with
planar aromatic bases is their ability to induce single-
stranded protein-associated DNA strand breaks in a fashion
similar to topoisomerase inhibitors. This group of platinum
complexes forms DNA-topoisomerase I complexes. Inter-
estingly, cis-counterparts barely produce DNA–protein
cross-links and protein-associated strand breaks [58]. Fur-
thermore, complexes with planar bases decrease telomerase
activity. Noteworthy, many telomerase inhibitors also pos-
sess planar aromatic moieties [58].
As in vivo activity is concerned, there is little data
available. Trans-[PtCl2(NH3)(tz)] was only moderately
active against P388 leukemia. A platinum complex with
iminoethers trans-[PtCl2(E-iminoether)2] (trans-EE)
decreased the level of lung metastases but less efficiently
than cisplatin. Treatment with this complex also did not
lead to increased survival in mice compared to cisplatin.
Trans-[PtCl2(ipa)(dma)] exhibited no antitumor activity
in the human ovarian CH1 xenograft, possibly due to its
inactivation by plasma proteins [58]. Trans-[PtCl2(NH3)
(pip–pip)] and trans-[PtCl2(n-butylamine)(pip–pip)] were
studied in BALB/c mice bearing A2780 ovarian carcinoma
and mice with cisplatin-resistant counterpart A2780cisR. In
spite of similar activity in vitro, trans-complexes extended
life expectancy by 79 and 46 %, respectively, in contrast
to 160 % increase by cisplatin. Being the most promising
compound with respect to the cytotoxicity in cisplatin-
resistant cell line, trans-[PtCl2(NH3)(pip–pip)] showed no
activity in BALB/c mice with A2780cisR tumor. Trans-
[PtCl2(n-butylamine)(pip–pip)] was less effective than cis-
platin [58].
Platinum complexes with trans-geometry do indeed
form structurally different DNA adducts, which are also

13
 Cancer Chemother Pharmacol

processed in the other fashion than adducts of the conven-
tional platinum drugs. Trans-configured complexes show
promising activity in vitro, especially in platinum-resistant
cells. Unfortunately, these findings do not transform into
therapeutic efficacy in vivo. It is likely that altered bio-
distribution of trans complexes compared to the approved
platinum drugs, e.g., fast deactivation by plasma proteins,
is a key hurdle on the way to the clinical success.
Polynuclear platinum complexes
As 1,2-d(GpG)-intrastrand cross-link induced by cisplatin
causes DNA bending toward the major groove creating a
kink susceptible to DNA damage recognition and repair
proteins, the attention turned to polynuclear (also called
multinuclear) platinum complexes. They were expected to
form DNA adducts, which would span over several base
pairs and would induce less distortion on the DNA double
helix. One class of interesting anticancer polynuclear plati-
num compounds is represented by azolato-bridged dinu-
clear platinum complexes (Fig. 7).
Similarly to cisplatin, these compounds preferentially
form intrastrand cross-links on adjacent guanines [65].
For the triazolato-bridged member of this compound class
AMTA, additional electrostatic interaction with DNA was
reported [66]. The DNA adducts of the dinuclear com-
plexes partially unwind the double helix; however, in con-
trast to cisplatin, only a small extent of DNA bending is
observed. These relatively little conformational changes
result in the lack of recognition by HMG proteins [67]. The
cross-links of the azolato-bridged complexes on DNA are
also expected to be poor substrates for the NER enzymes
[65]. These dinuclear complexes exhibit much higher cyto-
toxicity than cisplatin. They have a different spectrum of
antitumor activity compared to the clinically approved
platinum drugs as found on a panel of 39 tumor cell lines
(JFCR39) [68]. The azolato-bridged complexes largely
overcome resistance in PC-9 and PC-14 cisplatin-resistant
non-small cell lung cancer cell lines with resistance fac-
tors ranging from 0.5 to 0.8 for PC-9 cells and from 0.9
to 2.0 for PC-14 cells [69]. A tetrazolato-bridged dinuclear
platinum complex 5-H-Y shows remarkably high antitumor
activity in pancreatic cancer [70]. However, as these com-
plexes were not patented, they have no chance to be devel-
oped for clinical use.
A different class of polynuclear platinum complexes
was designed by Farrell and colleagues. They first focused
on highly charged trans-configured complexes with ali-
phatic amines. The most prominent member of this class
is the trinuclear complex BBR3464 (Fig. 7). This com-
pound showed better uptake by tumor cells than cisplatin

