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296 Anti-Cancer Agents in Medicinal Chemistry, 2013, 13, 296-306

Platinum Compounds: A Hope for Future Cancer Chemotherapy

Imran Ali*, Waseem A. Wani, Kishwar Saleem and Ashanul Haque

Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi-110025, India

Abstract: The discovery of cis-platin and its second and third generation analogues created a hope in cancer chemotherapy. Cis-platin
and its second generation analogue carboplatin have been used for the treatment of some cancers from a long time. The third generation
analogues have superior anti-cancer profiles for curing a few cancers. Unfortunately, certain side effects such as renal impairment,
neurotoxicity and ototoxicity etc. are associated with these drugs. But, combination therapy makes these analogues more effective with
fewer side effects. In addition, the results of some ongoing clinical trials will make the safety profile clear in near future. The present
article describes the current status of cis-platin and its analogues in cancer chemotherapy. In addition, special emphasis has been made on
cis-platin discovery, development of second (carboplatin, oxaliplatin, nedaplatin) and third (lobaplatin, heptalatin) generation analogues,
comparison of their chemotherapies, mechanism of action, therapeutic status, recent developments and chronology. Moreover, attempts
have been made to describe the future perspectives of these drugs in the cancer treatment.
Keywords: Cis-platin and its analogues, Comparison of chemotherapies, Mechanism of action, Therapeutic status, Recent developments,
Chronology and future perspectives.

INTRODUCTION Discovery of Cis-platin : A Breakthrough in Drug Development

The medicinal use of metal ions dates back to about 5000 years
[1]. Many compounds with metal ions have been used for various
medicinal purposes including cancer [2]. Metal based molecules are
biologically active due to their binding capacities with important
biological entities such as proteins, enzymes, hormones, nucleic
acids etc. Probably, it is due to the presence of vacant d-orbitals and
positive charge on metal ions, which act as binding sites [3]. It
was Barnett Rosenberg in 1965, who accidentally discovered the
biological activity of cis-platin, which was recognized as an
anticancer drug [4-6]. This miraculous discovery was followed by
extensive research and, thus, as a result many platinum based
complexes were synthesized and tested as anti-cancer agents.
Besides, some other structurally diverse coordination compounds
have been synthesized and reported along with their cell line
activities for the treatment of cancer; with a quest for the
development of new antitumor agents [7, 8]. However, metal ion
based molecules could not achieve a good status in cancer treatment
due to their several side effects. Therefore, for safe medication,
the knowledge of the mechanism of action is essential for the
development of novel agents. A good understanding of the
mechanism of action of metal complexes is also important for their
clinical success as well as to the rational drug design [9]. Unlike
other drugs, metal centered drugs affect cellular processes in much
dramatic fashion. They not only affect natural processes (cell
division and gene expression) but also non-natural processes
including toxicity, carcinogenicity, and antitumor chemistry [10-
17]. Some reviews have been published [3, 10, 18-19, 20-21] on
this topic during last two decades; describing different aspects of
platinum complexes. Now, it is the time to review the status of
platinum compounds in cancer treatment. In view of these facts,
attempts have been made to describe the state-of-art of platinum
complexes as anti-cancer drugs. The present article describes
various aspects such as the discovery of cis-platin, second and third
generation cis-platin analogues, comparison of platinum
complexes chemotherapies, mechanism of action, therapeutic
status and future perspectives of platinum anti-cancer drugs.
*Address correspondence to this author at the Department of Chemistry,
Jamia Millia Islamia (Central University), New Delhi-110025, India;
Tel: 091-9211458226; Fax: 0091-11-26985507;
E-mails: drimran_ali@yahoo.com, drimran.chiral@gmail.com
Home: http://jmi.nic.in/Fnat/imran_ch.htm
Cis-platin {cis-[Pt(NH3)2Cl2]}, (1) was first synthesized by
Peyrone in 1844 (Italy) but, unfortunately, its biological activity
was discovered much late by Rosenberg et al. [4-6] (1965). The
biological significance of platinum was observed during a study of
effect of alternating currents on the growth of Escherichia coli by
Rosenberg et al. [4-6]. He observed the inhibition of binary cell
division of bacterial cell with no effect on the cell growth, which
was an interesting observation that led to extensive research. It was
concluded that small amounts of platinum from the electrodes had
reacted with NH4Cl to produce various platinum amine halide
complexes. Among the complexes formed cis-[Pt(NH3)2Cl2] and its
corresponding tetrachloro complex cis-[Pt (NH3)2Cl4] were capable
to induce filamentous growth in the absence of an electric field
[19]. Later on, Rosenberg and coworkers [22, 23] screened cis-
platin on sarcoma 180 and leukemia L1210 bearing mice for the
evaluation of its biological activity, which led this complex in phase
I clinical trials in 1971. As a result of these studies, cis-platin was
approved for the treatment of testicular and ovarian cancer [24].
Nowadays, cis-platin is one of the most widely used antitumor
drugs for testicular, ovarian, bladder, cervical, head and neck and
small-cell and non-small cell lung cancers [22, 24]. Despite of good
clinical success of cis-platin, it lacks tumor tissue selectivity
leading to some severe side effects like renal impairment,
neurotoxicity and ototoxicity (loss of balance/hearing). Moreover,
long term or high-dose therapy of cis-platin may cause severe
anemia. To combat these problems, new cis-platin analogues,
leading to second and third generation platinum based drugs have
been synthesized over the last past 30 years [3].
Cl NH3
Pt
Cl NH3
Cisplatin
1: Cis-platin - The Precursor molecule to whole lot of metal centered anti-
cancer drugs.
Second Generation Cis-platin Analogues
As discussed above, some side effects restricted the applications
of cis-platin, which compelled scientists to exploit different

