The status of platinum anticancer drugs in the clinic and in clinical trials.

TL;DR: The status of platinum anticancer drugs currently approved for use, those undergoing clinical trials and those discontinued during clinical trials are updated, and the results in the context of where the field will develop over the next decade are discussed.

Abstract: Since its approval in 1979 cisplatin has become an important component in chemotherapy regimes for the treatment of ovarian, testicular, lung and bladder cancers, as well as lymphomas, myelomas and melanoma. Unfortunately its continued use is greatly limited by severe dose limiting side effects and intrinsic or acquired drug resistance. Over the last 30 years, 23 other platinum-based drugs have entered clinical trials with only two (carboplatin and oxaliplatin) of these gaining international marketing approval, and another three (nedaplatin, lobaplatin and heptaplatin) gaining approval in individual nations. During this time there have been more failures than successes with the development of 14 drugs being halted during clinical trials. Currently there are four drugs in the various phases of clinical trial (satraplatin, picoplatin, Lipoplatin™ and ProLindac™). No new small molecule platinum drug has entered clinical trials since 1999 which is representative of a shift in focus away from drug design and towards drug delivery in the last decade. In this perspective article we update the status of platinum anticancer drugs currently approved for use, those undergoing clinical trials and those discontinued during clinical trials, and discuss the results in the context of where we believe the field will develop over the next decade.

Summary

Carboplatin (approved world-wide)

• The toxicity of platinum-based drugs is directly related to the ease with which the leaving groups are aquated.
• Platinum complexes with highly labile ligands, such as water or nitrate, are very toxic whereas ligands such as bis-carboxylates, which aquates very slowly, are significantly less toxic.
• Diammine[1,1cyclobutanedicarboxylato(2-)-O,O¢]platinum(II) was designed specifically to reduce the side effects associated with cisplatin treatment (Fig. 2 ).
• The side effects of carboplatin are also different with leukopenia, neutropenia and thrombocytopenia as the dose limiting toxicities (DLTs).
• Once aquated carboplatin yields the same active component as cisplatin and forms the same DNA adducts, and is therefore only clinically useful for treating the same cancer types.

Oxaliplatin (approved world-wide)

• [Oxalate(2-)-O,O¢][1R,2R-cyclohexanediamine-N ,N¢]platinum-(II) was the first drug approved that was capable of overcoming cisplatin resistance.
• In oxaliplatin the two ammine ligands have been replaced by a single bidentate ligand, (1R,2R)-cyclohexane-1,2-diamine (R,R-dach).
• 14 Whilst it predominantly forms GpG intrastrand adducts, the bulky hydrophobic dach ligand points into the DNA major groove which prevents binding of DNA repair proteins.
• Until then sales were worth more than US$1.3 billion per year.
• Recent clinical trials have tried to extend its spectrum of activity to include the treatment of metastatic gastric and oesophagogastric adenocarcinoma, 16 and improve its effectiveness against colorectal cancers through its administration with different drugs such as irinotecan and capecitabine.

Nedaplatin (approved in Japan)

• Diammine[hydroxyacetato(2-)-O,O¢]platinum(II) is a secondgeneration platinum analogue that is ten times more water soluble than cisplatin, and is significantly less nephrotoxic than both cisplatin and carboplatin.
• 18, 19 Preclinical and clinical studies demonstrated that nedaplatin has anticancer activity superior to that of carboplatin and equivalent to that of cisplatin.
• Lobaplatin is currently approved for the treatment of chronic myelogenous leukaemia (CML), inoperable metastatic breast cancer and SCLC.
• 38 In 2003 Ainan Tianwang International Pharmaceutical signed a US$4.3 million deal for manufacturing and marketing rights in China.
• 48 Previous studies have shown that patients experience lower nephrotoxicity with heptaplatin (360 or 400 mg m -2 ) when compared to cisplatin (60 mg m -2 ), 47-50 however, one randomised Phase III study highlighted that nephrotoxicity was more severe with heptaplatin.

Discontinued drugs

• In order to develop drugs that are more cytotoxic to cancers and have fewer and/or less severe side effects, it is important to know what drugs have previously undergone clinical trials but subsequently failed either due to a lack of activity or because of their toxicity (Table 2 ).
• In some instances drugs may also be discontinued in clinical trials simply for economic reasons.
• To date, 14 platinum-based drugs (Fig. 3 ) have completed at least one Phase I trial with only a few reaching Phase III.