H3N 2+ H3N 2+ H3N 2+

NH3 NH3 NH3
Pt Pt N Pt
N N N
OH OH OH
N N N
Pt N Pt N Pt
NH3 NH3 NH3
H3N H3N H3N

AMPZ AMTA 5-H-Y

4+
H2 H3N Cl
H2 H3N N
H3N N Pt
Pt
Pt N NH3
Cl N NH3 H2
NH3 H2

BBR3464

H2 8+
H2 H3N N
H2 H3N N NH3
H3N N Pt
Pt
H3N Pt N NH3
N N NH3 H2
H2 NH3 H2

Triplatin-NC

Fig. 7  Chemical structures of some polynuclear platinum complexes

13
Cancer Chemother Pharmacol
and overcame accumulation defects present in cisplatin-
resistant cell lines [71]. As in the case of cisplatin, CTR1 is
involved in cellular uptake of BBR3464. However, strong
interaction of BBR3464 with phospholipid membrane
models due to the high positive charge may point out at an
alternative mechanism of the cellular entry [72]. BBR3464
was shown to platinate DNA to a higher extent than cis-
platin [71]. The trinuclear complex forms long-range delo-
calized intra- and interstrand cross-links between guanines
spanning up to six base pairs compared to a maximum of
three base pairs in the case of cisplatin [73]. As a result of
increased flexibility, DNA adducts induced by BBR3464
lack severe distortion due to bending and twisting. While
both intra- and interstrand cross-links are not recognized by
HMG proteins, intrastrand lesions are effectively removed
by NER in contrast to the interstrand cross-links [74, 75].
The central tetraam(m)ineplatinum unit also plays an
important role as it interacts with DNA by pre-association
[76]. The trinuclear complex provokes differential cellular
response to p53 activation and recognition, which is likely
to account for its activity in cells featuring p53 mutations
and therefore resistant to cisplatin [77]. All these proper-
ties are reflected in the cytotoxicity of BBR3464. The com-
pound was found highly active in various cell lines (often
more than 100-fold compared to cisplatin), and it overcame
resistance in neuroblastoma, ovarian carcinoma and mela-
noma cells with different mechanisms of resistance [78].
Testing BBR3464 on the NCI cell line panel revealed a
markedly different spectrum of activity compared to the
clinically used drugs. The trinuclear complex was highly
active in mice bearing GFX214 and MKN45 gastric car-
cinoma xenografts, which did not respond to cisplatin
therapy. Interestingly, BBR3464 prolonged tumor growth
inhibition even after the end of the treatment. However,
the maximum tolerated dose of BBR3464 was tenfold to
15-fold lower than that of cisplatin [78]. In spite of these
encouraging results, in Phase II trials in non-small cell lung
cancer, small cell lung cancer, ovarian and gastric cancer
only sporadic response was observed [76]. The maximum
tolerated dose was manifold lower than for cisplatin. The
patients suffered from severe dose-limiting gastrointesti-
nal and hematological side effects [76], which are likely
to have resulted from higher plasma protein binding in
human as compared to mice [79]. Apparently, progressive
biotransformation and fast drug degradation facilitated by
the trans-configuration of the chloride leaving groups are
responsible for the disappointing results of the Phase II
studies with BBR3464.
As the central platinum unit of BBR3464 interacts with
DNA electrostatically, it was hypothesized that complexes
with several tetraam(m)ineplatinum units may repre-
sent an inert alternative to BBR3464 in terms of reactiv-
ity. Moreover, a high positive charge would increase the
affinity for DNA. Such trinuclear platinum complex tri-
platin-NC (Fig. 7) showed higher accumulation in A2780
ovarian carcinoma cells than BBR3464, supposedly due to
the increased charge. The complex was reported to enter
the cells via macropinocytosis facilitated by its interaction
with cell surface glycosaminoglycans, which was observed
to a lesser extent for BBR3464 and not at all for cispl-
atin and oxaliplatin [80]. Triplatin-NC appears to avoid
deactivation by intracellular nucleophiles [81]. It binds to
DNA in a non-covalent fashion: square planar tetraam(m)
ineplatinum moieties form bidentate N–O–N complexes
with phosphate oxygens through hydrogen bonding (phos-
phate clamps) [82]. Triplatin-NC also induces DNA con-
densation in nucleoli and transfer RNA aggregation lead-
ing to DNA transcription inhibition at the concentrations
lower compared to the natural condensing agents like
spermine [83]. The complex induces a robust G1 arrest in
a p53-independent manner [80]. These features account
for high cytotoxicity in various cancer cell lines, which is
barely affected by p53 or Bax mutations [83]. Therefore, it
is possible that triplatin-NC has overcome the limitations
of BBR3464 and may represent a promising antitumor
drug candidate.
Platinum(IV) prodrugs
Platinum(IV) prodrugs are a new class of molecules
that might improve the pharmacological properties
of the platinum(II) anticancer agents currently in use.
Platinum(IV) complexes feature additional ligands in the
axial positions, which allows further chemical modifica-
tion and adjusting properties. Platinum(IV) complexes
are substitution inert. As a result, they are more stable in
blood circulation due to decreased interaction with plasma
proteins. Platinum(IV) prodrugs are activated by reduction
transforming them into square planar platinum(II) com-
plexes. Glutathione and ascorbate are believed to act as
reducing agents, but substantial reduction by cellular pro-
teins was also reported [84]. As the axial ligands are lost
during activation step, they can be used to carry favorable
pharmacological properties in the prodrugs, for instance,
to maximize cellular uptake. In contrast, the nature and
geometry of equatorial ligands determine cytotoxicity of
platinum(IV) compounds. Platinum(IV) complexes have
several advantages over their platinum(II) counterparts:
(1) due to their high stability, they can be administered
orally; (2) they have diminished side effects as they are less
prone to react with proteins; (3) their axial ligands can be
modified to improve the pharmacological properties, e.g.,
to target the platinum moiety to the tumor. Platinum(IV)
anticancer complexes can be classified into three catego-
ries: complexes with axial ligands without any bioactivity
13
 Cancer Chemother Pharmacol

O
O

O
H2 Cl H2 HO H3N Cl O
N Cl N Cl Pt H3N Cl
N Cl Pt
Pt Pt
H2 O N Cl
N Cl H2 O
N Cl
H2 Cl H2 OH
O O
tetraplatin iproplatin satraplatin LA-12