1875-5992/13 $58.00+.00 © 2013 Bentham Science Publishers

Platinum Compounds: A Hope for Future Cancer Chemotherapy
strategies for developing new platinum based drugs. Of course,
some attempts have been made and the second generation platinum
complexes were synthesized and tested as anti-cancer drugs [25].
The second generation platinum based drugs include carboplatin,
oxaliplatin and nedaplatin. These complexes are discussed below.
Carboplatin
Carboplatin is sold by the trade name of Paraplatin® while its
IUPAC name is Diammine-[1,1-cyclobutyldicarboxylato-(2-)O,O'])
platinum(II)]. This is the first complex of second generation
analogues. It was introduced by Johnson Matthey Plc. Institute of
Cancer Research, London, UK, through a collaborative project of
platinum drug discovery and development. This molecule differs
from cis-platin in having cyclobutyldicarboxylato; a didentate
ligand as the leaving group in place of two chlorides (2). Like cis-
platin, carboplatin exhibits anti-cancer activities for ovarian
carcinoma, lung, head and neck cancers. It is interesting to note that
this complex has fewer side effects, which are supposed to be due
to the presence of the chelating Cyclobutane-1,1-dicarboxylate
ligand [26]. Carboplatin has been suggested as pro-drug for cis-
platin [21] and the rate of aquation is slow in former as compared to
the latter [27]. Frey et al. [28] showed that the major reaction path
of carboplatin involves the direct attack by nucleophiles via ring
opening in carboplatin and subsequent binding with DNA
constituents. Owing to the reduced spectrum of deleterious side
effects, carboplatin is well tolerated by patients and can be used at
high doses than cis-platin [29].
Oxaliplatin
Oxaliplatin with IUPAC and brand name as {[(1R,2R)-
Cyclohexane-1,2-diamine][ethanedioato-O,O']-platinum(II)} and
Eloxatin® was the first drug approved for overcoming cis-platin
resistance. Kidani et al. [30] was the first to synthesize oxaliplatin
and the drug is known to exhibit stronger antitumor activity against
various colon cancer cell lines than its predecessors, cis-platin and
carboplatin. In oxaliplatin (2) a single didentate ligand, (1R,2R)-
cyclohexane- 1,2-diamine (R, R-dach) replaces two ammine ligands
of cis-platin [31]. Probably, the overcome of cis-platin resistance by
this drug is thought to be because of different adduct formation with
DNA [32]. The drug was first approved in France (1996), USA
(2002) and Japan (2005). Sanofi-Aventis developed and marketed
the drug throughout the world. USA Food and Drug Administration
approved generic formulations of this drug in 2009. The drug has
wide acceptance for the treatment of adjuvant and metastatic
colorectal cancers when used with 5- FU and folinic acid [33].
Recently, clinical trials have been carried out to extend its
spectrum of activity for the treatment of metastatic gastric and
oesophagogastric adenocarcinoma [34]. Besides, attempts have
been made to improve its effectiveness against colorectal cancers
through administration with different drugs such as capecitabine
and irinotecan [35]. Recent clinical trials of this drug (April 2010)
included examination for efficacy in gastric, fallopian tube, ovarian,
breast, non-small cell lung cancer, pancreatic cancers, acute
myeloid leukemia, indolent lymphoma and heptoma. The drug
mainly forms GpG intrastrand adducts with the bulky hydrophobic
dach ligand pointing into DNA major groove and preventing the
binding of DNA [36]. Moreover, the oxalate ligand is also known to
reduce the severity of side effects of the drug compared with cis-
platin [33, 37].
Nedaplatin
Nedaplatin is known by the name of Diamine[hydroxyacetato
(2-)-O,O'] platinum(II) and Aqupla® as IUPAC and brand names,
respectively (2). It is a second-generation cis-platin analogue
synthesized by Shionogi & Co., Ltd. (Osaka, Japan). It has tenfold
greater water solubility than cis-platin, and quite significantly less
Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 2 297
nephrotoxicity than both cis-platin and carboplatin [38, 39].
Nedaplatin has been shown to possess better anticancer activity
than carboplatin. It has also similar potencies as of cis-platin with
fewer side effects [39, 40]. Since the approval of this drug (1995)
it has been used in the treatment of non-small cell lung cancer,
small cell lung cancer, esophageal cancer and head and neck
cancers [39-41]. The minimum therapeutic dose (MTD) of
nedaplatin is 90.0 mgm-2 with thrombocytopenia and neutropenia as
dose limiting toxicities (DLTs) [42]. Promising results have been
obtained from several Phase I and Phase II studies when nedaplatin
was used in combination therapies e.g. treatment of oral squamous
cell carcinoma. Nedaplatin and docetaxel regime gave a partial
response (PR) rate of 33% [43]. Nedaplatin in combination with
paclitaxel; in the treatment of metastatic oesophageal carcinoma;
gave a complete response (CR) rate of 3% and a partial response
(PR) rate of 41%. Moreover, the treatment by nedaplatin with
irinotecan drugs; followed by gefitnib dosage of non-small cell
lung cancer (NSCLC) had an overall response (OR) rate of 43%
[44].
O
HN
3
O N O O O O
2+ NH3
Pt Pt Pt
HN
3
O
N O O O
-
NH3
Carboplatin
O
Oxaliplatin Nedaplatin
2: Second generation cis-platin analogues.
Third Generation Cis-platin Analogues
In spite of good biological activities of second generation
platinum complexes, scientists furthermore attempted to improve
these drugs by minimizing their side effects. This approach resulted
into the syntheses of third generation platinum analogues.
Lobaplatin and heptaplatin represent the third generation platinum
anticancer drugs. A brief description of these two third generation
anti-cancer drugs has been discussed below.
Lobaplatin
Lobaplatin has {[2-Hydroxypropanoato (2-)-O1,O2] [1,2-
cyclobutanedimethanamine-N,N']-platinum(II)} as IUPAC name
(3). DNA alkylating activity of this drug was developed by ASTA
Medica (Degussa) for the treatment of cancer. This drug is often
administered as a diastereomeric mixture of S,S- and R,R-
configurations of the carrier ligand. Lobaplatin has been approved
for the treatment of chronic myelogenous leukemia, inoperable
metastatic breast cancer and small cell lung cancer [45]. Moreover,
a combination of lobaplatin with vinorelbine was tried for the
treatment of the of late-stage non-small cell lung cancer. But no
improvement in the efficacy of the treatment was observed as
compared to a vinorelbine/ cis-platin regime. Contrarily, lobaplatin/
vinorelbine regime produced 37% PR rate in patients of advanced
breast cancer [46]. Currently, a combination of lobaplatin with 5-
FU and leucovorin is under phase III clinical trials for the treatment
of recurrent or metastatic esophageal carcinoma [47]. It is
interesting to note that no alopecia [49] renal, neuro-ototoxic side
effects are observed after IV bolus injection [49-53]. However,
anemia, nausea and vomiting, are observed as side effects [48, 49,
54]. In addition, thrombocytopenia is the most commonly observed
dose limiting toxicity associated with this drug [46, 48, 50, 52-56].
Heptaplatin
IUPAC and brand names of heptaplatin are {[Propanedioato
(2-)-O,O'][2-(1-methylethyl)-1,3-dioxolane-4,5-dimethanamine-N,N']-
platinum(II)} and Sunpla, respectively (3). The drug was originally
298 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 2
developed and marketed by S.K. Chemicals Life Sciences
and entered clinical trials because of its superior in vitro and
in vivo cytotoxicity as compared to cis-platin in various cell lines
[57-59]. The salient features of this drug include high solution
stability [58], no remarkable toxicity [57-58] and potent anticancer
activity towards cis-platin resistant cells [49]. The minimum
therapeutic dose (MTD) of heptaplatin is 480 mgm-2 with dose
limiting toxicities such as hepatotoxicity, nephrotoxicity and
myelosuppression. Currently, heptaplatin is used in the treatment
of gastric cancer [60-61]. A phase II trial was carried out to
investigate the effect of a combination regime of heptalatin, 5-FU
and leucovorin on patients with advanced stomach cancer. An
increased response rate of 38% was obtained by its combination
with 5-FU and leucovorin [62], which is greater than the single
agent response rate of 21% [63]. The advantages of the heptaplatin
treatment were the lower toxic side effects of neutropenia with less
emesis and proteinuria levels [64]. A supporting phase III trial
demonstrated that the two heptaplatin/5-FU regimes (34 and 36%
RR) were comparable with a cis-platin/5-FU regime (34% RR)
[65].
- O
O
NH2 2+ O NH2
2+
Pt NH2
Pt
NH2
O O
- O Lobaplatin
Heptaplatin
3: Third generation cis-platin analogues.
Comparison of Platinum Complex Chemotherapies
The discovery of cis-platin served as a source of inspiration for
further research that ultimately led to the development of new
platinum complexes i.e. second and third generation ones. Cis-
platin has long been used for the treatment of various cancers.
However, the use of cis-platin was associated with some side
effects as mentioned above. It is clear from the above discussion
Table 1. A general Comparison of cis-platin with its Second and Third Generation Analogues
Drugs Applications
First Generation
Cis-platin Testicular, ovarian, bladder, cervical, head and neck
and small-cell and non-small cell lung cancers.
Second Generation
Carboplatin Ovarian carcinoma, lung, head and neck cancers.
Oxaliplatin Adjuvant and metastatic colorectal cancers when
used in combination with 5- FU and folinic acid.
Nedaplatin Non-small cell lung cancer (NSCLC), small cell lung
cancer (SCLC), esophageal cancer and head and neck
cancers
Third Generation
Lobaplatin Chronic myelogenous Leukemia (CML), inoperable
metastatic breast cancer and single cell lung cancer
(SCLC)
Heptalatin Gastric cancer
Ali et al.
that the side effects were minimized in second generation analogues
followed by third generation ones. A general comparison of cis-
platin with its second and third generation analogues has been
summarized in Table 1. However, some important features of
these analogues are discussed herein. Oxaliplatin was the first drug
approved and capable of overcoming cis-platin resistance. Later on,
the solubility problem of cis-platin was overcome by nedaplatin;
with tenfold higher water solubility [38, 39]. Furthermore, nedaplatin
possessed better anticancer activity than carboplatin. Still clinical
trials are undergoing to study the effect of nedaplatin replacement
of cis-platin. A regime of cis-platin and 5-FU was replaced by
Nedaplatin for esophageal squamous cell carcinoma [38, 66] and
loco regionally advanced nasopharyngeal carcinoma [68]. No
difference in the overall survival rates has been reported by both
the studies. It was concluded that replacement of cis-platin by
nedaplatin might prove effective for these malignancies [38, 66].
The third generation analogue lobaplatin was very effective in the
treatment of chronic myelogenous Leukemia (CML), inoperable
metastatic breast cancer and single cell lung cancer (SCLC) with
some side effects. The development of heptalatin was overwhelmed
with the treatment to gastric cancer. The beauty of heptalatin lies in
- its high solution stability, no remarkable toxicity and potent
O
anticancer activity towards cis-platin resistant cells. The patients
experienced lower nephrotoxicity with heptaplatin (360 or 400 mg
O- O m-2) when compared to cis-platin (60 mg m -2) [62, 63, 68, 69]. In
Phase III clinical trials with advanced gastric cancer patients; a
comparison of heptaplatin (400 mg m-2)/5-FU regime with a cis-
platin (60 mg m -2)/5-FU regime; showed a comparable survival and
response rates of 7.3 months vs. 7.9 months and 34% vs. 36%,
respectively [65].
Mechanism of Action of Platinum Anti-Cancer Drugs
Usually, cis-platin is administered intravenously because of its
poor water solubility. As soon as it reaches the bloodstream, it
enters into the cytoplasm of the cells by passive diffusion [70].
Besides, it rarely diffuses into cells via active transport; mediated
by copper transporter i.e. (Ctr1p) in yeast and mammals [71, 72].
Due to lower chloride concentration inside the cells as compared to
Toxicities Remarks
Platinum Anti-Cancer Drug
Renal impairment, neurotoxicity and Lacked tumor tissue selectivity and with time cells
ototoxicity. became resistant.
Platinum Anti-Cancer Drugs
Myelo suppressive Fewer side effects than cis-platin , higher dose
effect, Nausea and vomiting. toleration.
Neuropathy, fatigue, neutropenia, Overcame cis-platin resistance and considerably
ototoxicity, hypoleukemia. lower side effects as compared to cis-platin .
Mild nausea, vomiting and nephrotoxicity Tenfold higher water solubility than cis-platin.
than other platinum-containing drugs. Less nephrotoxicity than both cis-platin and
carboplatin.
Platinum Anti-Cancer Drugs
Anaemia and leukopenia. Neither alopecia nor renal, neuro- or ototoxic side
effects after IV bolus injection are observed
Hepatotoxicity, nephrotoxicity and High solution stability, no remarkable toxicity and
myelosuppression. potent anticancer activity towards cis-platin -
resistant cells.
Platinum Compounds: A Hope for Future Cancer Chemotherapy
cell membrane itself, equilibrium is set up as shown in (4).
Platinum metal centre is attacked by a water molecule forming
cationic platinum complexes, such as [Pt (NH3)2(H2O) Cl] + with
the elimination of a chloride ion which acts as a non-coordinating
anion. The cell essentially traps cis-platin by transforming it into a
cationic component of a neutral molecule. After the loss of two Cl -
ions, hydrolyzed cis-platin reacts with DNA, forming coordinate
bonds to nitrogen atoms of the nucleotide bases. Thus, the active
species in the cell is (NH3)2Pt2+. Changes in DNA structure are
brought about by the binding of (NH3)2Pt2+ to DNA. NMR studies
revealed that Pt2+ binds to N7 atoms of a pair of guanine bases on
adjacent strands of DNA. A pathway for GG intrastrand cross-
linking of DNA by cis-platin is shown in Fig. (1), where aquation
of the complex is followed by monofunctional adduct formation,
followed by ring closure to give the bifunctional GG macro
chelate. In the GG chelate, two G bases are in the head-to-head
conformation with (NH3)2Pt2+ creating a unique junction between
the strands. This local distortion leads to impairment in the
processing of DNA in tumor cells. The distortion is characterized
by high mobility group (HMG) i.e. an 80 amino acid sequence
found in many proteins that dramatically bend DNA [73]. HMG
protein binds to the DNA- cis-platin adducts in a 1:1 ratio and
mimicks them from DNA repair enzymes. Hence, it is not simply
the distortion of DNA by the (NH3)2Pt2+ that disrupts the function
of DNA, but also the ability of the platinated-DNA function to
attract HMGs [3].
Binding of cis-platin to DNA and the formation of covalent
cross-links are responsible for its cytotoxicity. This binding causes
significant distortion of DNA double helical structure and
consequently results in inhibition of DNA replication and
transcription. The distorted, platinated-DNA adduct also serves as a
recognition binding site for cellular proteins [74, 75] such as
transcription factors, repair enzymes, histones and HMG-domain
proteins. Binding of HMG-domain proteins to cis-platin-DNA
Fig. (1). Pathways for GG intrastrand crosslinking of DNA by cis-platin.
Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 2 299
lesions has excision. The binding of HMG-domain proteins to cis-
platin-DNA lesions has been suggested to mediate the antitumor
activity of the drugs [73, 76-78]. Efficacy of cis-platin is also
affected by the efficiency of cis-platin-DNA adduct removal by the
cellular repair machinery, with nucleotide excision repair being a
major pathway. The repair of platinum-DNA crosslink is retarded
when the DNA is bound to the histones in a nucleosome core
particle [79, 80]. Mello et al. [81] demonstrated that the human
mismatch-repair protein (hMSH2) binds specifically to DNA
containing cis-platin adducts and displayed selectivity for the DNA
adducts of therapeutically active platinum complexes. These results
strongly suggest a role of hMSH2 in mediating cis-platin activity.
Various adducts are formed upon interaction of platinum complexes
with nucleotides, but contribution of individual adducts to
antitumor activity and toxicity of platinum complexes still remains
to be examined. Similar mechanisms have been suggested for
second and third generation analogues of platinum. Briefly, cis-
platin and its analogues show anti-cancer activities through their
various processes such as hydrolysis, transport into the cells,
binding to DNA (specific binding at adjacent guanine bases;
and especially a specific distortion of DNA) and changing its
interactions with proteins leading to either repair of the damage, or
cell killing by apoptosis [3].
Obviously, platinum based anti-cancer drugs are better than
other metal ion drugs. It may be due to long life of the former in
human body. Platinum metal ion drugs are advantageous as they
may have a life span of one year longer than other metal ion
chemotherapy treatments. Besides, platinum drugs act through a
combination of mechanisms. For example, cis-platin controls
cancer by inhibition of DNA synthesis and repair. This results in
cell cycle arrest at G1, S, or G2-M phases. Besides, platinum
compounds induce cell free radicals and reactive species, which
cause cancerous cell death. The formation of free radicals and
reactive species depends on the concentration and the duration of
300 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 2 Ali et al.

