CISPLATIN IN ANTICANCER

DRUGS.
Presented By:
Imliwati Longkumer
Department of
Chemistry
F.A.C. Mokokchung

OUTLINE OF MY PRESENTATION
INTRODUCTION

Cancer

Causes of cancer

Different forms of cancer treatment

CISPLATIN
MECHANISM OF ACTION OF CISPLATIN

SOME 2nd GENERATION PLATINUM BASED ANTICANCER DRUG

INTRODUCTIO
N
What is cancer?
Cancer is a class of diseases
in which a group of cells
display uncontrolled growth,
invasion that intrudes upon
and destroys adjacent tissues,
and sometimes metastasis, or
spreading to other locations in
the body via lymph or blood.

Causes
Cancers are primarily an environmental
disease with 90-95% of cases attributed to
environmental factors and 5-10% due to
genetics. Environmental, as used by cancer
researchers, means any cause that is not
genetic. Common environmental factors that
contribute to cancer death include: tobacco
(25-30%), diet and obesity (30-35%),
infections (15-20%), radiations (both ionizing
and non ionizing, up to 10%), stress, lack of
physical
activity,
and
environmental
pollutants.
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FERENT FORMS OF CANCER TREATME

1. Radiation therapy
2. Chemotherapy
3. Surgery
4. Targeted Therapy
5. Immunotherapy
6. Hyperthermia
7. Stem Cell Transplant.

Radiation therapy:
Radiation therapy (or radiotherapy) is
an important technique for shrinking
tumors. High energy waves(such as
X-ray) are targeted at the cancerous
growth. The waves cause damage
within the cells, disrupt cellular
processes, prevent accurate cell
division, and ultimately cause the
cells to die. The death of the cells
causes the tumor to shrink. One
drawback of radiotherapy is that
radiation is not specific to cancerous

Chemotherapy:
In the most simple sense, is the treatment of
an ailment by chemicals especially by killing
micro-organisms or cancerous cells. Most
commonly, chemotherapy acts by killing cells
that divide rapidly, one of the main properties
of most cancer cells.
This means that it also harms cells that
divide rapidly under normal circumstances.
Cells in the bone marrow, digestive tract and
hair follicles; this results in the most common
side
effects
of
chemotherapy:
myelosuppression (decreased production of
blood cells, hence also immunosuppression),
mucositis (inflammation of the lining of the7

SURGERY
Surgery can be used to diagnose, treat, or
even help prevent cancer in some cases.
Most people with cancer will have some
type of surgery. It often offers the greatest
chance for cure, especially if the cancer
has not spread to other parts of the body.

Cisplatin

Histo
The discovery of platinums anticancer
ry was made by chance during an
properties

experiment in 1965, conducted at Michigan

State University by Barnett Rosenberg.
Rosenberg used a platinum electrode to
apply an electric field to a colony of E. coli,
which was observed to inhibit their growth
He was able to show that the compound
cisplatin [Pt(NH3)2Cl2 ] was responsible for the
effect and this was found to be effective
against treating some cancers.
The American Food and Drugs
Administration (FDA) approved cisplatin for
cancer therapy in 1978.
It has since become the most widely used
anticancer drug, with an estimated 70% of
patients receiving the
compound as part of their treatment.

Pt
NH4
Cl

BARNETT
ROSENBERG
1926-2009

Geometric Isomers Differ in

Behavior

Geometric
isomerism
occurs in both organic and
inorganic compounds.
Diaminedichloroplatnium
(II) (DDP) also called
cisplatin is an inorganic
complex that has been
used
to
treat
many
different types of cancers.
Diaminedichloroplatnium
(II) exists in both cis and
trans isomers.

Cisplatin
is
an
effective
anticancer drug,
while Transplatin
is not effective at
all.

1
0

Action of cisplatin
Cisplatin is a relatively unreactive molecule. In aqueous
solution, however, the chloro ligands of cisplatin may
be replaced in a stepwise manner as shown below:
+H2O
-Cl

+H2O
-Cl

-H+

-H+

To be effective, cisplatin must be activated by hydrolysis and loss

of the chlorine atoms to produce a positive ion, which is highly
electrophilic and capable of interacting with DNA.
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Cisplatin as an Anti-cancer Drug

Cisplatin
can
diffuse through a
cancer
cell
membrane.
In
the
cell
it
exchanges
a
chloride ion for a
water
molecule
forming a complex
ion.
This complex ion
binds to the cancer
cell DNA preventing

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Fate of Cisplatin in the cell.