Cl
O O Cl
O H O O
N O
O
O n O
H3N O H3N Cl
Cl O
Pt Pt
O O
H3N Cl H3N Cl
O O
N O O
n
H O
O O Cl
O O
Cl

Pt(IV)- estradiol conjugate Pt(IV) complex with ethacrynic acid

O
O

CHCl2 O OH OH OH
O
H3N Cl H3N N3 H3N N3 H3N N3
Cl NH3
Pt Pt Pt Pt Pt
H3N Cl H3N N3 N3 NH3 N3 N
Cl NH3
O O OH OH OH
CHCl2
O O

mitaplatin Pt(IV)-VPA photoactivatable Pt(IV) complexes

Fig. 8  Chemical structures of some platinum(IV) prodrugs

(hydroxides, chlorides, acetates, etc.), complexes with bio-
active or targeting axial ligands and photoactivatable com-
plexes (Fig. 8).
Platinum(IV) complexes without bioactive ligands
Tetraplatin, iproplatin, satraplatin (formerly JM-216) and
LA-12 (Fig. 8) are platinum(IV) complexes without bio-
active axial ligands that entered clinical trials. Tetraplatin
was abandoned due to severe cumulative neurotoxicity,
and iproplatin did not show any better activity than cispl-
atin or carboplatin [15]. Satraplatin was the first lipophilic
platinum(IV) drug developed for oral administration. It
is rapidly taken up by cells and overcomes accumulation
defects in cisplatin-resistant cell lines [85]. In human, satra-
platin is readily absorbed and yields several products upon
reduction in the bloodstream, the most abundant and active
species is thereby cis-amminedichlorido(cyclohexylamine)
platinum(II) [15]. In a Phase III trial in hormone-refracted
prostate cancer, the complex led to an increase in progres-
sion-free survival and reduced the risk of disease progres-
sion by 40 %. However, because of the lack of convincing
benefit in terms of overall survival, approval by the US
Food and Drug Administration did not follow. It was attrib-
uted to the insufficient power of the study and/or difficulty
to determine the actual reasons of death [15]. At present,
satraplatin is undergoing Phase I, II and III clinical trials
in combination with various drugs for treatment of prostate
and non-small cell lung cancer as well as advanced solid
tumors. However, as these studies are in a much earlier
stage and will require further funding, it appears unlikely
that the company would keep on developing satraplatin.
LA-12, an analog of satraplatin, showed higher uptake
in A2780 and cisplatin-resistant A2780cisR cell lines
than cisplatin, although its accumulation was reduced in
A2780cisR cells compared to the sensitive counterparts.

13
Cancer Chemother Pharmacol
The complex induced DNA lesions similar to those of cis-
platin [85]. It overcame cisplatin resistance in A2780cisR
cells caused by elevated GSH levels, as glutathione is
responsible for activation of Pt(IV) complex through reduc-
tion, and not for deactivation as in the case of Pt(II) com-
plexes [85]. LA-12 showed promising in vivo activity in
mice bearing ADJ/PC6 plasmacytoma and A2780 ovarian
cancer [86] and has just finished Phase I clinical trials.
Platinum(IV) complexes with bioactive ligands
The axial sites of platinum(IV) prodrugs offer the opportu-
nity to increase the selectivity for cancerous tissue or intra-
cellular targeting. As mentioned above, pre-treatment with
estrogen increased cisplatin cytotoxicity in hormone-positive
tumors [43]. Thus, estrogen receptor-positive [ER (+)] breast
and ovarian cancer cells were targeted by a Pt(IV) complex
with estradiol tethered to the axial positions (Fig. 8). How-
ever, an extracellular mixture of cisplatin and estrogen was
more cytotoxic than the Pt(IV) prodrug indicating its inef-
ficient cellular uptake or different pharmacokinetics [43].
Platinum(IV) complex with ethacrynic acid in axial
position (Fig. 8) was developed to overcome glutathione-
S-transferase (GST) resistance. Ethacrynic acid is an inhib-
itor of cytosolic GST. This prodrug was rapidly taken up
and had higher efficacy than cisplatin after short incubation
but only a moderate effect after 72 h [87]. A similar strat-
egy was employed by Lippard and colleagues who added
dichloroacetate ligands in axial positions of platinum(IV)
prodrugs (mitaplatin, Fig. 8). Dichloroacetate alters the
mitochondrial membrane potential in cancer cells. Sub-
sequently, the cytochrome c is released and the apotosis-
inducing factor is translocated to nucleus. The cytotoxicity
of mitaplatin is equivalent or exceeded that of other plati-
num compounds and comparable to that of cisplatin [88].
A Pt(IV) derivative of cisplatin-containing valproic acid
(VPA) as axial ligands (Fig. 8) kills cancer cells more effi-
ciently than cisplatin. VPA inhibits histone deacetylase
activity to decondense chromatin and thereby increases the
accessibility of DNA within chromatin for DNA-binding
agents. The treatment of ovarian cancer cells with Pt(IV)-
VPA complex resulted in enhanced histone H3 acetyla-
tion and decondensation of heterochromatin compared to
free VPA. Pt(IV)-valproic acid conjugate binds to DNA to
a higher extent than the complexes with biologically inac-
tive ligands. Together with increased cellular accumulation,
these factors seem to account for the enhanced cytotoxicity
of Pt(IV)-VPA [89].
Photoactivatable platinum(IV) prodrugs
Sadler and co-workers prepared a series of Pt(IV) com-
plexes with azides (Fig. 8) to enable their selective
activation in tumor tissue by radiation. The complexes are
inert in the dark and stable toward deactivation by glu-
tathione. Interestingly, trans isomers were more cytotoxic
than their cis-counterparts. The use of pyridine ligands led
to a marked increase in potency and activity at longer wave-
lengths [90]. When irradiated with blue light, the activity of
trans, trans, trans-[Pt(N3)2(OH)2(NH3)(py)] (Fig. 8) toward
esophageal cancer was enhanced in vivo [90]. The mecha-
nism of action is distinct from that of conventional plati-
num drugs such as cisplatin. The photodecomposition route
involves two one-electron transfers from azido ligands
generating N2 and Pt(II) species, which in turn form DNA
lesions. These lesions are able to stall RNA polymerase II
more efficiently than cisplatin [90].
Taken together, platinum(IV) prodrugs represent a
promising class of anticancer compounds; especially, the
employment of the axial ligands targeting the drug to the
tumor has potential. In this case, it is important to ensure
that the ligands stay attached to platinum all the way to
the tumor but are cleaved off at the disease site. In gen-
eral, many questions regarding cellular accumulation, bio-
transformation in the bloodstream and inside the cells and
in vivo activity of platinum(IV) prodrugs remain unan-
swered. Better understanding of how these complexes
work may provide a key to the development of the first
platinum(IV) compound in clinical use.
Improved delivery
Although platinum drugs have brought major advances in
oncology, their clinical success is often hindered by the
adverse side effects and development of resistance. Addi-
tional obstacles include low bioavailability and low water
solubility. Carrier-based delivery of platinum drugs spe-
cifically to the tumor is a strategy to overcome these lim-
itations because of its potential to improve drug efficacy,
reduce unwanted side effects and overcome defects in cel-
lular accumulation accounting for drug resistance. Drug
delivery systems often exploit the differences between
healthy and tumor tissue in order to increase drug selectiv-
ity for the malignant tissue. Passive drug delivery is based
on the ability of macromolecules to accumulate better in
tumor tissue because of its increased permeability and poor
lymphatic clearance, a phenomenon known as increased
permeability and retention (EPR) effect [91]. Drugs cou-
pled to liposomes, lipid particles, micelles and various
other polymeric carriers selectively accumulate in tumors,
while the clinically used cancer drugs have low molecular
weight and easily pass through the membranes of cancer-
ous as well as normal tissue. Therefore, the nanoscale size
of the carrier is important, as it prevents extravasion in
normal tissue and removal by renal clearance. Active drug
13