-
-Cl +H+
cis-Pt(NH3)2Cl2 cis-Pt(NH3)2Cl(H2O)+ cis-Pt(NH3)2Cl(OH)
+Cl - -H+
+Cl -Cl

cis-Pt(NH3)2Cl(H2O)22+

-H+ +H+

cis-Pt(NH3)2Cl(H2O)OH+ Oligomers

-H+ +H+

cis-Pt(NH3)2(OH2)

4: Attainment of equilibrium process for cis-platin in cancer cells.

exposure of platinum drugs. Contrarily, it is interesting to observe
that the free radicals generated by other metal ions are causing
DNA damage leading to more cancer; rather than curing
malignancies like in case of platinum compounds [82, 83].
Therapeutic Status of Platinum Drugs
All the drugs with their brand names/formulation names, CAS
numbers, Development company/Marketer, dose limiting toxicities
and approval country have been summarized in Table 2. It is clear
from this table that cis-platin and its second generation analogues
carboplatin and oxaliplatin have been approved globally for the
treatment of several cancer types. However, the dose limiting
toxicities like nephrotoxicity, myelosuppression and neurotoxicity
are still associated with the use of these drugs. cis-platin is sold
under brand names such as, Platinol®, Platinex® and Platiblastin®.
Carboplatin and oxaliplatin are sold as Paraplatin®, Carbomedac®
and Eloxatin®, Dacotin®, respectively. The approval of the other
second generation analogue nedaplatin is restricted to Japan where
it is sold under the brand name Aqupla®. Myelosuppression is the
mostly observed dose limiting toxicity associated with the use of
nedaplatin. The approval of the third generation cis-platin
analogues (heplatin and lobaplatin) is restricted to Korea and China,
respectively. Till now, they have not been approved globally. Their
commonly observed dose limiting toxicities are nephrotoxicity/intra
abdominal bleeding and thrombocytopenia. A number of other
platinum(II) centered drugs also entered human clinical trials but
have not been given marketing approval due to several therapeutic
inefficiencies like poor blood/urine clearance, issues of poor water
solubility, severe and unpredictable cumulative neurotoxicity, no or
very low activity in Phase I trials etc. Till date, 14 platinum-based
drugs have completed at least one Phase I trial with only a few
reaching Phase III [46].
Recent Developments in Platinum Drug Design
In 2009, Jian et al. [84] reported a novel class of platinum(II)
complexes and determined their in vitro anticancer activities against
the breast cancer cell-line (MCF-7) and the normal cell-line (MCF-
10A). They observed that the reported platinum complexes (d-f)
and their corresponding ligands (a-c) (5) exhibited higher drug
efficiencies than both cis-platin and oxaliplatin against MCF-7
cells. Moreover, increased cellular accumulation and DNA binding
of the complexes were observed as compared to cis-platin. The

