Changes in blood-brain barrier permeability to docetaxel in the presence of

Changes in blood-brain
barrier permeability to
docetaxel in the presence of
docetaxel in the presence of
cancer influences cognitive
fifi
f
unct
i
on o
f
m
i
ce
J
oanna Fardell,
J
i Zhan
g
, Ra
q
uel De
JJgq
Souza, Ian Johnston, Janette
Vardy, Micheline Piquette-Miller

Chemotherapy & Cognition
What is known
F b f i h h i
•
F
or a su
b
set o
f
surv
i
vors c
h
emot
h
erapy
i
s
associated with cognitive impairment
▫Subtle impairment
▫Affects a range of cognitive domains:
VisualandverbalProcessingspeedand
memory executivefunction
Attentionand
concentration

Chemothera
py
& co
g
nition animal studies:
py g
What has been done so far?
•Previous animal studies have shown:
▫Methotrexate
▫5-fluorouracil Co
g
nitive
▫Doxorubicin/adriamycin
▫
Cyclophosphomide
g
impairment in
health
y
animals
Cyclophosphomide
▫Cytosine arabinoside
y
•Other chemotherapeutics??
•
A
ND –
w
hat about the role of cancer??

Aims
•
To examine the role of cancer in cognitive
•
To examine the role of cancer in cognitive
decline associated with docetaxel (DTX)
chemotherapy
chemotherapy
▫Using a murine model of ovarian cancer (ID8
cancer cells)
cancer cells)
•Secondary aims:
▫
Examine the role of ABC transporters (Pgp and
▫
Examine the role of ABC transporters (Pgp and
mrp7) in brain exposure to DTX

DTX and ABC transporters
•DTX is a substrate for ABC transporters
=
P
-
glycoprotein (Pgp)
P
glycoprotein (Pgp)
(known as mdr1 in humans and mdr1a and mdr1b in mice)
=Mr
p7
p7
•Transporters located in blood-brain barrier
A ti l t t DTX t f th ll
▫
A
c
ti
ve
l
y
t
ranspor
t
s
DTX
ou
t
o
f th
e ce
ll
▫Has a role in multidrug resistance