delivery achieves selectivity of a carrier-conjugated anti-
cancer drug by using specific antibodies or ligands recog-
nizing receptors present exclusively in tumor cells.
The most widely used motif in anticancer drug carri-
ers is the hydrophilic polymer polyethylene glycol (PEG).
Due to its high aqueous solubility, high mobility and large
exclusion volume, hydrated PEG forms a dense brush of
polymer chains stretching out and covering the particle sur-
face. Thus, PEG coating serves to decrease particle opsoni-
zation and thus make the carrier less recognizable by the
reticuloendothelial system in the liver and spleen [92].
Liposomal formulations of platinum drugs
Liposomes prepared from various amphiphilic phospholip-
ids are lipid bilayer vesicles with an aqueous interior. The
major advantage of this technique is that it can be used for
both hydrophobic and hydrophilic drugs utilizing the phos-
pholipid bilayer and aqueous cavity, respectively.
Lipoplatin (Regulon, Inc.) is one of the most promising
liposomal platinum drugs currently under investigation.
This drug is prepared using soy phosphatidylcholine (SPC-
3), cholesterol, dipalmitoyl phosphatidylglycerol (DPPG)
and methoxy-PEG-distearoyl phosphatidylethanolamine
(mPEG2000-DSPE). Lipoplatin comprises 9 % cisplatin
and 91 % lipid (w/w) corresponding to drug-to-lipid ratio
of 1:10. Preclinical studies of lipoplatin in mice, rats and in
severe combined immunodeficient mice revealed that it has
lower side effects, especially nephrotoxicity, compared to
cisplatin [93]. A Phase I clinical trial showed elevated accu-
mulation of cisplatin in tumor tissues compared to normal
tissue and did not show cisplatin-specific side effects such
as nephro-, neuro-, ototoxicity and hair loss. Phase II stud-
ies of lipoplatin in combination with gemcitabine showed
significant clinical benefit in patients who were previously
resistant to first- and second-line chemotherapy. Phase III
trials in NSCLC and pancreatic cancer are ongoing. Moreo-
ver, lipoplatin has obtained an orphan drug status from the
European Medicines Agency (EMA) for treatment of pan-
creatic adenocarcinoma [93].
SPI-77 (Alza Pharmaceuticals, formerly Sequus Phar-
maceuticals) is another liposomal formulation of cisplatin.
In this case, cisplatin is encapsulated in stealth liposomes
composed of hydrogenated soy phosphatidylcholine, cho-
lesterol and PEG-modified phosphatidyl-ethanolamine. The
drug loading capacity of SPI-77 is very low (drug-to-lipid
ratio ~1:70). Phase I studies of SPI-77 showed good toler-
ance in all patients with lack of toxicity typical for the cis-
platin regimen [94]. But the trial was discontinued due to
modest antitumor response. This could be due to low drug
loading capacity and/or high stability of liposomes and
inefficient release of the drug as was clear from low plasma
concentration of free cisplatin and diminished platination
13
Cancer Chemother Pharmacol
of DNA in tumor cells [95]. The example of SPI-77 shows
that not only successful delivery but also efficient release
of the drug is important for the efficacy of a drug delivery
system.
Aroplatin (L-NDDP, originally Aronex Pharmaceuti-
cals, now Agenus, Inc.) is a liposomal formulation of cis-
bis-(neodecanoato)-{(1R,2R)-1,2-diaminocyclohexane}
platinum(II) (NDDP, Fig. 9), a structural analog of oxali-
platin with two branched aliphatic leaving groups of ten
carbon atoms, incorporated in a matrix of dimyristoylphos-
phatidylcholine and dimyristoyl phosphatidyl glycerol
(DMPG). Due to high lipophilicity of the oxaliplatin
analog, the drug-to-lipid ratio is 1:15 [96]. The liposo-
mal carrier plays a crucial role in mediating the cytotox-
icity and antitumor activity of the drug as the free drug
itself has a very low cytotoxicity. It has been suggested
that active intermediates are formed within a lipid bilayer.
The activation appears to rely on the presence of DMPG
and lipophilic leaving groups of NDDP [92]. A Phase II
study showed significant but manageable toxicity in mes-
othelioma patients. In general, the response was promis-
ing; however, in some patients the areas of mesothelioma,
which were not in direct contact with pleural space, were
not exposed to the drug leading to poor efficacy [92].
Lipoxal (Regulon, Inc.) is another oxaliplatin formula-
tion prepared in a manner similar to lipoplatin. A Phase I
study in advanced gastrointestinal cancer patients showed
adequate effectiveness and greatly reduced side effects
compared to oxaliplatin [97]. MBP-426 is an oxaliplatin
formulation made of transferrin-conjugated N-glutaryl
phosphatidylethanolamine. This drug binds preferentially
to transferrin receptors expressed in tumor cells. Thus, the
drug delivery is enhanced via uptake of MBP-426 by trans-
ferrin receptors in human cancer cells. This drug has shown
encouraging anticancer activity in the preclinical setting
and has entered clinical trials in gastric and esophageal
cancer [92].
Cisplatin nanocapsules contain the platinum complex
with high encapsulation efficiency (the average drug-to-
lipid ratio exceeds 10:1). They are taken up by caveolae-
mediated endocytosis or by the clathrin-mediated route in
cells, which do not express caveolin-1. The cytotoxicity
of cisplatin nanocapsules was twofold greater than that of
the free drug [98]. This formulation did not show enhanced
antitumor efficacy in animal models of ovarian cancer,
which was attributed to insufficient accumulation of nano-
capsules in the tumor tissue and disruption of the capsule
structure due to the interaction with plasma proteins [99].
Nevertheless, this encapsulation strategy is rather encour-
aging, and if the problems of plasma stability and poor
delivery can be properly addressed, for example, through
active targeting, platinum drug nanocapsules may get a
clinical perspective.
Cancer Chemother Pharmacol

