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S807 Mini Review v4

S807 Mini Review v4

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Published by Daen de Leon
Daen de Leon

S807 Mini-Review : Cisplatin Resistance

M3852083

S807 Mini-Review

Cisplatin Resistance
Daen de Leon M3852083 September 15th 2002

Page 1 of 37

14 oktober 2010

Daen de Leon

S807 Mini-Review : Cisplatin Resistance

M3852083

1 INTRODUCTION...........................................................................................................................................2 2 CANCER AND CISPLATIN...............................................................................
Daen de Leon

S807 Mini-Review : Cisplatin Resistance

M3852083

S807 Mini-Review

Cisplatin Resistance
Daen de Leon M3852083 September 15th 2002

Page 1 of 37

14 oktober 2010

Daen de Leon

S807 Mini-Review : Cisplatin Resistance

M3852083

1 INTRODUCTION...........................................................................................................................................2 2 CANCER AND CISPLATIN...............................................................................

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Published by: Daen de Leon on Oct 15, 2010
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Daen de Leon
S807 Mini-Review : Cisplatin Resistance
M3852083
S807 Mini-Review
Cisplatin Resistance
Daen de Leon M3852083September 15
th
2002
Page 1 of 3714 oktober 2010
 
Daen de Leon
S807 Mini-Review : Cisplatin Resistance
M3852083
1 INTRODUCTION...........................................................................................................................................22 CANCER AND CISPLATIN..........................................................................................................................4
2.1 T
HE
E
UKARYOTIC
C
ELL
C
YCLE
..................................................................................................................52.2 DNA R
EPAIR
M
ECHANISMS
......................................................................................................................62.3 A
DDUCT
F
ORMATION
................................................................................................................................72.4 C
YTOTOXICITY
........................................................................................................................................8
3 MECHANISMS OF CISPLATIN RESISTANCE..........................................................................................10
3.1 D
ECREASED
U
PTAKE
.............................................................................................................................113.2 I
NCREASED
E
FFLUX
..............................................................................................................................123.3 G
LUTATHIONE
 
AND
M
ETALLOTHIONEIN
I
NACTIVATION
.......................................................................................133.4 I
NCREASED
N
UCLEOTIDE
E
XCISION
R
EPAIR
(NER)......................................................................................143.5 M
ISMATCH
R
EPAIR
M
ECHANISMS
(MMR)..................................................................................................163.6 I
NCREASED
A
DDUCT
T
OLERANCE
...............................................................................................................173.7 H
OMOLOGOUS
R
ECOMBINATION
................................................................................................................183.8 R
EGULATORY
P
ROTEINS
.........................................................................................................................20
4 PROBLEMS OF INVESTIGATING CISPLATIN RESISTANCE.................................................................23
4.1 M
ULTIFACTORIAL
N
ATURE
 
OF
C
ISPLATIN
R
ESISTANCE
.....................................................................................244.2 C
ELL
L
INES
.........................................................................................................................................254.3 I
N
V
IVO
 
VS
I
N
V
ITRO
.............................................................................................................................27
5 PROSPECTS FOR INTERVENTION..........................................................................................................28
5.1 R
EPLACING
C
ISPLATIN
............................................................................................................................295.2 C
OMBINATION
T
HERAPY
 
WITH
C
ISPLATIN
.....................................................................................................305.3 O
THER
A
PPROACHES
.............................................................................................................................31
6 CONCLUSION............................................................................................................................................327 FIGURES & REFERENCES.......................................................................................................................33
1 Introduction
This review examines the mechanisms of resistance to
cis
-Diamminedichloroplatinum(II)(cisplatin,
cis
-DDP or CDDP - see Fig. 1).
Section 2
starts by reviewing the eukaryotic cell cycle
Page 2 of 3714 oktober 2010
 
Daen de Leon
S807 Mini-Review : Cisplatin Resistance
M3852083
and DNA repair, and explains one of the proposed models of how cisplatin is believed to achieveits cytotoxicity, namely that it induces the mismatch repair (MMR) mechanism to enter a futilecycle of repair, ultimately leading to apoptosis.
Section 3
provides an explanation of the knowntypes of resistance to cisplatin – reduced drug uptake, increased efflux, inactivation bymetallothioneins and glutathione, increased nucleotide excision repair (NER), damage to mismatchrepair mechanisms, homologous recombination and alteration to apoptotic pathways.
Section 4
considers the many problems with studying cisplatin resistance : the complex nature of thesignalling pathways involved and the uncertainty as to the exact cytotoxic mechanism may bemasked by the use of non-isogenic cell lines used by different researchers ; the problems of studying cisplatin resistance
in vivo
; the multifactorial nature of cisplatin resistance.
Section 5
looks at some ways of overcoming cisplatin resistance – replacing cisplatin itself, developing newcombination therapies, targetting signal transduction pathways, and targetting efflux andinactivation mechanisms. Several exciting new therapies are being developed in this area, some of which are just beginning to enter clinical trials. Finally,
Section 6
attempts draw some conclusionsabout cisplatin resistance and future directions for tackling it.
Figure 1 : Cisplatin
Page 3 of 3714 oktober 2010

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