NSC 170898

• Dichloridobisplatinum(II) is a simple derivative of cisplatin where the ammines of cisplatin have been functionalised with ligands.
• 56 Despite its very poor water solubility, in vivo testing showed that the drug was less toxic than cisplatin and had a much better therapeutic index (200-235) compared with cisplatin (8.1) in PC6 tumour bearing mice.
• 56 This drug underwent a single Phase I trial but was not further developed because of its poor solubility.

SPI-077

• This drug is a liposomal formulation of cisplatin which utilises steric stabilisation to avoid rapid clearance by macrophages.
• Treatment in Phase I and II clinical trials was generally well tolerated with little or no haematological, renal, hepatic, gastrointestinal or neurological toxicities and no requirement for routine hydration.
• 139-141 A lack of clinical activity despite the administration of large doses, coupled with an apparent absence of cisplatin related toxicities raised concerns over the bioavailability of cisplatin from the liposomes.
• A pharmacokinetic study revealed platinum-DNA adduct levels in white blood cells were more than ten-fold lower than after comparable doses of non-liposomal cisplatin.
• 139 In vitro studies confirmed negligible (< 10%) release from the liposomes, with extremely slow release kinetics.

Aroplatin TM

• Also known as L-NDDP consists of a lipophilic cisplatin analogue, cis-bis-neodecanaota-trans-(1R,2R-diaminocyclohexane)platinum(II), liposomally encapsulated in a 7:3 ratio of dimyristoyl phosphatidylcholine (DMPC) and dimyristol phosphatidylglycerol (DMPG) with a drug to lipid ratio of 1 : 15.
• 147 Preclinical studies have demonstrated that the bioavailability of NDDP is dependent on liposomal encapsulation.
• 148 Anticancer activity is exerted via chemical activation by forming one or more active intermediates in situ by intercalating between phospholipid molecules of the bilayer.
• 156 Treatment was generally well tolerated with 45% of patients receiving a dose escalation and the response rate was comparable to single agent oxaliplatin.
• 156, 157 A second Phase I trial looking at intrapleural administration of Aroplatin for 30 minutes every 21 days in patients with malignant pleural effusions determined a MTD of 450 mg m -2 (50% higher than IV administration) with chemical pleuritis as the DLT.

Drugs currently in clinical trials

• There are currently four drugs (Table 3 ) in various stages of clinical trials, with two of these being close to gaining marketing approval (satraplatin and picoplatin).
• Both of these drugs have demonstrated efficacy in Phase III trials and both are active when administered orally.
• Two other drugs (ProLindac TM and Lipoplatin TM ) will become the first polymer/liposomal-based platinum drugs if approved.

ProLindac TM

• This drug is a nanopolymer consisting of [Pt(R,R-dach)], the active moiety of oxaliplatin, bound to a hydrophilic biocompatible polymer (hydroxypropylmethacrylamide, HPMA) so as to better target solid cancers through the enhanced permeability and retention effect. [210] [211] [212] [213].
• Investigation into the in vitro effects of ProLindac showed that there were 20 times more platinum-DNA adducts at pH 3 than pH 7.4, presumably due to better drug release from the polymer at the lower pH.
• The treatment was well tolerated with no neutropenia or significant hematologic toxicity and a MTD of 640 mg m -2 .
• 216 A Phase I/II trial evaluated the anticancer activity of ProLindac as a single agent in the treatment of advanced ovarian cancer, where patients had previously been treated with platinums (except oxaliplatin) at least twice.
• Weekly doses were considered unsuitable due to the prolonged half life of ProLindac, so patients were administered with a two hour IV infusion every two or three weeks.