Fig. 9  Chemical structures of H2 O
NDDP (an active complex of N O
Aroplatin), AP5280, AP5346 Pt
(ProLindac), EFG-tethered O
N
cisplatin–nanotube conjugate H2 O
and Pt(IV) complex attached to
a SWNT nanotube NDDP

C C C C
H2 H2
O
O NH 95 HN 5
C C C C
H2 H2
O
O O NH x HN y
HO NH
O
O HO NH
HN
O
O HN
NH
O H2N
O O O N Pt
N
N H2
+
Na-O NH3 +
Na-O O
Pt
O NH3 O
O

AP5280 AP5346 (ProLindac)

H O
Cl NH3
N Pt = EFG
O NH3
O

EFG-tethered cisplatin-nanotube conjugate

OEt
OEt
H3N Cl
H3N Cl Pt
Pt
O H3N Cl
H3 N Cl
O
O
OH
O

Pt(IV) complex and its SWNT-conjugate

O
O
O O
= H O- H
O O O N
P N OCH2CH2
H 45
O O O

Platinum‑polymer conjugates clinical trials, which demonstrated promising efficacy and

This concept is based on covalent binding of the drug to
a hydrophilic polymer. The most frequently used polymer
for conjugation of anticancer compounds is the N-(2-hy-
droxypropyl)methacrylamide (HPMA). AP5280 is one of
the platinum-HPMA-copolymers (Fig. 9). It contains cispl-
atin linked to the polymer through a malonate end group.
This conjugate with platinum loading capacity of 10 %
by weight was 20-fold less toxic than cisplatin in vivo but
showed 19-fold increase in platinum accumulation in B16
mouse tumors. Based on the improved therapeutic index
in other mouse models, AP5280 advanced into Phase I/II
less platinum-based toxicity [100]. However, the company
chose to proceed with a more promising conjugate AP5346
(Fig.  9), which represents an improved polymer carrier
linked to a more potent oxaliplatin-like DACH-Pt moiety.
AP5346 or ProLindac (Access Pharmaceuticals, Inc.)
consists of a biocompatible and water-soluble polymer
bound to DACH-Pt via a pH-sensitive chelating group.
The chelate is stable at physiological pH but releases the
platinum moiety in more acidic environment of hypoxic
tumors or endosomal/lysosomal vesicles inside the cells.
ProLindac showed better tumor inhibition, reduced toxicity
toward normal cells, increased and more sustained plasma