Table 2. Platinum Based Anti-cancer Drugs Currently Under Use

Drug Brand Names CAS Number Development company/Marketer Dose Limiting Toxicities Country

Cis-platin Platinol® 15663-27-1 Generic Nephrotoxicity Global

Platidiam
Platinex®
Platistin
Platosin
Cisplatyl
Platiblastin®

Carboplatin Paraplatin® 41575-94-4 Generic Myelosupression Global

Paraplatine
Carbomedac® Carbosin

Oxaliplatin Eloxatin® 61825-94-3 Sanofi-Aventis Neurotoxicity Global

Dacotin®

Nedaplatin Aqupla® 95734-82-0 Shionogi Pharmaceuticals Myelosupression Japan

Heplaplatin Sunpla 146665-77-2 SK Chemicals Life Sciences Nephrotoxicity/Intra-abdominal bleeding Korea

Lobaplatin --- --- Asta-Medica Thrombocytopenia China

Platinum Compounds: A Hope for Future Cancer Chemotherapy
2007
2006
2002
P
1997
1993
Oxaliplatin + 5FU 1992 A
for colorectal cancer
Carboplatin approved 1989
for ovarian cancer
1982
1978
Fig. (2). Chronology of Platinum drug development.
authors concluded that these new platinum(II) based antitumor
agents were different from marketed platinum drugs in several
critical aspects with potential future in cancer therapy. Recently,
Navarro et al. [85] reported the anticancer activities of a series of
trans-platinum complexes with chloroquinine. Among the three
compounds evaluated for anticancer activities, one complex shown
in (6) exhibited greater in vitro activity than chloroquinine and cis-
platin. Recently, Banerjee and co-workers [86] compared DNA
compaction by cis-platin and the trisplatinum anticancer agent
BBR3464 (7). The primary cellular target of both cis-platin and
BBR3464 is DNA, but, later was found to exhibit 10-1000 times
lower dose limits; even in cis-platin-resistant cancer cells. The
authors explained these differential pharmacologic effects of these
two platinum complexes on the basis of the nature of DNA
structural changes. The authors observed that both compounds
compacted the whole double stranded DNA molecules, though
the degree of compaction in case of BBR3464 treatment was more.
In addition to this, local compaction in terms of loop structure
formation induced by both BBR3464 and cis-platin; with greater
microloops and macroloops by BBR3464. It was a significant
observation that BBR3464 induced relatively drastic DNA
structural changes in terms of loop formation as well as overall
DNA compaction at a molar ratio, which was 50 times less than
that applied for cis-platin treatment. In 2011, Varbanov et al.
[87], reported the cytotoxic properties of a series of six novel
bis(carboxylato)dichloridobis(ethylamine)platinum(IV) complexes
on four human tumor cell lines originating from ovarian carcinoma,
colon carcinoma and non-small cell lung cancer (A549) by MTT
calorimetric assay. The authors observed that the compounds with
4-propyloxy-4-oxobutanoato and 4-(2-propyloxy)-4-oxobutanoato
axial ligands (8) were the most lipophillic and most active among
the compounds screened with IC50 values down to the low
Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 2 301
S
1971
T
1968 1965
cis-platin shown
to be active
against mouse
model of cancer
nanomolar range. The first and effective approach to the design of
novel platinum anticancer drugs bearing adenine-based ligands was
demonstrated by Starha and co-workers in 2010. The authors
reported a series of platinum complexes involving adenine-based
ligands. In vitro cytotoxicity of the complexes was tested by MTT
assay against osteosarcoma and breast adenocarcinoma human
cancer cell lines. Interestingly, the best results were achieved for
the complexes (a) and (b) (9) in the case of both cell lines, whose
IC50 values equalled 3.6±1.0, and 4.3±2.1 µM (for a), and 5.4±3.8,
and 3.6±2.1 µM (for b), respectively. The IC50 equals 9.2±1.5 µM
against MCF7 cells in case of compound (c). In vitro cytotoxicity of
the mentioned complexes significantly exceeded commercially used
cis-platin (34.2± 6.4 µM and 19.6±4.3 µM) and oxaliplatin (> 50.0
µM for both cancer cell lines) [88]. Saha and co-workers [89]
reported antiproliferative activity and estrogen receptor affinity of
novel estradiol-linked platinum(II) complex analogs to carboplatin
and oxaliplatin they assumed these complexes as potential vectors
to target estrogen-dependent tissues. The authors described three
estradiol-linked platinum(II) complex analogs to cis-platin viz. VP-
128, CD-38 and JMP-39 (10). These complexes were observed to
exhibit potent in vitro and in vivo activities. Moreover, the
complexes showed interaction with the estrogen receptor a (ERa)
against MCF-7 and MDA-MB-231 human mammary carcinoma
cell lines.
Chronology of Platinum Drug Development
Platinum drug development involves interesting chronology and
is shown in Fig. (2). A perusal of this figure indicates that the research
began with the accidental discovery of the mysterious biological
properties of cis-platin in bacteria in 1965. This extremely
fascinating discovery was followed by further experimentation in
302 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 2 Ali et al.

HO HO
HO

NH NH
NH

NH NH
NH

HO HO
HO
(R ,R ) (S ,S ) (R ,S )
(a ) (b ) (c )

HO HO
HO

NH NH
Cl NH Cl
Cl
Pt Pt
Cl Pt
Cl Cl
NH NH
NH

HO HO
HO
(R ,R ) (S ,S ) (R ,S )
(d ) (e ) (f)

5: Novel class of ligands (a- c) and their platinum complexes (d-f) reported by Jian et al. having better anticancer properties than both cis-platin and oxaliplatin
against MCF-7 cells.

N
HN

Cl N

Cl Pt Cl

N
N
Cl
N
H
6: Chemical structure of a trans platinum complex with chloroquinine showing better anticancer properties than both cis-platin and chloroquine.
Cl NH3
Pt
NH2 NH3
NH3 H2N
Pt
NH3 NH2
H2N NH3
Pt
NH3 Cl
7: Chemical structure of BBR3464: A trisplatinum anticancer agent.

O O
O O
NH2 O NH2 O
Cl Cl
Pt Pt
NH2 Cl Cl
NH2
O O
O O
O O

8: Platinum complexes bearing 4-propyloxy-4-oxobutanoato and 4-(2-propyloxy)- 4-oxobutanoato axial ligands reported by Verbanov et al.
MeO Cl Cl
Cl
N N N
N OMe N
N N N N
H H H

N N N N N
N O O O O O O
Pt Pt Pt
O O O O O O
N N N N N
N

H H H
N N N N N
N OMe
N N
N Cl Cl
Cl
MeO
(a) (b) (c)

9: Platinum complexes with adenine based ligands.