Lipoplatin TM

• Lipoplatin is a liposomally encapsulated form of cisplatin developed in an effort to reduce cisplatin's systemic toxicity profile and allow administration of greater doses whilst improving targeting to primary tumours and metastases.
• The nanoparticulate liposomes are reverse-miscelles, 222 composed of dipalmitoyl phosphatidyl glycerol (DPPG), soy phosphatidyl choline (SPC-3), cholesterol and methoxypolyethylene glycol-distearoyl phosphatidylethanolamine (mPEG2000-DSPE).
• This was compared to a 32% DCR in a cisplatin/gemcitabine control study.
• 230 A safety profile more favourable than cisplatin was also observed, with particular regard to nephrotoxicity, neurotoxicity and asthenia.
• 234 Response rates reached 80% tumour disappearance in patients receiving five cycles, supporting further studies of Lipoplatin in adjuvant postoperative or preoperative radio-chemotherapy regimes for the treatment of gastric cancer.

Conclusions

• The design and synthesis of platinum anticancer drugs is very much a mature field.
• In the 40 years since the discovery of cisplatin only six drugs have gained marketing approval whereas 14 were discontinued during clinical trials.
• All of these drugs demonstrate severe side effects which greatly limit the dose which can be administered, thereby reducing the effectiveness of the drugs.
• Instead, the last decade has witnessed a shift in focus towards the use of delivery vehicles, and three of these types of "drugs" (Aroplatin, Lipoplatin and ProLindac) entered clinical trials during this time.
• The development of new and better delivery vehicles for platinum drugs will rely almost entirely on inorganic and physical chemists, rather than pharmacists or medical researchers as the issues are almost entirely chemical.

Figures

Table 2 Platinum(II)-based drugs which entered human clinical trials but which have not been given marketing approval

Fig. 3 The platinum-based anticancer drugs which entered human clinical trials, but their development was not continued because of severe/unpredictable side effects from Phase I, because of a lack of activity in Phase II/III trials, or for economic reasons. Cycloplatam: where R = OH, R¢ = H and where R = H, R¢ = OH.

Fig. 4 The platinum-based anticancer drugs which are currently undergoing clinical trials for human use. Not shown: Lipoplatin.

Table 3 Platinum-based anticancer drugs which are currently undergoing clinical trials in humans

Fig. 1 Simplified biological processing of cisplatin inside cells showing (blue) drug aquation, (red) DNA binding through the N7 of guanine and (green) deactivation and degradation by the tripeptide L-glutathione. Charges have been omitted for charity.

Table 1 Platinum-based anticancer drugs which have achieved marketing approval for human use in at least one nation state

Fig. 2 Theplatinum-based anticancer drugswhich have gainedmarketing approval for human use in at least one nation state.