13

platinum levels and up to 16-fold increased platinum deliv-
ery to the tumor and 14-fold to tumor DNA. The conjugate
works better than oxaliplatin in three colon xenograft mod-
els (Colo-26, HT-29 and HCT116), in the L1210 murine
leukemia and 0157 hybridoma models [101]. ProLindac
was well tolerated and showed no neutropenia or signifi-
cant hematologic toxicity in patients with advanced solid
tumors in Phase I trial [92]. Phase II study in recurrent
ovarian cancer was initiated; however, in the last two years
there has been no update on the status of the trial, which
may indicate disappointing outcome. Interestingly, ProLin-
dac is no longer listed as a drug under development by the
company [102].
Platinum delivery using dendrimers
Dendrimers are highly branched polymers with multiple
end groups, which allow encapsulation or conjugation of
various drug molecules in the core or at the surface. There
is a wide variety of dendrimers, which are made from poly-
amidoamines, polyamines, polypeptides, polyesters, car-
bohydrates or DNA. The most frequently studied ones are
polyamidoamines (PAMAM). PAMAM dendrimers can
carry either amino groups or carboxylate groups at the end
of their branches. Cisplatin conjugate with PAMAM den-
drimers induced growth retardation of the subcutaneous
B16F10 murine melanoma, while cisplatin alone had no
antitumor activity [103]. Oxaliplatin conjugate with den-
drimers has also been reported. The PAMAM dendrimers
with carboxylic acid terminal group containing up to 40
DACH-Pt moieties at the surface retained water solubility
and showed sustained release of active platinum species
over 24 h at physiological conditions. But further study did
not progress due to the modest efficiency of the conjugate
[92]. A possible reason for this is irreversible binding of
platinum to easily accessible amino groups abundantly pre-
sent in the dendrimer. Two dendrimers featuring a PEG unit
as a core and citric acid on the periphery with molecular
weight of ca. 1000 Da and ca. 2000 Da, respectively, were
synthesized. Cisplatin conjugate of the latter polymer dem-
onstrated greater cytotoxicity in both sensitive and resistant
HT1080 human fibrosarcoma cells, CT26 fibroblasts and
SKOV3 human ovarian cells compared to cisplatin, while
cisplatin conjugate of the former polymer demonstrated
greater cytotoxicity toward HT1080 and CT26 cell lines.
Increased cytotoxicity of both conjugates over the parent
drug is encouraging for the possible use of dendrimer con-
jugates as carriers for platinum drugs [104].
Platinum drugs in nanotubes
Nanotubes have tubular shape with one dimension in the
nanometer scale, usually a diameter. Some examples of
13
Cancer Chemother Pharmacol
nanotubes are single-walled carbon nanotubes (SWCNTs)
or multi-walled carbon nanotubes (MWCNTs), peptide
nanotubes and template-synthesized nanotubes. The pres-
ence of open ends and a large inner volume facilitate incor-
poration of pharmaceutical species at high-loading capaci-
ties [92]. The possibility of incorporating and releasing
cisplatin from SWCNTs was demonstrated. The released
cisplatin retained the ability to kill human lung cancer
cells, while the SWCNTs themselves were not toxic [105].
The cytotoxicity of cis, cis, trans-[Pt(NH3)2Cl2(OEt)(OOC-
CH2CH2COOH)], a platinum(IV) complex, was increased
by >100-fold after it was tethered to a surface of carbon
nanotubes (Fig. 9). The conjugate was taken up by endo-
cytosis, and lower endosomal pH triggered the reduction
and release of the active Pt(II) complex [106]. Targeted
cisplatin–nanotube conjugates modified with folate or epi-
dermal growth factor (EGF) (Fig. 9) demonstrated selective
accumulation and enhanced activity against folate recep-
tor-positive tumor cells or EGF-overexpressing head and
neck squamous carcinoma cells, respectively [107]. Ultra-
short carbon nanotubes (USCNTs) of ca. 1.4-nm-diameter
encapsulating cisplatin were more potent than the free
platinum drug in two breast cancer cell lines (MCF7 and
MDA-MB-231). Wrapping of USCNTs with a surfactant
hindered the release of cisplatin resulting in higher cyto-
toxicity. For in vivo application, the surfactant molecules
could be replaced with a cancer-specific protein [108].
Platinum complexes in polymer micelles
Polymer micelles represent aggregates of block copoly-
mers featuring core–shell architecture. They entrap drugs
in the micelle core and increase the solubility of a drug.
Poly(amino acid)-based copolymers, such as poly(aspartic
acid), PAsp and poly(glutamic acid), PGlu, have been used
most frequently for platinum drug delivery. Incorporation
of cisplatin in such polymer micelles decreased nephro-
toxicity, increased the circulation of micelle-bound drug in
plasma and thereby increased exposure of the drug to the
tumors. The size of cisplatin-containing micelles is about
30 nm, which allows them to penetrate into tumor tissues
including poorly permeable tumors. PGlu-based cisplatin
micelles incorporating cisplatin showed prolonged blood
circulation and better accumulation in tumors. This for-
mulation, called NC-6004 or Nanoplatin, led to complete
tumor regression in some mice bearing C26 tumor, which
was not accompanied by a significant weight loss [92].
The cytotoxicity of NC-4006 was comparable to that of
free cisplatin in mice implanted with MKN-45 human gas-
tric cancer cells [109]. A Phase I clinical trial of NC-6004
showed significantly better tolerability than free cisplatin
with reduced side effects [110]. A Phase II study of the
combination with gemcitabine in pancreatic cancer patients