Platinum Compounds: A Hope for Future Cancer Chemotherapy
OH
H Cl
HO
VP- 128
OH
OH
Cl
HO
CD- 38
OH
OH
O reactions of platinum complexes with nucleic acids and proteins
O NH
Cl Pt
HO
JMP- 39 Cl
10: Chemical structures of estradiol-linked platinum(II) complex analogs to
cis-platin derivatives; VP-128, CD-38 and JMP-39.
1968 that proved cis-platin as active agent against a mouse model
of cancer. It was only three years later that first ever human patient
was treated with cis-platin. Owing to these facts cis-platin was
approved by US FDA for the treatment of testicular and bladder
cancers in 1978. All these findings fostered a renewed interest in
harnessing the rich potential of metal based drugs in the treatment
of cancer. As a result several analogues of the parent cis-platin
molecule were developed; with the first human patient treatment by
carboplatin (second generation cis-platin analogue) in 1982. Seven
years later (1989), carboplatin was approved for the treatment of
ovarian cancer. In 1992, the first clinical study showed the promise
of oxaliplatin in combination with 5-fluorouracil in patients with
colorectal cancer. Further advancement was witnessed in platinum
drug design in 1993, as first ever patient was treated with an orally
administered platinum drug, JM216 (satraplatin) (11). Later on, in
1999 another platinum drug JM473 (picoplatin) (12) was used to
treat human patients. 2002 was a golden year in the therapeutic
history of oxaliplatin as the drug got initial US FDA approval for
the treatment of colorectal cancer. Fig. (2) supports the fact that
considerable advancement has been observed in combination
chemotherapy by the approval of bevacizumab in non-small-cell
lung cancer used in combination with carboplatin and paclitaxel.
More importantly, satraplatin was approval by the US FDA for the
treatment of prostate cancer. The present status of platinum drugs
comprises of the design, syntheses and clinical trials of several
platinum complexes for different malignancies. This is because of
much interest in the development of novel anticancer drugs with
reduced or no toxicity and a good activity against cancer cells.
Efforts are also being made by scientists of the entire world over for
efficient and safe delivery of these drugs to tumor sites.
O Therefore, it is expected that combination therapies may be useful
O into consideration, there is an urgent need to understand the
Cl
Pt
NH2 O Cl
O
11: Chemical structure of satraplatin.
Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 2 303
Cl NH3
NH Pt
Pt
Cl N
N
Cl
12: Chemical structure of picoplatin.
FUTURE PERSPECTIVES
NH Applications of coordination chemistry to living systems are not
only limited to metal-ligand bond formation and metal ligand
Pt
N
stability but controls the binding of metal complexes to DNA via
Cl simultaneous coordination and hydrogen bonding. The above
discussion is in support of the fact that there can be a number of
fascinating future opportunities for research in this area in the
coming decade. The development of new techniques to monitor the
will be an asset to the detection of otherwise invisible intermediate
products. A good understanding of the mode of action of cis-platin
N is highly useful in the processes of drug design. It is expected that
in the next decade improved antitumor drugs based on the
knowledge of Pt-DNA interactions (and their repair) and on the
kinetics of binding of platinum compounds to proteins and DNA
will be developed. The usefulness of cis-platin and carboplatin in
chemotherapy and the resistance of many tumors to these
compounds provided the necessary impetus for the development of
new site specific, less toxic and more effective platinum antitumor
drugs. This quest for the design of platinum complexes exclusively
selective for the tumor site with no or minimum systemic toxicity
(‘magic bullets’) is a great hope in fighting against cancer. It has
also served a driving force within the expanding field of
bioinorganic chemistry [90]. The drugs with targeted action on
cancerous cells and low side effects can be achieved by
synthesizing their nano counterparts. Trapping drug molecules into
nano cages avoids their diffusibility and ensures site specific
delivery. Also, these drugs are bestowed with usefulness of
selectivity, specificity and fast action with long lives of patients
[91]. Nano identities of platinum based drugs may be expected to
cure a number of cancers with fewer side effects [92]. Yang et al.
[93] studied the targeted delivery of cis-platin to oral cancer by cis-
platin loaded poly lactic acid polyethylene glycol nanoparticles
(CDDP-PLA-PEG-NP). They also reported that CDDP-PLA-PEG-
NP delivered CDDP to oral carcinoma tissues by vein injection.
The stealth anticancer nanoparticles system can be regarded as a
valuable drug delivery system to treat oral carcinoma. As per the
reports of Peer and Margalit [94], loaded mitomycin C in liposomes
(tHA-LIP) increased drug potency 100 times in cancerous cells in
mice tumor models. Additionally, the development of photo-
activatable platinum prodrugs is expected to increase the selectivity
and lower toxicity of platinum antitumor drugs, which may find use
in treating localized tumors accessible to laser-based fiber-optic
devices [95]. A few reports are in favour of the fact that synergistic
effects in breast cancer cells have been observed by the use of
platinum complexes in combination with other agents. This has
been proved by the combinations of cis-platin/carboplatin with
taxanes or the antibody trastuzumab as the combination agents [96].
to get novel drug combinations in near future. Keeping these points
molecular mechanism of apoptosis induced by new platinum based
drugs and to synthesize their nano counterparts. Scientists and
oncologists all over the world should work together to develop
hundred percent safe platinum based drugs (either in nano regime
of the normal size range) for all sorts of cancers. Briefly, the overall
observation, experience and literature update dictate that the future
of platinum based drugs is quite bright in the treatment of cancer.
304 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 2
Moreover, this sort of medication has strong potential to eradicate
other diseases; even via gene therapy. Let’s hope for the best future
of platinum based anticancer drugs for the service of mankind in the
coming time.
CONCLUSION
The design and synthesis of platinum based anticancer drugs is
a mature field of research. Since the discovery of cis-platin only six
drugs have gained marketing approval whereas fourteen were
discontinued during clinical trials. The severe side effects
associated with the use of these drugs limit the dose at which the
drugs can be administered; thereby, reducing the effectiveness of
these drugs. A look at the last decade global cancer statistics is
horrifying as the number of cancer patients is observed to increase
in large numbers annually. The increasing cancer patients not only
become a burden on the society but also destroy the economy of the
country [97]. Therefore, it is the need to take bold challenges for
the development of novel metal based drugs able to cure cancer
even in late stages. The development of nano-anticancer drugs