Full text

Registered Charity No. 207890
1477-9226(2010)39:35;1-1
ISSN 1477-9226
Dalton
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An international journal of inorganic chemistry
Volume 39 | Number 35 | 2010 Dalton Transactions
Pages 8097–8340
www.rsc.org/dalton Volume 39 | Number 35 | 21 September 2010 | Pages 8097–8340
PERSPECTIVE
Wheate et al.
The status of platinum anticancer drugs
in the clinic and in clinical trials
COMMUNICATION
Kloo et al.
Dichloromethane as solvent for the
synthesis of polycationic clusters at
room temperature – a link to standard
organometallic chemistry
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PERSPECTIVE www.rsc.org/dalton | Dalton Transactions
The status of platinum anticancer drugs in the clinic and in clinical trials
Nial J. Wheate,* Shonagh Walker, Gemma E. Craig and Rabbab Oun
Received 12th April 2010, Accepted 8th May 2010
First published as an Advance Article on the web 30th June 2010
DOI: 10.1039/c0dt00292e
Since its approval in 1979 cisplatin has become an important component in chemotherapy regimes for
the treatment of ovarian, testicular, lung and bladder cancers, as well as lymphomas, myelomas and
melanoma. Unfortunately its continued use is greatly limited by severe dose limiting side effects and
intrinsic or acquired drug resistance. Over the last 30 years, 23 other platinum-based drugs have entered
clinical trials with only two (carboplatin and oxaliplatin) of these gaining international marketing
approval, and another three (nedaplatin, lobaplatin and heptaplatin) gaining approval in individual
nations. During this time there have been more failures than successes with the development of 14 drugs
being halted during clinical trials. Currently there are four drugs in the various phases of clinical trial
(satraplatin, picoplatin, Lipoplatin
TM
and ProLindac
TM
). No new small molecule platinum drug has
entered clinical trials since 1999 which is representative of a shift in focus away from drug design and
towards drug delivery in the last decade. In this perspective article we update the status of platinum
anticancer drugs currently approved for use, those undergoing clinical trials and those discontinued
during clinical trials, and discuss the results in the context of where we believe the field will develop over
the next decade.
Introduction
Since the discovery of the therapeutic potential of cis-
diamminedichloridoplatinum(
II), or cisplatin, by Barnett Rosen-
berg (1926–2009)
1
it has become one of the major drugs in
cancer chemotherapy. Today it is used in 32 of 78 treatment
regimes listed in Martindale
2
in combination with a wide range
of other drugs including: topoisomerase II inhibitors (doxoru-
bicin, etoposide, mytomycin, bleomycin and epirubicin), mustards
(cyclophosphamide, melphalan and ifosfamide), antimetabolites
Strathclyde Institute of Pharmacy, and Biomedical Sciences, University of
Strathclyde, John Arbuthnott Building, 27 Taylor Street, Glasgow, UK G4
0NR. E-mail: nial.wheate@strath.ac.uk; Fax: +44 141 548 4962
Nial J. Wheate
Nial completed a BSc (Hons I)
and PhD (2002) at the Uni-
versity of New South Wales
under the direction of Assoc.
Prof. J. Grant Collins. He is
also a graduate of the Australian
Defence Force Academy (1997)
and served as an Officer in the
Royal Australian Navy (1995–
2005). After leaving the Navy in
2005, Nial was a Senior Fellow at
the University of Western Sydney
where he worked in the group
of Assoc. Prof. Janice Aldrich-
Wright. Currently he holds a lectureship in medicinal chemistry at
the University of Strathclyde, where his group undertakes research
into novel platinum drugs and drug delivery systems.
Shonagh Walker
Shonagh recently completed a
MSci in Chemistry with Drug
Discovery (Hons I) at the Uni-
vers ity of Strathclyde. During her
degree she completed a place-
ment year in industry with Pfizer
Veterniary Medicine where she
worked on a number of projects
dealing with quality control,
pharmaceutical formulation and
materials science. Shonagh is
currently completing a PhD in
platinum anticancer drug deliv-
ery, where her time is split be-
tween drug delivery research and pharmaceutical formulation re-
search. She enjoys taiko drumming, walking and is a warranted
leader in Girlguiding UK.
(gemcitabine, 5-fluorouracil (5-FU) and methotrexate), vinca
alkaloids (vinblastine and vinorelbine) and taxols (paclitaxel).
2
Cisplatin is currently used to treat testicular cancer (for which it
has a 90% cure rate), ovarian, bladder, melanoma, non-small cell
lung cancer (NSCLC), small cell lung cancer (SCLC), lymphomas
and myelomas.
2,3
In the blood stream where the chloride concentration is
relatively high (100 mM) the chloride ligands stay attached to
the drug although binding to serum proteins, such as human
serum albumin, does occur (Fig. 1).
4
When it reaches the tumour,
cisplatin is thought to be taken up into the cells by three possible
mechanisms: passive diffusion, copper transporter proteins (e.g .
CTR1) and/or organic cation transporters.
5
Once inside the
cell, the lower chloride concentration (4–20 mM) results in drug
This journal is
©
The Royal Society of Chemistry 2010 Dalton Trans., 2010, 39, 8113–8127 | 8113