Cancer Chemother Pharmacol
demonstrated that platinum hypersensitivity could be com-
pletely inhibited by prophylactic treatment and that there
was no need for pre-hydration as required for the standard
cisplatin regimen. Oxaliplatin-containing micelles (NC-
4016) were also prepared and could overcome oxaliplatin
resistance in vivo because of drug release in the perinu-
clear region targeting it directly to DNA. Clinical trials of
NC-4016 are currently under way [92].
In summary, specific delivery of platinum drugs to
the tumor is an attractive way to improve their therapeu-
tic properties. A great diversity of carriers facilitates rapid
design of new formulations. Although most of constructs
under clinical evaluation rely on EPR effect, active target-
ing is likely to become a major strategy in the future. In the
era of targeted drugs, this may be the best opportunity to
bring a new platinum-based drug to the market. The avail-
able nanotechnology provides a good basis for the develop-
ment in this direction.
Novel combinations
Platinum drugs approved for clinical use are seldom given
to patients as monotherapy. They are usually combined
with other drugs in order to achieve a synergistic effect
through different mechanisms of action and thereby to
enable dose reduction for each drug. Good understanding
of how platinum complexes work and which mechanisms
are involved in platinum drug resistance paves the way for
the development of new combination regimens. Here, we
summarize the most interesting recent developments in this
field.
As downregulation of copper transporter 1 is associated
with cisplatin resistance, copper-chelating agents (e.g., tri-
entine), which stimulate expression of this transporter, have
been supposed to boost cisplatin uptake and thereby to sen-
sitize tumor cells to the drug. Despite encouraging results
in cell line models, therapeutic response in patients was
low (19 %). It may be due to the heterogeneous cohort of
patients and tumor entities in the study resulting in differ-
ent capacity of copper chelation to induce CTR1 [111].
Reports on synergistic interaction between platinum
drugs and various inhibitors of EGFR signaling have drawn
attention of clinicians to these combinations. However, so
far the results have been mostly disappointing. Combina-
tion of carboplatin/paclitaxel with sorafenib even increased
mortality in patients with squamous cell lung carcinoma in
a Phase III trial [112]. Addition of gefitinib did not improve
efficacy of the cisplatin/gemcitabine regimen in a Phase II
study [113]. Nevertheless, compared to the standard pem-
etrexed/platinum treatment gefitinib was able to improve
progression-free survival in NSCLC patients with EGFR
mutations [114].
In addition, there is growing interest in combining plati-
num drugs with PARP inhibitors targeting DNA repair sys-
tem. A combination of cisplatin with PARP inhibitors acted
synergistically in several NSCLC cell lines independently
of their p53 status, whereas treatment with either drug alone
had no effect. Synergistic interaction was attributed to the
induction of DNA damage foci, mitochondrial membrane
permeabilization, caspase activation and plasma membrane
rupture [23]. In Phase I studies, combination of olaparib
with cisplatin or cisplatin/gemcitabine regimen was not
very well tolerated, but promising activity in patients with
BRCA1/2 mutations warrants further investigation [115]. A
Phase II randomized study in NSCLC showed no benefit
from iniparib addition to the standard cisplatin/gemcitabine
therapy. However, the results could have been influenced
by imbalances in key baseline characteristics, such as per-
formance status, gender and disease stage [116].
Lessons to be learned and future directions
When considering efforts put into understanding how plati-
num drugs work and into development of new anticancer
platinum complexes, one may wonder why we have not yet
got another platinum drug approved for clinical use. A vast
number of new compounds have been prepared and tested
in cell line models. Unfortunately, the latter only poorly
reflect the clinical situation. High cytotoxicity in tumor
cell cultures should be in the first place viewed as a sign of
general toxicity, and not of anticancer activity. And indeed
some very promising drug candidates were abandoned due
to their toxic effects (Table 1). Parallel testing on healthy
cells (e.g., human fibroblasts) could help to discriminate
between toxic and antitumor effects at the early stage. It is
also important not to discard the compounds with moderate
activity in vitro right in the beginning but to estimate the
therapeutic window in the early animal studies. After all,
the widely and successfully used carboplatin is only mod-
erately cytotoxic. Regarding platinum drug delivery sys-
tems, which largely avoid the toxicity problems, not only
successful delivery but also sufficient release of the drug at
the tumor site is important (Table 1).
The differences between test animals and humans also
need to be taken into account. Besides different pharma-
cokinetics, the perception of tolerability and efficacy in
animal experiments is distinct from that in the clinical set-
ting. The accepted level of toxicity is high (body weight
loss  ≤15 % and lethality ≤10 % [76]) and may result in
severe intolerable side effects in patients. In animal stud-
ies, inhibition of tumor growth is seen as a sufficient end-
point, whereas therapeutic response in patients requires the
reduction in tumor lesions. Clinical development requires
improvement as well (Table 1). The setup of clinical trials
13