should be encouraged since the matter in nano regime shows
excellent properties. Nano regimes of the drugs increase their
bioavailability and site specific delivery. In nutshell, cancer is a
deadly disease killing millions of people annually, so it is the duty
of the scientific community all over the world to stand united so
that new potent drug molecules can be made available. Let’s hope
and wish for the revolution of chemotherapy in providing relief to
the people suffering from deadly fatal cancer.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no conflict of
interest.
ACKNOWLEDGEMENTS
Mr. Waseem Ahmad Wani and Ashanul Haque are highly
thankful to University Grants Commission (UGC) New Delhi for
providing them UGB-BSR Meritorious fellowship.
REFERENCES
[1] Orvig, C.; Abrams, M.J. Medicinal inorganic chemistry:
introduction. Chem. Rev., 1999, 99, 2201-2203.
[2] Alderden, R.A.; Hall, M.D.; Hambley, T.W. The Discovery and
development of cis-platin. J. Chem. Edu., 2006, 83, 728-734.
[3] Kostova, I. Platinum Complexes as Anticancer Agents. Rec. Pat.
Anti-Canc. Drug Disc., 2006, 1, 1-22.
[4] Rosenberg, B.; Van Camp, L.; Krigas, T. Inhibition of cell division
in Escherichia coli by electrolysis products from a platinum
electrode. Nature, 1965, 205, 698-699.
[5] Bertini, I.; Gray, H.B.; Lippard, S.J.; Valentine, J.S. Bioinorganic
Chemistry; University Science Books: Sausalito, California, 1994;
pp. 523-590.
[6] Kaim, W.; Schwederski, B. Bioinorganic chemistry: Inorganic
element in the chemistry of life, Wiley: Stuttgart, 1993; pp. 363-384.
[7] Grunicke, H.; Doppler, W.; Helliger, W.; Hermann, B.J.; Hofmann,
J.; Lindner, H.; Puschendorf, B. Tumor biochemistry as basis for
advances in tumor chemotherapy. Arch. Geschwulst. Forsch., 1986,
56, 193-201.
[8] Zhukova, O.S.; Dobrynin, IaV. Current results and perspectives of
the use of human tumor cell lines for antitumor drug screening.
Vopr. Onkol., 2001, 47, 706-709.
[9] Wang, Y.; Chiu, J.F. Proteomic Approaches in Understanding
action mechanisms of metal-based anticancer drugs. Metal-Based
Drugs, 2008, 1-9.
[10] Burger, H.; Loos, W.J.; Eechoute, K.; Verweij, J.; Mathijssen,
R.H.J.; Wiemer, E.A.C. Drug transporters of platinum-based
anticancer agents and their clinical significance. Drug Res. Up.,
2011, 14, 22-34.
[11] Andrews, P.A.; Jones, J.A.; Varki, N.M.; Howell, S.B. Rapid
emergence of acquired cis-diamminedichloroplatinum(II) resistance
Ali et al.
in an in vivo model of human ovarian carcinoma. Cancer Commun.
1990, 2, 93-100.
[12] Ardizzoni, A.; Boni, L.; Tiseo, M.; Fossella, F.V.; Schiller, J.H.;
Paesmans, M.; Radosavl-Jevic, D.; Paccagnella, A.; Zatloukal, P.;
Mazzanti, P.; Bisset, D.; Rosell, R. Cis-platin versus carboplatin
based chemotherapy in first line treatment of advanced non-small-
cell lung cancer: an individual patient data meta-analysis. J. Natl.
Cancer Inst., 2007, 99, 847-857.
[13] Blair, B.G.; Larson, C.A.; Safaei, R.; Howell, S.B. Copper
transporter 2 regulates the cellular accumulation and cytotoxicity
of cis-platin and carboplatin. Clin. Cancer Res., 2009, 15,
4312-4321.
[14] Borst, P.; Rottenberg, S.; Jonkers, J. How do real tumours become
resistant to cis-platin? Cell Cycle, 2008, 7, 1353-1359.
[15] Brabec, V.; Kasparkova, J. Modifications of DNA by platinum
complexes: relation to resistance of tumors to platinum antitumor
drugs. Drug Resist. Update, 2005, 8, 131-146.
[16] Briz, O.; Serrano, M.A.; Rebollo, N.; Hagenbuch, B.; Meier, P.J.;
Koepsell, H.; Marin, J.J. Carriers involved in targeting the cytostatic
bile acid-cis-platin derivatives cis-diammine-chlorocholylglycinate-
platinum(II) and cis-diammine-bisursodeoxycholate-platinum(II)
toward liver cells. Mol. Pharmacol., 2002, 61, 853-860.
[17] Buchdunger, E.; Cioffi, C.L.; Law, N.; Stover, D.; Ohno-Jones, S.;
Druker, B.J.; Lydon, N.B. Abl protein-tyrosine kinase inhibitor
STI571 inhibits in vitro signal transduction mediated by c-kit and
platelet-derived growth factor receptors. J. Pharmacol. Exp. Ther.,
2000, 295, 139-145.
[18] Abu-Surrah, A.S.; Kettunen, M. Platinum group antitumor chemistry:
Design and development of new anticancer drugs complementary
to cis-platin . Curr. Med. Chem., 2006, 13, 1337-1357.
[19] Rosenberg, B.; Van Camp, L.; Trosko, J.E.; Mansour, V.H.
Platinum Compounds: a new class of potent antitumour agents.
Nature, 1969, 222, 385-386.
[20] Rosenberg, B. Platinum complexes for the treatment of cancer:
Why the search goes on, in Chemistry and biochemistry of a
leading anticancer drug. B. Lippert, Ed.; Wiley-VCH, New York,
1999; pp. 1-27.
[21] Tinker, N.D.; Sharma, H.L. McAuliffe, C.A. In Platinum and
Other Metal Complexes in Cancer Chemotherapy, M. Nicolini Ed.;
Martinus Nijhoff: Boston, MA, 1988; pp 144-159.
[22] Rosenberg, B.; Van Camp, L. The successful regression of large
solid sarcoma 180 tumors by platinum compounds. Cancer Res.,
1970, 30, 1799-1802.
[23] Kociba, R.; Sleiht, S.D.; Rosenberg, B. Inhibition of Dunning
ascitic leukemia and Walker 256 carcinosarcoma with cis-
diamminedichloroplatinum (NSC-119875). Cancer Chemother.
Rep., 1970, 54, 325-328.
[24] Weiss, R.B.; Christian, M.C. New cis-platin analogues in
development: A review. Drugs, 1993, 46, 360-377.
[25] Bruijnincx, P.C.A.; Sadler, P.J. New trends for metal complexes
with anticancer activity. Curr. Opin. Chem. Biol., 2008, 12, 197-
206.
[26] Neidle, S.; Ismail, I.M.; Sadler, P.J.J. The structure of the antitumor
complex cis-(diammino)(l,l-cyclobutane-dicarboxylato)-Pt(II): X-
ray and NMR studies. Inorg. Biochem., 1980, 13, 205-212.
[27] Canovese, L.; Cattalini, L.; Chessa, G.; Tobe, M.L. Kinetics of
the displacement of cyclobutane-1,1-dicarboxylate from diammine
(cyclobutane-1,1-dicarboxylato)platinum(II) in aqueous solution. J.
Chem. Soc., Dalton Trans., 1988, 2135-2140.
[28] Frey, U.; Ranford, J.D.; Sadler, P.J. Ring-opening reactions of the
anticancer drug carboplatin: NMR characterization of cis-
[Pt(NH 3)2(CBDCA-O)(5'-GMP-N7)] in solution. Inorg. Chem.,
1993, 32, 1333-1340.
[29] Jakupec, M.A.; Galanski, M.; Keppler, B.K. Tumor inhibiting
platinum complexes- state of the art and future perspectives. Rev.
Physiol. Biochem. Pharmacol., 2003, 146, 1-53.
[30] Armand, J.P.; Bolgie, V.; Raymond, E.; Fizazi, K.; Faivre, S.;
Ducreux, M. Oxaliplatin in colorectal cancer: an overview. Semin.
Oncol., 2000, 27, 96-104.
[31] Kelland, L. The Resurgence of Platinum-based Cancer
Chemotherapy. Nat. Rev. Cancer, 2007, 7, 573-584.
[32] Boulikas T.; Vougiouka, M. Cis-platin and platinum drugs at the
molecular level. Oncol. Rep., 2003, 10, 1663-1682.
[33] Martindale. The complete drug reference,; 35th ed.; S.C.
Sweetman, Ed.; Pharmaceutical Press: London, 2007.
Platinum Compounds: A Hope for Future Cancer Chemotherapy
[34] Lordick, F.; Luber, B.; Lorenzen, S.; Hegewisch-Becker, S.;
Folprecht, G.; Woll, E.; Decker, T.; Endlicher, E.; Rothling, N.;
Schuster, T.; Keller, G.; Fend, F.; Peschel, C. Cetuximab plus
oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric
cancer: a phase II study of the Arbeitsgemeinschaft Internistische
Onkologie (AIO). Br. J. Can., 2010, 102, 500-505.
[35] Zarate, R.; Rodriguez, J.; Bandres, E.; Patino-Garcia, A.; Ponz-
Sarvise, M.; Viudez, A.; Ramirez, N.; Bitarte, N.; Chopitea A.;
Gacia-Foncillas, J. Oxaliplatin, irinotecan and capecitabine as