Fig. 1 Simplified biological processing of cisplatin inside cells showing
(blue) drug aquation, (red) DNA binding through the N7 of guanine
and (green) deactivation and degradation by the tripeptide
L-glutathione.
Charges have been omitted for charity.
aquation with the loss of one or both of the chloride ligands.
4
When aquated, cisplatin can go on to bind to its target, DNA.
Cisplatin will bind at the N7 position of guanine, and to a lesser
extent adenine, through the formation of a covalent coordinate
bond with the lone pair of the nitrogen atom.
4
Ring closure
through the formation of a second DNA bond forms a range
of adducts, particularly 1,2-GpG intrastrand adducts that bend
the DNA (between 30 and 60
◦
towards the major groove) and
unwinds the helix (up to 23
◦
).
6
This DNA distortion prevents
replication and transcription, which ultimately leads to cellular
apoptosis.
4
Cisplatin is also known to bind to RNA and interfere
with cellular RNA processing, which may assist in the action of
the drug.
7
Unfortunately, the use of cisplatin is restricted because of severe
dose-limiting side effects which arise from the indiscriminate
uptake of the drug into all rapidly dividing cells (tumours,
but also for example bone marrow) and the body’s attempt
to excrete the drug through the kidneys. These side effects
include: nephrotoxicity (reduced kidney function and damage),
neurotoxicity (nervous system damage), ototoxicity (hearing loss),
and myelosuppression (reduction in bone marrow activity). To
some degree the nephrotoxicity of cisplatin can be reduced through
the use of saline hyperhydrat ion before and after treatment.
8
As a
single agent, cisplatin does not cause alopecia (hair loss).
The severe side effects of cisplatin mean that the dose delivered
to patients can be sub-lethal to tumours, particularly ovarian
cancers, which means they are then able to develop resistance
to further drug treatment. There are three main mechanisms of
drug resistance:
9
∑ Reduced drug uptake and/or increased drug efflux.
∑ Degradation and deactivation by intracellular thiols. In
particular this may be due to raised glutathione levels which can
be as high as 10 mM inside resistant cells.
∑ Improved repair or tolerance of DNA–cisplatin adducts.
The toxicity of, and cellular resistance to, cisplatin have driven
the development of improved platinum-based anticancer drugs
that display fewer or more tolerable side effects and/or are
able to overcome one or more resistance mechanisms. In the
30 years since cisplatin’s first approval for human use, 23 other
platinum-based drugs have entered clinical trials with only two
Gemma E. Craig
Gemma completed her BSc
(Hons I) Chemistry with Foren-
sics at the University of Strath-
clyde. During her degree she also
completed a placement year in in-
dustry with P rocter and Gamble
in London where she worked on
Clairol Perfect 10 hair colorant.
Gemma is currently undertaking
a PhD in platinum anticancer
drug delivery and has an interest
in rugby, cooking, reading and
socialising.
Rabbab Oun
Ruby completed a BSc (Hons) in
Medical Biochemistry at the Uni-
vers ity of Glasgow then attended
Napier University, Edinburgh
and graduated with an MSc in
Drug Design and Biomedical Sci-
ence (with distinction). Ruby’s
PhD project is split between the
University of Strathclyde and the
Beatson Institute for Cancer Re-
search, University of Glasgow
through a studentship from the
Scottish Universities Life Sci-
ence Alliance. She has an in-
terest in photography, enjoys travelling, cooking, reading and
swimming.
8114 | Dalton Trans., 2010, 39, 8113–8127 This journal is
©
The Royal Society of Chemistry 2010

Table 1 Platinum-based anticancer drugs which have achieved marketing approval for human use in at least one nation state
Drug
Other names/brand
names/formulation names CAS number
Development
company/Marketer DLT Country
Cisplatin Platinol
R
 Briplatin 15663-27-1 Generic Nephrotoxicity Global
Platidiam Abiplatin
R

Platinex
R
 Lederplatin
Platistin Neoplatin
Platosin Platibastin
Cisplatyl Peyrone’s
Platiblastin
R
 chloride
Carboplatin Paraplatin
R
 JM 8 41575-94-4 Generic Myelosuppression Global
Paraplatine Cycloplatin
Carbomedac
R
 CBDCA
Carbosin Ribocarbo
Oxaliplatin Eloxatin
R
 Dacplat
R
 61825-94-3 Sanofi-Aventis Neurotoxicity Global
Dacotin
R
 Elplat
R

