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ET-A antag. Saline. Reversal of temporal and spatial heterogeneities in tumor perfusion identifies the tumor vascular tone as a tunable parameter to improve drug delivery. - PowerPoint PPT Presentation
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This work is supported by grants from the FNRS (FRSM - Télévie), the J. Maisin Fundation, the Belgian Federation against Cancer and the Fortis Cancerology Research Fund.
Reversal of temporal and spatial heterogeneities in tumor perfusion identifies the tumor vascular tone as a tunable parameter to improve drug delivery.
Philippe Martinive1, Julie DeWever1, Caroline Bouzin1, Pierre Sonveaux1, Christine Baudelet2, Vincent Grégoire3, Bernard Gallez2, Olivier Feron1
UCL Medical School, 1Pharmacology & Therapeutics Unit (FATH 5349), 2Biomedical Resonance Magnetic, 3Center for Molecular Imaging and Experimental Radiotherapy, Ave E. Mounier 53, B-1200 Brussels, Belgium
1.To characterize the effects of an ET-1 antagonist on the tumor vascular tone and blood flow heterogeneities.2. To modulate the ET-1 pathway to improve tumor response to chemotherapy.
AIMS
INTRODUCTION
1.Tumor Blood flow heterogeneities impairs drug delivery and chemotherapy efficacy.2.Pericytes covering endothelial tubes qive them the ability to react to substances present into the tumor.3.Endothelin 1 known as a growth factor in oncology but also as a potent vasoconstrictor in cardiology.
Laser Doppler Needle
50µm50µm50µm
ET-A antag.Saline
Hoechst 33342 labeling (blue) and CD31-immunostained tumor vasculature (red)
0
0,005
0,01
0,015
0,02
0,025
0,03
0,035
0,04
0,045
0 10 20 30 40 50
[P7
92]
(mM
)
Time (min)
0
0,005
0,01
0,015
0,02
0,025
0,03
0,035
0,04
0,045
0 10 20 30 40 50
Time (min)
Before After0.00.51.01.52.02.53.03.54.04.55.05.56.06.5 *
[P792]
(mM
)
Before After0.00.51.01.52.02.53.03.54.04.55.05.56.06.5
ns
[P792]
(mM
)
Saline (I.P.)
ET-A antag. (I.P. 1mg/kg)
Before
After
0 1 2 3 4 5 6 7 8 9
100
125
150
175
200
225
250
Cyclophosphamide
Cyclophos.+ET-A antag.
ET-A antag. (1mg/kg)
Saline
*
Time (Days)
0 2 4 6 8 10 12 14 16
100
125
150
175
200
225
250
Time (Days)
Tu
mo
r D
iam
eter
(%
)
*
Saline ET-A antag.
-15
-10
-5
0
5
10
15
20
25 *
Ch
ang
es i
n T
um
or
Vo
xels
(%
)
Before ET-A antag.
After ET-A antag.
0
10
20
30
40
50
60
70
80
200-250 mm3
800-1000 mm3
***
*
IFP
(m
mH
g)
« Wick-in-Needle »25-nm fluorescent microspheres (red) and CD-31-immunostained tumor/muscle vasculature (green)
TumorTumor
Muscle Muscle
TumorTumor
ET-A antag.
RESULTS
Saline
2. ET-A antag. decreases blood flow heterogeneities
3. ET-A antag. improves « global» tumor perfusion (DCE-MRI)
Saline
ET-A antag.
Co-opted tumor arteriole
Isolated tumor and size-matched arterioles (myography)
Tumor contrast agent concentration
[P7
92]
(mM
)
Tumor perfused voxels
4. ET-A antag. «qualitatively» improves tumor perfusion (DCE-MRI)
CONCLUSIONS
5. ET-A antag. increases IFP 6. ET-A antag. improves the efficacy of conventional chemotherapy
1. Specific tumor vascular reactivity: Endothelin Receptor A antagonist
Vascular smooth muscle cells
Endothelial cells
ETA receptors
Blood flow
constriction
ET-1
ET-A antag.