first-line therapy in metastatic colorectal cancer (mCRC): a dose-
finding study and pharmacogenomic analysis. Br. J. Can., 2010,
102, 987-994.
[36] Kasparkova, J.; Vojtiskova, M .; Natile G.; Brabec, V. Unique
properties of DNA interstrand cross-links of antitumor oxaliplatin
and the effect of chirality of the carrier ligand. Chem. Eur. J., 2008,
14, 1330-1341.
[37] Cassidy, J.; Misset, J.L. Oxaliplatin-related side effects: characteristics
and management. Semin. Oncol., 2002, 29,11-20.
[38] Kuwahara, A.; Yamamori, M.; Nishiguchi, K.; Okuno, T.;
Chayahara, N.; Miki, I.; Tamura, T.; Inokuma, T.; Takemoto, Y.;
Nakamura , T.; Kataoka, K.; Sakaeda, T. Replacement of cis-platin
with nedaplatin in a definitive 5-fluorouracil/cis-platin -based
chemoradiotherapy in Japanese patients with esophageal squamous
cell carcinoma. Int. J. Med. Sci., 2009, 6, 305-311.
[39] Alberto, E.M.; Lucas, M.F.A.; Pavelka, M.; Russo, N. The second-
generation anticancer drug nedaplatin: a theoretical investigation
on the hydrolysis mechanism. J. Phys .Chem. B., 2009, 113, 14473-
14479.
[40] Kawai, Y.; Taniuchi, S.; Okahara, S.; Nakamura, M.; Gemba, M.
Relationship between cis-platin or nedaplatin induced nephrotoxicity
and renal accumulation. Biol. Pharm. Bull., 2005, 28, 1385-1388.
[41] Boulikas, T.; Pantos, A.; Bellis, E.; Christofis, P. Designing platinum
compounds in cancer: structures and mechanisms. Cancer Ther.,
2007, 5, 537-583.
[42] Kodaira, T.; Nobukazu, F.; Tachibana H.; Hidano, S. Phase I study
of S-1 and nedaplatin for patients with recurrence of head and neck
cancer. Antican. Res., 2006, 26, 2265-2268.
[43] Kurita, H.; Yamamato, E.; Nozaki, S.; Wada, S.; Furuta, I.; Miyata,
M.; Kurashina, K. Multicenter phase 2 study of induction
chemotherapy with docetaxel and nedaplatin for oral squamous cell
carcinoma. Can. Chemother. Pharmacol., 2010, 65, 503-508.
[44] Oshita, F.; Yamada, K.; Saito, H.; Noda, K.; Hamanaka N.; Ikehara
, M. Phase II study of nedaplatin and irinotecan for elderly patients
with advanced non-small cell lung cancer. J. Exp. Ther. Oncol.,
2004, 4, 343-348.
[45] A.I. Limited, Drugs R&D, 2003, 4, 369-372.
[46] Wheate, N.J.; Walker, S.; Craig, G.E.; Oun, R. The status o f
platinum anticancer drugs in the clinic and in clinical trials. Dalton
Trans., 2010, 39, 8113-8127.
[47] Shchepinov, M.S.; Denissenko, M.F.; Smylie, K.J.; Worl, R.J.;
Leppin, A.L.; Cantor C.R.; Rodi, C.P. Matrix-induced fragmentation
of P3 '-N5 ' phosphoramidate-containing DNA: high-throughput
MALDI-TOF analysis of genomic sequence polymorphisms.
Nucleic Acids Res., 2001, 29, 3864-3872.
[48] Mross, K.; Meyberg, F.; Fieberg, H.H.; Hamm, K.; Hieber, U.;
Aulenbacher, P.; Hossfeld, D.K. Pharmacokinetic and pharma-
codynamic study with lobaplatin (D-19466), a new platinum
complex, after bolus administration. Onkologie, 1992, 15, 139-146.
[49] Gietema, J.A.; Guchelaar, H.J.; de Vries, E.G.E.; Alenbacher, P.;
Seifer, D.Th.; Mulder, N.H. A phase I study of lobaplatin (D-
19466) administered by 72 h continuous infusion. Anti-Cancer
Drugs, 1993, 4, 51-55.
[50] Gietema, J.A.; Veldhuis, G.J.; Guchelaar, H.J.; Willemse, P.H.B.;
Uges, D.R.A.; Cats, A.; Boonstra, H.; Van Der Graaf, W.T.A.;
Sleijfer, D.T.; de Vries, E.G.E.; Mulder, N.H. Phase II and
pharmacokinetic study of lobaplatin in patients with relapsed
ovarian cancer. Br. J. Cancer, 1995, 71, 1302-1307.
[51] Kavanagh, J.J.; Edwards, C.L.; Freedman, R.S.; Finnegan, M.B.;
Balat, O.; Tresukosol, D.; Bunk, K.; Loechner, S.; Hord, M.;
Franklin J.L.; Kudelka, A.P. A trial of lobaplatin (D-19466) in
platinum resistant ovarian cancer. Gynecol. Oncol., 1995, 58,
106-109.
[52] Degardin, M.; Armand, J.P.; Chevallier, B.; Cappeleare, P.; Lentz,
M.A.; David, M.; Roche, H. A clinical screening cooperative group
phase II evaluation of lobaplatin ASTA D-19466) in advanced head
and neck cancer. Invest. New Drugs, 1995, 13, 253-255.
Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 2 305
[53] Welink, J.; Boven, E.; Ver morken, J.B.; Gall H.E.; Vijgh,
W.J.F.v.d. Pharmacokinetics and pharmacodynamics of lobaplatin
(D-19466) in patients with advanced solid tumors, including
patients with impaired renal of liver function. Clin. Cancer Res.,
1999, 5, 2349–2358.
[54] Gietema, J.A.; de Vries, E.G.E.; Sleijfer, D.T.; Willemse, P.H.B.;
Guchelaar, H.J.; Uges, D.R.A.; Aulenbacher, P.; Voegeli, R.;
Mulder, N.H. A phase I study of 1, 2-diamminomethyl-cyclobutane-
platinum (II)-lactate (D-19466; lobaplatin) administered daily for 5
days. Br. J. Can., 1993, 67, 396-401.
[55] Manegold, C.; Drings, P.; Gatzemeier, U.; Pawal, J.V.; Fiebig,
H.H.; Queisser, W.; Edler, L. Lobaplatin (D-19466) in Patients
with advanced non-small-cell lung cancer: a trial of the association
for medical oncology (AIO) phase II study group. Onkologie, 1996,
19, 248-251.
[56] Sternberg, C.N.; de Mulder, P.; Fossa, S.; Kaye, S.; Roberts, T.;
Pawinsky, A.; Daamen, S. Lobaplatin in advanced urothelial tract
tumors. Ann. Oncol., 1997, 8, 695–696.
[57] Kim, D.K.; Kim, G.; Gam, J.; Cho, Y.B.; Kim, H.T.; Tai,
J.H.; Kim, K.H.; Hong, W.S.; Park, J.G. Synthesis and antitumor
activity of a series of [2-substituted-4,5-bis(aminomethyl)-1,3-
dioxolane]platinum(II) complexes. J. Med. Chem., 1994, 37, 1471-
1485.
[58] Kim, D.K.; Kim, H.T.; Tai, J.H.; Cho, Y.B.; Kim, T.S.; Kim,
K.H.; Park J.G.; Hong, W.S. Pharmacokinetics and antitumor
activity of a new platinum compound, cis-malonato[(4R,5R)-
4,5-bis(aminomethyl)-2-isopropyl-1,3- dioxolane]platinum(II), as
determined by ex vivo pharmacodynamics. Cancer Chemother.
Pharmacol., 1995, 37, 1-6.
[59] Kim, D.K.; Kim, H.T.; Cho, Y.B.; Tai J.H.; Ahn, J.S.; Kim, T.S.;
Kim, K.H. Antitumor activity of cis-malonato[(4R,5R)-4,5-
bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II), a new
platinum analogue, as an anticancer agent. Cancer Chemother.
Pharmacol., 1995, 35, 441-445.
[60] Lee, J.W.; Park, J.K.; Lee, S.H.; Kim, S.Y.; Cho Y.B.; Kuh, H.J.
Antitumor activity of heptaplatin in combination with 5-
fluorouracil or paclitaxel against human head and neck cancer cells
in vitro. Anti-Cancer Drugs, 2006, 17, 377-384.
[61] Kim, N.K.; Kim, T.S.; Shin, S.G.; Park, Y.L.; Lee, J.A.; Cho, Y.B.;
Kim, K.H.; Heo, D.S.; Bang, Y.J. A Phase I study of cis-
malonato[(4R,5R)-4,5-bis(aminomethyl)-1,3-
dioxolane]platinum(II) in patients with advanced malignancies.
Cancer, 2001, 91, 1549-1556.
[62] Lee, W.S.; Lee, G.W.; Kim, H.W.; Lee, O.J.; Lee, Y.J.; Ko, G.H.;
Lee, J.S.; Jang, J.S.; Ha, W.S. A phase II trial of heptaplatin/5-FU
and leucovorin for advanced stomach cancer. Cancer Res. Treat.,
2005, 37, 208-211.
[63] Oh, S.C.; Yoon, S.Y.; Seo, J.H.; Choi, C.W.; Kim, B.Y.S.; Shin,
S.G.; Kim, H.; Kim, S.Y.; Yoon, H.J.; Cho, K.S.; Kim, J.S. Pilot
study of heptaplatin, UFT-E, and leucovorin in advanced gastric
carcinoma. Cancer Res Treat., 2003, 35 , 117-122.
[64] Lee, K.H.; Hyun, M.S.; Kim, H.K.; Jin, H.M.; Yang, J.; Song, H.S.;
Do, Y.R.; Ryoo, H.M.; Chung, J.S.; Zang, D.Y.; Lim, H.Y.; Jin,
J.Y.; Yim, C.Y.; Park, H.S.; Kim, J.S.; Sohn, C.H.; Lee, S.N.
Randomized, multicenter, phase III trial of heptaplatin 1-hour
infusion and 5-fluorouracil combination chemotherapy comparing
with cis-platin and 5-fluorouracil combination chemotherapy in
patients with advanced gastric cancer. Cancer Res. Treat., 2009,