13

Possible Mechanisms of cis-platin

Structure of DNA
Deoxyribonucleic
acid(DNA)
is
amoleculethat
encodes
thegenetic
instructions used in the development and
functioning of all known livingorganisms.
DNA is a double-helix and has two strands
running in opposite directions.
Each strand has a backbone made up of
(deoxy-ribose)
sugar
molecules
linked
together by phosphate groups.
Each sugar molecule is linked to one of 4
possible bases (Adenine,Guanine,Cytosine
andThymine). A and G are double-ringed
larger molecules (calledpurines); C and T
are
single-ringed
smaller
molecules
calledpyrimidines).
In the double-stranded DNA, the two
strands run in opposite directions and the
bases pair up such that A always pairs with

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DNA binding
Cisplatin binds to DNA
and causes a critical
structural change in the
DNA a bend of 45
degrees
Cisplatin binds to two
adjacent Gs at N7 on the
DNA.
this leads to the
formation of interstrand or
intrastrand cross-links of
the DNA
block replication and/or

15

Different modes of binding:

Cisplatin-DNA Adduct

DNA

1,2-Intrastrand
Crosslink

1,2-Interstrand
Crosslink
16

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Mechanism of Cell
Death

It has been found that the 1,2-intrastrand adducts are less effectively removed from DNA by
repair enzymes than 1,3-intrastrand adducts. Further support for 1,2-intrastrand cross-links
as the main adducts responsible for the antitumor activity of cisplatin came from the
discovery that some HMG (high mobility group) domain proteins specifically recognize this
type of DNA adduct . So, it has been proposed that specific HMG proteins may be involved in
the cellular processing of the 1,2-intrastrand cross links formed by cis-DDP.

Several mechanisms have been proposed

to explain how HMG domain proteins
might modulate the sensitivity of cells to
cis- platin.
Two of them seem to be the most feasible
ones.
The HMG proteins could protect
cisplatin-DNA adducts from recognition
by DNA repair enzymes.
The second one establishes that
HMG proteins could modulate cell
cycle events after DNA damage and
trigger cell death.
High-Mobility Groupor HMG is a group
ofproteinsthat are involved in the
regulation of DNA-dependent processes
such
astranscription,
replication,recombination, andDNA repair.

IT APPEARS THAT HMG PROTEIN DOES NOT

OCCUR IN HEALTHY CELLS IN LARGE AMOUNTS
AND THEREFORE CANNOT PROTECT AGAINST
EXCISION REPAIR
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Cisplatin and new drugs

From a clinical pointof-view the current
challenges in drug development include:
addressing the poor solubility of cisplatin and
analogues in water
cellular resistance of cancer cells to cisplatin
toxic side effects of cisplatin
(e.g. nausea, neurotoxicity, kidney damage)
use of platinum-based therapeutics to treat
cisplatin resistant cell lines

19

STRUCTURE OF 2nd GENERATION GRUGS

1979

1994
Approved in Japan

Approved in China

(Satraplatin)

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CONCLUSION
Cisplatin has become one of the most widely used anti cancer drugs
and is highly effective in treating several cancers such as ovarian and
testicular cancers.
Cisplatin binds to the DNA of cancer cells and brings about a critical
structural change in the DNA which ultimately leads to cell death.
Though cisplatin shows remarkable antitumor activity, its large scale
application is hampered due to its severe toxic side effects such as
nausea, vomiting, bone marrow toxicity, neurotoxicity and renal
toxicity.
The clinical application of cisplatin has increased enormously mainly
as a result of improved administration procedures and its use in
combination therapy, i.e. the simultaneous application of a variety of
synergistic anti-tumor drugs.
The limitations of cisplatin have stimulated research in the field of
platinum antitumor chemistry in trying to synthesize compounds with
lesser or no toxic effects.
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Some of the 2nd generation platinum based anticancer drugs are

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