Nedaplatin Aqupla
R
 254-S 95734-82-0 Shionogi Pharmaceuticals Myelosupression Japan
NSC375101D
Lobaplatin — — 135558-11-1 Asta-Medica Thrombocytopenia China
Heptaplatin Sunpla SKI 2053R 146665-77-2 SK Chemicals Life Sciences Nephrotoxicity/ Korea
Eptaplatin Intra-abdominal
bleeding
NSC-644591
NSC-D-644591
gaining global approval and another three gaining marketing
approval in individual nations. In this perspective we appraise the
current status of platinum drugs in the clinic and those currently
undergoing clinical trials. We also examine those drugs whose
development was halted during clinical trials and discuss the future
of platinum drug development.
Clinically approved drugs
A list of platinum-based anticancer drugs which have achieved
marketing approval for human use in at least one nation state is
given in Table 1.
Carboplatin (approved world-wide)
The toxicity of platinum-based drugs is directly related to
the ease with which the leaving groups are aquated. Platinum
complexes with highly labile ligands, such as water or nitrate,
are very toxic whereas ligands such as bis-carboxylates, which
aquates very slowly, are significantly less toxic. Diammine[1,1-
cyclobutanedicarboxylato(2-)-O,O¢]platinum(
II) was designed
specifically to reduce the side effects associated with cisplatin
treatment (Fig. 2). This is achieved through the replacement of
the dichloride ligands with 1,1-cyclobutanedicarboxylate, which
aquates with a rate constant of 10
-8
s
-1
, compared with 10
-5
s
-1
for
cisplatin.
10,11
Because of its lower reactivity, carboplatin can be administered
in much higher doses (300–450 mg m
-2
) than cisplatin (20–120 mg
m
-2
), depending on the administration schedule.
2
The side effects
of carboplatin are also different with leukopenia, neutropenia and
thrombocytopenia as the dose limiting toxicities (DLTs). Once
aquated carboplatin yields the same active component as cisplatin
and forms the same DNA adducts, and is therefore only clinically
Fig. 2 The platinum-based anticancer drugs which have gained marketing
approval for human use in at least one nation state.
This journal is
©
The Royal Society of Chemistry 2010 Dalton Trans., 2010, 39, 8113–8127 | 8115