41, 12–18.
[65] Ohstu, A.; Shimada, Y.; Shirao, K.; Boku, N.; Hyodo, I.; Saito, H.;
Yamamichi, N.; Miyata, Y.; Ikeda, N.; Yamamoto, S.; Fukuda, H.;
Yoshida, S. Randomized phase III trial of fluorouracil alone versus
fluorouracil plus cis-platin versus uracil and tegafur plus
mitomycin in patients with unresectable, advanced gastric cancer:
The Japan Clinical Oncology Group Study (JCOG9205). J. Clin.
Oncol., 2003, 21, 54-59.
[66] Yamashita, H.; Nakagawa , H.; Tago, M.; Igaki, H.; Nakamura, N.;
Shiraishi, M.; Sasano, N.; Ohtomo, K. Radiation therapy combined
with cis-diammine-glycolatoplatinum (nedaplatin) and 5-fluorouracil
for Japanese stage II-IV esophageal cancer compared with cis-
platin plus 5-fluorouracil regimen: a retrospective study. Dis.
Esophagus., 2006, 19, 15-24.
[67] Zheng, J.; Wang, G.; Yang, G.Y.; Wang, D.; Luo, X.; Chen, C.;
Zhang, Z.; Li, Q.; Xu, W.; Li, Z. Wang, D. Induction chemotherapy
with nedaplatin with 5-FU followed by intensity-modulated
radiotherapy concurrent with chemotherapy for locoregionally
306 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 2
advanced nasopharyngeal carcinoma. Jpn. J. Clin. Oncol., 2010,
40, 425–431.
[68] Kim, N.K.; Im, S.A.; Kim, D.K.; Lee, M.H.; Jung, C.W. Cho, E.K.;
Lee, J.T.; Ahn, J.S.; Heo, D.S.; Bang, Y.J. Phase II clinical trial of
SKI-2053R, a new platinum analog, in the treatment of patients
with advanced gastric adenocarcinoma. Cancer, 1999, 86, 1109-
1115.
[69] Min, Y.J., Bang, S.J.; Shin, J.W.; Kim, D.H.; Park, J.H.; Kim,
G.Y.; Ko, B.K.; Choi, D.H.; Cho, H.R. Combination chemotherapy
with 5-fluorouracil and heptaplatin as first-line treatment in patients
with advanced gastric cancer. J. Korean Med. Sci., 2004, 19,
369-373.
[70] Jamieson, E.R.; Lippard, S.J. Structure, recognition, and processing
of cis-platin -DNA adducts. Chem. Rev., 1999, 99, 2467-2498.
[71] Ishida, S.; Lee, J.; Thiele, D.J.; Herskowitz, I. Uptake of the anti-
cancer drug cis-platin mediated by the copper transporter Ctr1 in
yeast and mammals. Proc. Natl. Acad. Sci., 2002, 99, 14298-14302.
[72] Lin, X.; Okuda, T.; Holzer, A.; Howell, S.B. The copper
transporter CTR1 regulates cis-platin uptake in Saccharomyces
cerevisiae. Mol. Pharmacol., 2002, 62, 1154-1159.
[73] Kane, S.A.; Lippard, S.J. Photoreactivity of platinum(II) in cis-
platin -modified DNA affords specific cross-links to HMG domain
proteins. Biochem., 1996, 35, 2180-2188.
[74] Cohen, S.M.; Lippard, S.J. Cis-platin: From DNA damage to
cancer chemotherapy. Prog. Nuc. Acid Res. Mol. Biol., 2001, 67,
93-130.
[75] Kartalou, M.; Essigmann, J.M. Recognition of cis-platin adducts by
cellular proteins. Mutat. Res., 2001, 478, 1-21.
[76] He, Q.; Liang, C.H.; Lippard S.J. Steroid hormones induce HMG1
over expression and sensitize breast cancer cells to cis-platin and
carboplatin. Proc. Natl. Acad. Sci., 2000, 97, 5768-5772.
[77] Zamble, D.B.; Mikata, Y.; Eng, C.H.; Sandman, K.E.; Lippard, S.J.
Testis specific HMG-domain protein alters the responses of cells to
cis-platin. J. Inorg .Biochem., 2002, 91, 451-462.
[78] Wong, B.; Masse, J.E.; Yen, Y.M.; Giannikoupolous, P.;
Feigon, J.; Johnson, R.C. Binding of cis-platin-modified DNA by
Saccharomyces cerevisiae HMGB Protein Nhp6A. Biochem., 2002,
41, 5404-5414.
[79] Wang, D.; Hara, R.; Singh, G.; Sancar, A.; Lippard, S.J. Nucleotide
excision repair from a site-specifically platinum-modified
nucleosomes. Biochem., 2003, 42, 6747-6753.
[80] Carte, N.; Legendre, F.; Leize, E.; Potier N.; Reeder F.; Chottard
J.C.; Van Dorsselaer A. Determination by electrospray mass
spectrometry of the outer sphere association constants of
DNA/platinum complexes using 20-mer oligonucleotides and
([Pt(NH 3)4] 2+ 2Cl-) or ([Pt(py)4]2+, 2Cl-). Anal. Biochem., 2000,
284, 77-86.
[81] Mello, J.A.; Acharya, S.; Fishel, R.; Essigmann, J.M. The
mismatch-repair protein hMSH2 binds selectively to DNA adducts
of the anticancer drug cis-platin. Chem. Biol., 1996, 3, 579-589.
[82] Brozovic, A.; Ambriović-Ristov, A.; Osmak, M. The relationship
between cis-platin-induced reactive oxygen species, glutathione,
Received: February 02, 2012 Revised: April 13, 2012 Accepted: April 16, 2016
Ali et al.
and BCL-2 and resistance to cis-platin. Crit. Rev. Toxicol., 2010,
40, 347-359.
[83] Florea, A.M.; Büsselberg, D. Cis-platin as an anti-tumor drug:
Cellular mechanisms of activity, drug resistance and induced side
effects. Cancers, 2011, 3, 1351-1371.
[84] Gao, J.; Liu, Y.G.; Zingaro, R.A. Cytotoxic activities, cellular
uptake, gene regulation, and optical imaging of novel platinum(II)
complexes. Chem. Res. Toxicol., 2009, 22, 1705-1712.
[85] Navarro, M.; Castro, W.; Higuera-Padilla, A.R.; Sierraalta, A.; Abad
M.J.; Taylor, P.; Sánchez-Delgado R.A. Synthesis, characterization
and biological activity of trans-platinum(II) complexes with
chloroquine. J. Inorg. Biochem., 2011, 105, 1684-1691.
[86] Banerjee, T.; Dubey, P.; Mukhopadhyay R. DNA compaction by
mononuclear platinum cancer drug cis-platin and the trisplatinum
anticancer agent BBR346 4: Differences and similarities.
Biochimie., 2012, 94, 494-502.
[87] Varbanov, H.; Valiahdi, S.M.; Legin, A.A.; Jakupec, M.A.; Roller,
A. Galanski, M.; Keppler B.K. Synthesis and characterization of
novel bis(carboxylato)dichloridobis(ethylamine) platinum( IV)
complexes with higher cytotoxicity than cis-platin . Euro. J. Med.
Chem., 2011, 46, 5456-5464.
[88] Štarha, P.; Trávníček, Z.; Popa, I. Platinum (II)oxalato complexes
with adenine-based carrier ligands showing significant in vitro
antitumor activity. J. Inorg. Biochem., 2010, 104, 639-647.
[89] Saha, P.; Descôteaux, C.; Brasseur, K.; Fortin, S.; Leblanc, V.;
Parent, S.; Asselin, E.; Bérubé, G. Synthesis, antiproliferative
activity and estrogen receptor a affinity of novel estradiol linked
platinum (II) complex analogs to carboplatin and oxaliplatin.
Potential vector complexes to target estrogen-dependent tissues.
Euro. J. Med. Chem., 2012, 48, 385-390.
[90] Galanski, M.; Keppler, B.K. Searching for the magic bullet:
anticancer platinum drugs which can be accumulated or activated in
the tumor tissue. Anti-Cancer. Agents Med. Chem., 2007, 7, 55-73.
[91] Ali, I.; Rahis-Uddin.; Salim, K.; Rather, M.A.; Wani, W.A.; Haque,
A. Advances in Nano Drugs for Cancer Chemotherapy. Curr. Can.
Drug Tar., 2011, 11, 135-146.
[92] Ali, I. Nano anti-cancer drugs: pros and cons and future
perspectives. Curr. Can. Drug Tar., 2011, 11(2), 131-134.
[93] Yang, K.; Chen, S.W.; Chen, R., Wan, Y.M. Experimental study of
cis-platin loaded polylactic acid-polyethylene glycol nanoparticles
for targeting oral carcinoma. Hua Xi Kou Qiang Yi Xue Za Zhi,
2005, 23, 445-448.
[94] Peer, D.; Margalit, R. Loading mitomycin C inside long circulating
hyaluronan targeted nano-liposomes increases its antitumor activity
in three mice tumor models. Int. J. Can., 2004; 20, 780-789.
[95] Mackay, F.S.; Sadler, P.J.; Bednarski, P.J. Photoactivatable platinum
complexes. Anti-Cancer Agents Med. Chem., 2007, 7, 75-93.
[96] Ott, I.; Gust R. Preclinical and clinical studies on the use of
platinum complexes for breast cancer treatment. Anti-Cancer
Agents Med. Chem., 2007, 7, 95-110.
[97] Ali, I.; Wani, W.A.; Saleem, K. Cancer scenario in India with
future perspectives. Cancer Therapy, 2011, 8, 56-70.