Table 1  Overview of factors halting the development of platinum drug candidates
Drug The furthest development stage and tumor entity
Picoplatin Phase III, SCLC
BBR3464 Phase II, metastatic SCLC,
metastatic pancreatic cancer
Tetraplatin Phase I, refractory solid tumors
Iproplatin Phase II, ovarian cancer, metastatic breast cancer
Satraplatin Phase III, prostate cancer
SPI-77 Phase II, platinum-sensitive recurrent ovarian cancer
should be carefully planned to avoid influence of external
factors such as post-study chemotherapy within a control
group (as in the case of picoplatin). Pharmaceutical com-
panies sometimes tend to aim at wider indication than the
drug candidate actually offers. On the contrary, clinical
studies would benefit from the focus on the advantages of
novel drugs. Satraplatin was developed as an oral plati-
num drug, which after reduction yields active platinum(II)
species sharing mechanistic principles with cisplatin and
carboplatin. It might have been advantageous to evalu-
ate satraplatin in the salvage setting in platinum-sensitive
tumors and not in refractory prostate cancer. Phase II tri-
als in ovarian cancer suggested at least similar activity of
satraplatin and approved platinum drugs. Even in the case
of comparable efficacy an oral platinum drug could be a
rational choice in the salvage therapy.
In the clinical trials, it is also of importance to choose the
appropriate dosing. For instance, in the case of carboplatin
the dose is calculated based on the target AUC (area under
curve) of a plot of drug concentration versus time and based
on the renal function represented by the glomerular filtra-
tion rate (GFR), the so-called Calvert formula. This dosing
strategy helps to compensate for the interpatient variability.
It relies on the specific pharmacokinetics of carboplatin, as
nearly three quarters of the drug is excreted in the urine in
the intact form. Such pharmacology-based dosing could be
considered for new inert platinum complexes, since their
plasma protein binding is expected to be low resulting in
predominantly renal clearance. Nevertheless, the Calvert
formula has its drawbacks. It does not cover specific patient
groups such as older and overweight patients, as well as
children. For children, for example, a modification of the
equation by Newell has been introduced. Another prob-
lem is measurement or estimation of the GFR or creatinine
clearance, which substitutes GFR in some new algorithms.
Measurements are either inconvenient and expensive (radi-
oisotopic methods) or inaccurate (24-h urine collection).
For this reason, several new methods of GFR estimation
13
Cancer Chemother Pharmacol
Reason(s) for failure to get approval
Poor setup of clinical study (choice of the control group)
Toxicity due to fast biotransformation, low maximum tolerated dose
resulting in only sporadic response
Toxicity, likely due to inactivation
No improved activity
Lack of benefit in overall survival, insufficient
power of the study, wrong choice of tumor entity
Lack of efficacy due to low drug loading capacity
and insufficient drug release
have been developed. At present, it is, however, inconclu-
sive, which estimation formula is better [117].
Understanding the factors leading to the lack of clinical
success holds a key to the rational design of new drugs. In
the times of targeted drugs and personalized medicine, drug
development relies on distinguishing between healthy and
tumor tissue and between patients. Therefore, a new plati-
num drug featuring only a different activity profile would
not have the potential to attract the sponsors. Consequently,
compounds and formulations stable in the bloodstream and
in healthy tissues releasing active species in tumor environ-
ment (e.g., carrier-based formulations or Pt(IV) prodrugs)
appear the most promising. In the future, they will likely
utilize active targeting strategies, e.g., through binding to
cancer-specific receptors. It should be noted, however,
that the issues of platinum drug attachment and controlled
release still pose a challenge, since delivery vehicles are
often peptides rich in nitrogen and sulfur donors with high
affinity for platinum.
Development of platinum drug conjugates with biologi-
cally active molecules sometimes showed that the conju-
gates were less effective than a simple drug combination.
The advantage of a combination is that active substances
are not bound to each other and can exert their effect inde-
pendently. Combination of platinum drugs with copper-
chelating agents is worth further investigation because
it could become a low-cost treatment option and because
resistant cells with low CTR1 levels could be more sus-
ceptible to the induction of the transporter. This strategy
would get more promising if CTR1 expression levels could
be determined influencing the decision to use a copper che-
lator or not. Combing platinum complexes with inhibitors
of EGFR signaling may be considered for the treatment
of patients with EGFR mutations. Platinum combinations
with PARP inhibitors, e.g., olaparib, show promise for the
group of patients featuring BRCA1/2 mutations. In this
case, sequential treatment may be beneficial as olaparib
response correlated with prior platinum sensitivity [116].
Cancer Chemother Pharmacol
The example of combinations clearly demonstrates
interpatient variability and the necessity to identify predic-
tive factors for therapeutic response and toxicity. Predictors
of severe ototoxicity and of cisplatin efficacy in head and
neck cancer have been reported, but many more are yet to
be revealed [102]. Rapid development of functional genom-
ics and imaging technology opens possibilities to personal-
ize platinum-based treatment of cancer. The application of
these techniques is likely to influence platinum chemother-
apy to a similar extent as the development of new drugs or
drug combinations.
Platinum drugs represent a cornerstone of treatment
of various solid neoplasms. Although the interest in new
platinum compounds has been fading in the era of targeted
drugs, the potential to improve on platinum-based treat-
ment has not yet been fully exploited. New drugs and for-
mulations actively targeted to the tumors and successfully
released there, but also new platinum-based drug combi-
nations and identification of predictive markers for patient
response and side effects are likely to shape future develop-
ments in the field.
Acknowledgments  The authors are grateful to Ulrich Jaehde (Insti-
tute of Pharmacy, University of Bonn) for fruitful discussions.
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