useful for treating the same cancer types. Carboplatin is now
the drug of choice for ovarian cancer, in preference to cisplatin,
and has recently undergone additional Phase II and III trials for
the treatment of salivary gland cancer
12
and advanced mullerian
cancer
13
to further expand its clinical application.
Oxaliplatin (approved world-wide)
[Oxalate(2-)-O,O¢][1R,2R-cyclohexanediamine-N,N¢]platinum-
(
II) was the first drug approved that was capable of overcoming
cisplatin resistance. In oxaliplatin the two ammine ligands have
been replaced by a single bidentate ligand, (1R,2R)-cyclohexane-
1,2-diamine (R,R-dach).
4
Oxaliplatin is thought to overcome
cisplatin resistance through the different adducts it forms with
DNA.
14
Whilst it predominantly forms GpG intrastrand adducts,
the bulky hydrophobic dach ligand points into the DNA major
groove which prevents binding of DNA repair proteins.
15
The
oxalate ligand also greatly reduces the severity of the side effects
of the drug compared with cisplatin.
14
Oxaliplatin was first approved in France in 1996, the USA in
2002 and Japan in 2005. The drug was developed and marketed
throughout the world by Sanofi-Aventis and whilst t he Food and
Drug Administration in the USA (the biggest pharmaceutical
market in the world) approved generic formulations of the drug
in August 2009, deals between Sanofi-Aventis and six generics
manufactures means all will stop selling alternative versions of
oxaliplatin by 30 June 2010 until 09 August 2012. Until then
sales were worth more than US$1.3 billion per year. Oxaliplatin
currently has wide approval for t he treatment of adjuvant and
metastatic colorectal cancers when used in combination with 5-
FU and folinic acid.
2
Recent clinical trials have tried to extend
its spectrum of activity to include the treatment of metastatic
gastric and oesophagogastric adenocarcinoma,
16
and improve its
effectiveness against colorectal cancers through its administra-
tion with different drugs such as irinotecan and capecitabine.
17
Ongoing clinical trials as of April 2010 include examination for
efficacy in gastric, fallopian tube and ovarian, breast, NSCLC,
pancreatic cancers, acute myeloid leukaemia, indolent lymphoma,
and heptoma.
Nedaplatin (approved in Japan)
Diammine[hydroxyacetato(2-)-O,O¢]platinum(
II) is a second-
generation platinum analogue that is ten times more water
soluble than cisplatin, and is significantly less nephrotoxic than
both cisplatin and carboplatin.
18,19
Preclinical and clinical studies
demonstrated that nedaplatin has anticancer activity superior
to that of carboplatin and equivalent to that of cisplatin.
19,20
Since its approval in 1995, it has been used in the treatment
of NSCLC, SCLC, oesophageal cancer and head and neck
cancers.
19,21
The MTD of nedaplatin is 90 mg m
-2
and the DLTs
are thrombocytopenia and neutropenia.
22
Recently, several Phase I and Phase II studies have shown
promising results when nedaplatin is used in combination ther-
apies. For the treatment of oral squamous cell carcinoma, a
nedaplatin and docetaxel regime gave a partial response (PR) rate
of 33%.
23
Nedaplatin with paclitaxel in the treatment of metastatic
oesophageal carcinoma gave a complete response (CR) rate of 3%
and a PR rate of 41%,
24
and nedaplatin with irinotecan followed
by gefitnib in the treatment of NSCLC had an overall response
(OR) rate of 43%.
25
Two further clinical trials have been conducted to investigate the
effect of replacing cisplatin with nedaplatin in patients normally
treated with a regime of cisplatin and 5-FU for oesophageal
squamous cell carcinoma,
18,26
and locoregionally advanced na-
sopharyngeal carcinoma.
27
Both studies found no difference in
the overall survival rates. It was concluded, however, that replacing
cisplatin with nedaplatin may prove useful when treating cancer
patients that also present with renal impairment.
18,26
Lobaplatin (approved in China)
[2-Hydroxypropanoato(2-)-O1,O2][1,2-cyclobutanedimethan-
amine-N,N¢]platinum(
II) is a third-generation platinum anticancer
drug delivered as a diastereomeric mixture of S,S and R,R
configurations of the carrier ligand. The drug does not induce
alopecia,
28
renal, neuro- or ototoxic side effects after either IV
bolus injection or infusion.
29-33
Anaemia and leukopenia are
common,
28,29,34
as are nausea and vomiting, although the latter two
can be well-controlled with antiemetics.
28,29,34
The common DLT
is thrombocytopenia.
28,30,32–37
Lobaplatin is currently approved
for the treatment of chronic myelogenous leukaemia (CML),
inoperable metastatic breast cancer and SCLC.
38
In 2003 Ainan
Tianwang International Pharmaceutical signed a US$4.3 million
deal for manufacturing and marketing rights in China.
39
Recently, lobaplatin has been trialled in combination with
vinorelbine in the treatment of late-stage NSCLC but it demon-
strated no significant improvement in efficacy compared with a
vinorelbine/cisplatin regime.
40
A similar lobaplatin/vinorelbine
regime did however produce a 37% PR rate in patients treated
for advanced breast cancer with modest and recoverable non-
haematological toxicities.
36
Lobaplatin with 5-FU and leucovorin
is currently undergoing Phase III trials for the treatment of
recurrent or metastatic oesophageal carcinoma.
41
Heptaplatin (approved in the Republic of Korea)
[Propanedioato(2-)-O,O¢][2-(1-methylethyl)-1,3-dioxolane-4,5-
dimethanamine-N,N¢]platinum(
II) was selected for clinical trials
because its in vitro and in vivo cytotoxicity was equal, or superior,
to cisplatin in various cell lines.
42,43,44
It also displayed high
stability in solution,
42
no remarkable toxicity
42,43,44
and potent
anticancer activity towards cisplatin-resistant cells.
42,44
The MTD
of heptaplatin is 480 mg m
-2
with DLTs of hepatotoxicity,
nephrotoxicity and myelosuppression. It is currently used in the
treatment of gastric cancer.
45,46
Since obtaining marketing approval the drug has been further
evaluated in a Phase II trial where it demonstrated an increased
response rate in combination with 5-FU and leucovorin of
38%,
47
compared with 17% as a single agent.
48
Previous studies
have shown that patients experience lower nephrotoxicity with
heptaplatin (360 or 400 mg m
-2
) when compared to cisplatin (60 mg
m
-2
),
47–50
however, one randomised Phase III study highlighted that
nephrotoxicity was more severe with heptaplatin.
51
The most recent Phase III trial comparing a heptaplatin (400 mg
m
-2
)/5-FU regime with a cisplatin (60 mg m
-2
)/5-FU regime
demonstrates the survival and response rates to be comparable,
7.3 months vs. 7.9 months and 34% vs. 36%, respectively.
52
The
8116 | Dalton Trans., 2010, 39, 8113–8127 This journal is
©
The Royal Society of Chemistry 2010