Cisplatin

Cisplatin is a chemotherapy medication

used to treat a number of cancers.[1]
These include testicular cancer, ovarian
cancer, cervical cancer, breast cancer,
bladder cancer, head and neck cancer,
esophageal cancer, lung cancer,
mesothelioma, brain tumors and
neuroblastoma.[1] It is given by injection
into a vein.[1]
 Cisplatin

Clinical data
Trade names Platinol, others
Synonyms Cisplatinum, platamin,
neoplatin, cismaplat, cis-
diamminedichloridoplatinum(II)
(CDDP)
AHFS/Drugs.com Monograph
MedlinePlus a684036
Pregnancy AU: D
category
US: D (Evidence of risk)
Routes of Intravenous
administration
ATC code L01XA01 (WHO )

Legal status
Legal status AU: S4 (Prescription
only)
CA: ℞-only
UK: POM (Prescription
only)
US: ℞-only

Pharmacokinetic data
Bioavailability 100% (IV)
Protein binding > 95%
Elimination half-life 30–100 hours
Excretion Renal

Identifiers

IUPAC name
(SP-4-2)-diamminedichloroplatinum(II)

CAS Number 15663-27-1  

PubChem CID 84691

DrugBank DB00515  

ChemSpider 76401  

UNII Q20Q21Q62J
KEGG D00275  

ChEBI CHEBI:27899  

ChEMBL ChEMBL2068237  

PDB ligand CPT (PDBe ,

RCSB PDB )
ECHA InfoCard 100.036.106

Chemical and physical data

Formula [Pt(NH3)2Cl2]
Molar mass 300.01 g/mol
3D model (JSmol) Interactive image

SMILES
[NH3+]-[Pt-2](Cl)(Cl)[NH3+]

InChI
InChI=1S/2ClH.2H3N.Pt/h2*1H;2*1H3;/q;;;;+2/p-2 
Key:LXZZYRPGZAFOLE-UHFFFAOYSA-L 

   (what is this?)  (verify)

Common side effects include bone

marrow suppression, hearing problems,
kidney problems, and vomiting.[1][2] Other
serious side effects include numbness,
trouble walking, allergic reactions,
electrolyte problems, and heart disease.[1]
Use during pregnancy is known to harm
the baby.[1] Cisplatin is in the platinum-
based antineoplastic family of
medications.[1] It works in part by binding
to DNA and inhibiting its replication.[1]

Cisplatin was discovered in 1845 and

licensed for medical use in 1978/1979.[3][1]
It is on the World Health Organization's List
of Essential Medicines, the most effective
and safe medicines needed in a health
system.[4] The wholesale cost in the
developing world is about US$5.56 to
US$7.98 per 50 mg vial.[5] In the United
Kingdom this costs the NHS about £17.[6]

Medical use
Cisplatin is administered intravenously as
short-term infusion in normal saline for
treatment of solid and haematological
malignancies. It is used to treat various
types of cancers, including sarcomas,
some carcinomas (e.g., small cell lung
cancer, squamous cell carcinoma of the
head and neck and ovarian cancer),
lymphomas, bladder cancer, cervical
cancer,[7] and germ cell tumors.

Cisplatin is particularly effective against

testicular cancer; its adoption has
increased the cure rate from 10% to 85%.[8]

In addition, cisplatin is used in Auger

therapy.
Side effects
Cisplatin has a number of side effects that
can limit its use:

Nephrotoxicity (kidney damage) is a

major concern.[1] The dose should be
reduced when the person's kidney
function is impaired. Adequate hydration
is used in an effort to prevent damage.[1]
Amifostine has been studied in an effort
to prevent problems.[9] Nephrotoxicity is
a dose-limiting side effect.[1]
Neurotoxicity (nerve damage) can be
anticipated by performing nerve
conduction studies before and after
treatment. Common neurological side
effects of cisplatin include visual
perception and hearing disorder, which
can occur soon after treatment
begins.[10] While triggering apoptosis
through interfering with DNA replication
remains the primary mechanism of
cisplatin, this has not been found to
contribute to neurological side effects.
Recent studies have shown that
cisplatin noncompetitively inhibits an
archetypal, membrane-bound
mechanosensitive sodium-hydrogen ion
transporter known as NHE-1.[10] It is
primarily found on cells of the peripheral
nervous system, which are aggregated
in large numbers near the ocular and
aural stimuli-receiving centers. This
noncompetitive interaction has been
linked to hydroelectrolytic imbalances
and cytoskeleton alterations, both of
which have been confirmed in vitro and
in vivo. However, NHE-1 inhibition has
been found to be both dose-dependent
(half-inhibition = 30 µg/mL) and
reversible.[10]
Nausea and vomiting: cisplatin is one of
the most emetogenic chemotherapy
agents, but this symptom is managed
with prophylactic antiemetics
(ondansetron, granisetron, etc.) in
combination with corticosteroids.
Aprepitant combined with ondansetron
and dexamethasone has been shown to
be better for highly emetogenic
chemotherapy than just ondansetron
and dexamethasone.
Ototoxicity (hearing loss): there is at
present no effective treatment to
prevent this side effect, which may be
severe. Audiometric analysis may be
necessary to assess the severity of
ototoxicity. Other drugs (such as the
aminoglycoside antibiotic class) may
also cause ototoxicity, and the
administration of this class of
antibiotics in patients receiving cisplatin
is generally avoided. The ototoxicity of
both the aminoglycosides and cisplatin
may be related to their ability to bind to
melanin in the stria vascularis of the
inner ear or the generation of reactive
oxygen species.
Electrolyte disturbance: Cisplatin can
cause hypomagnesaemia,
hypokalaemia and hypocalcaemia. The
hypocalcaemia seems to occur in those
with low serum magnesium secondary
to cisplatin, so it is not primarily due to
the cisplatin.
Hemolytic anemia can be developed
after several courses of cisplatin. It is
suggested that an antibody reacting
 with a cisplatin-red-cell membrane is
responsible for hemolysis.[11]

Pharmacology
Cisplatin interferes with DNA replication,
which kills the fastest proliferating cells,
which in theory are cancerous. Following
administration, one chloride ion is slowly
displaced by water to give the aquo
complex cis-[PtCl(NH3)2(H2O)]+, in a
process termed aquation. Dissociation of
the chloride is favored inside the cell
because the intracellular chloride
concentration is only 3–20% of the
approximately 100 mM chloride
concentration in the extracellular
fluid.[12][13]

The water molecule in cis-

[PtCl(NH3)2(H2O)]+ is itself easily
displaced by the N-heterocyclic bases on
DNA. Guanine preferentially binds.
Subsequent to formation of [PtCl(guanine-
DNA)(NH3)2]+, crosslinking can occur via
displacement of the other chloride,
typically by another guanine.[14] Cisplatin
crosslinks DNA in several different ways,
interfering with cell division by mitosis.
The damaged DNA elicits DNA repair
mechanisms, which in turn activate
apoptosis when repair proves impossible.
In 2008, researchers were able to show
that the apoptosis induced by cisplatin on
human colon cancer cells depends on the
mitochondrial serine-protease
Omi/Htra2.[15] Since this was only
demonstrated for colon carcinoma cells, it
remains an open question if the Omi/Htra2
protein participates in the cisplatin-
induced apoptosis in carcinomas from
other tissues.

Most notable among the changes in DNA

are the 1,2-intrastrand cross-links with
purine bases. These include 1,2-
intrastrand d(GpG) adducts which form
nearly 90% of the adducts and the less
common 1,2-intrastrand d(ApG) adducts.
1,3-intrastrand d(GpXpG) adducts occur
but are readily excised by the nucleotide
excision repair (NER). Other adducts
include inter-strand crosslinks and
nonfunctional adducts that have been
postulated to contribute to cisplatin's
activity. Interaction with cellular proteins,
particularly HMG domain proteins, has
also been advanced as a mechanism of
interfering with mitosis, although this is
probably not its primary method of action.

Cisplatin resistance
Cisplatin combination chemotherapy is the
cornerstone of treatment of many cancers.
Initial platinum responsiveness is high but
the majority of cancer patients will
eventually relapse with cisplatin-resistant
disease. Many mechanisms of cisplatin
resistance have been proposed including
changes in cellular uptake and efflux of the
drug, increased detoxification of the drug,
inhibition of apoptosis and increased DNA
repair.[16] Oxaliplatin is active in highly
cisplatin-resistant cancer cells in the
laboratory; however, there is little evidence
for its activity in the clinical treatment of
patients with cisplatin-resistant cancer.[16]
The drug paclitaxel may be useful in the
treatment of cisplatin-resistant cancer; the
mechanism for this activity is unknown.[17]

Transplatin

Transplatin, the trans stereoisomer of

cisplatin, has formula trans-[PtCl2(NH3)2]
and does not exhibit a comparably useful
pharmacological effect. Two mechanisms
have been suggested to explain the
reduced anticancer effect of transplatin.
Firstly, the trans arrangement of the chloro
ligands is thought to confer transplatin
with greater chemical reactivity, causing
transplatin to become deactivated before
it reaches the DNA where cisplatin exerts
its pharmacological action. Secondly, the
stereo-conformation of transplatin is such
that it is unable to form the characteristic
1,2-intrastrand d(GpG) adducts formed by
cisplatin in abundance.[18]

Molecular structure

Cisplatin is the square planar coordination

complex cis-[Pt(NH3)2Cl2].[19][20] The prefix
cis indicates the cis isomer in which two
similar ligands are in adjacent
positions.[19][21] The systematic chemical
name of this molecule is cis–
diamminedichloroplatinum, where ammine
with two m's indicates an ammonia (NH3)
ligand, as opposed to an organic amine
with one m.[22]

History
The compound cis-[Pt(NH3)2Cl2] was first
described by Michele Peyrone in 1845, and
known for a long time as Peyrone's salt.[23]
The structure was deduced by Alfred
Werner in 1893.[14] In 1965, Barnett
Rosenberg, Van Camp et al. of Michigan
State University discovered that
electrolysis of platinum electrodes
generated a soluble platinum complex
which inhibited binary fission in
Escherichia coli (E. coli) bacteria. Although
bacterial cell growth continued, cell
division was arrested, the bacteria growing
as filaments up to 300 times their normal
length.[24] The octahedral Pt(IV) complex
cis-[PtCl4(NH3)2], but not the trans isomer,
was found to be effective at forcing
filamentous growth of E. coli cells. The
square planar Pt(II) complex, cis-
[PtCl2(NH3)2] turned out to be even more
effective at forcing filamentous
growth.[25][26] This finding led to the
observation that cis-[PtCl2(NH3)2] was
indeed highly effective at regressing the
mass of sarcomas in rats.[27] Confirmation
of this discovery, and extension of testing
to other tumour cell lines launched the
medicinal applications of cisplatin.
Cisplatin was approved for use in
testicular and ovarian cancers by the U.S.
Food and Drug Administration on 19
December 1978.,[14][28][29] and in the UK
(and in several other European countries)
in 1979.[30]

Synthesis
The synthesis of cisplatin starts from
potassium tetrachloroplatinate.[31][32] The
tetraiodide is formed by reaction with an
excess of potassium iodide. Reaction with
ammonia forms K2[PtI2(NH3)2] which is
isolated as a yellow compound. When
silver nitrate in water is added insoluble
silver iodide precipitates and
K2[Pt(OH2)2(NH3)2] remains in solution.
Addition of potassium chloride will form
the final product which precipitates [31] In
the triiodo intermediate the addition of the
second ammonia ligand is governed by the
trans effect.[31]

For the synthesis of transplatin K2[PtCl4] is

first converted to Cl2[Pt(NH3)4] by reaction
with ammonia. The trans product is then
formed by reaction with hydrochloric
acid.[31]

See also
Carboplatin
Dicycloplatin

References
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(2010). "Nongenomic effects of cisplatin:
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13. Johnstone, Timothy C.; Suntharalingam,
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22. Miessler, Gary L.; Tarr, Donald A. (1999).
Inorganic Chemistry (2nd ed.). Prentice
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23. Peyrone, M. (1844). "Ueber die
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(1): 1–29. doi:10.1002/jlac.18440510102 .
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(1965). "Inhibition of cell division in
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25. Rosenberg, B.; Van Camp, L.; Grimley, E.
B.; Thomson, A. J. (March 1967). "The
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26. Thomson, A. J. (2007). Christie, D. A.;
Tansey, E. M., eds. The Discovery, Use and
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27. Rosenberg, B.; Van Camp, L.; Trosko, J.
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power: organizational image and
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29. "Approval Summary for cisplatin for
Metastatic ovarian tumors" . FDA Oncology
Tools. Food and Drug Administration,
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19 December 1978. Archived from the
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31. Alderden, Rebecca A.; Hall, Matthew D.;
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Further reading
Riddell, Imogen A.; Lippard, Stephen J.
(2018). "Cisplatin and Oxaliplatin: Our
Current Understanding of Their Actions". In
Sigel, Astrid; Sigel, Helmut; Freisinger, Eva;
Sigel, Roland K. O. Metallo-Drugs:
Development and Action of Anticancer
Agents. Metal Ions in Life Sciences. 18.
Berlin: de Gruyter GmbH. pp. 1–42.
doi:10.1515/9783110470734-007 .
ISBN 978-3-11-046984-4.
PMID 29394020 .

External links
Cisplatin: The Invention of an Anticancer
Drug by Andri Smith
Anti-cancer Agents: A treatment of
Cisplatin and their analogues by Sia M.
Liu (excellent detailed overview)
MedlinePlus page on cisplatin
IARC Monograph: "Cisplatin"
Retrieved from
"https://en.wikipedia.org/w/index.php?
title=Cisplatin&oldid=889076810"

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