Blood flow
Chemotherapy, Cyclophos. I.P. (100mg/kg, d0 and d6; 25mg/kg, d0 and d1) co-injected with ET-A antag.
1.Endogenous ET-1 production largely participates in the tumor blood flow heterogeneities.
2.ET-A antag. may wipe out such heterogeneities and improves the delivery of chemotherapeutic drugs.
This work is supported by grants from the FNRS (FRSM - Télévie), the J. Maisin Fundation, the Belgian Federation against Cancer and the Fortis Cancerology Research Fund.
Reversal of temporal and spatial heterogeneities in tumor perfusion identifies the tumor vascular tone as a tunable parameter to improve drug delivery.
Philippe Martinive1, Julie DeWever1, Caroline Bouzin1, Pierre Sonveaux1, Christine Baudelet2, Vincent Grégoire3, Bernard Gallez2, Olivier Feron1
UCL Medical School, 1Pharmacology & Therapeutics Unit (FATH 5349), 2Biomedical Resonance Magnetic, 3Center for Molecular Imaging and Experimental Radiotherapy, Ave E. Mounier 53, B-1200 Brussels, Belgium
1.To characterize the effects of an ET-1 antagonist on the tumor vascular tone and blood flow heterogeneities.2. To modulate the ET-1 pathway to improve tumor response to chemotherapy.
AIMS
INTRODUCTION
1.Tumor Blood flow heterogeneities impairs drug delivery and chemotherapy efficacy.2.Pericytes covering endothelial tubes qive them the ability to react to substances present into the tumor.3.Endothelin 1 known as a growth factor in oncology but also as a potent vasoconstrictor in cardiology.
Laser Doppler Needle
50µm50µm50µm
ET-A antag.Saline
Hoechst 33342 labeling (blue) and CD31-immunostained tumor vasculature (red)
0
0,005
0,01
0,015
0,02
0,025
0,03
0,035
0,04
0,045
0 10 20 30 40 50
[P7
92]
(mM
)
Time (min)
0
0,005
0,01
0,015
0,02
0,025
0,03
0,035
0,04
0,045
0 10 20 30 40 50
Time (min)
Before After0.00.51.01.52.02.53.03.54.04.55.05.56.06.5 *
[P792]
(mM
)
Before After0.00.51.01.52.02.53.03.54.04.55.05.56.06.5
ns
[P792]
(mM
)
Saline (I.P.)
ET-A antag. (I.P. 1mg/kg)
Before
After
0 1 2 3 4 5 6 7 8 9
100
125
150
175
200
225
250
Cyclophosphamide
Cyclophos.+ET-A antag.
ET-A antag. (1mg/kg)
Saline
*
Time (Days)
0 2 4 6 8 10 12 14 16
100
125
150
175
200
225
250
Time (Days)
Tu
mo
r D
iam
eter
(%
)
*
Saline ET-A antag.
-15
-10
-5
0
5
10
15
20
25 *
Ch
ang
es i
n T
um
or
Vo
xels
(%
)
Before ET-A antag.
After ET-A antag.
0
10
20
30
40
50
60
70
80
200-250 mm3
800-1000 mm3
***
*
IFP
(m
mH
g)
« Wick-in-Needle »25-nm fluorescent microspheres (red) and CD-31-immunostained tumor/muscle vasculature (green)
TumorTumor
Muscle Muscle
TumorTumor
ET-A antag.
RESULTS
Saline
2. ET-A antag. decreases blood flow heterogeneities
3. ET-A antag. improves « global» tumor perfusion (DCE-MRI)
Saline
ET-A antag.
Co-opted tumor arteriole
Isolated tumor and size-matched arterioles (myography)
Tumor contrast agent concentration
[P7
92]
(mM
)
Tumor perfused voxels
4. ET-A antag. «qualitatively» improves tumor perfusion (DCE-MRI)
CONCLUSIONS
5. ET-A antag. increases IFP 6. ET-A antag. improves the efficacy of conventional chemotherapy
1. Specific tumor vascular reactivity: Endothelin Receptor A antagonist
Chemotherapy, Cyclophos. I.P. (100mg/kg, d0 and d6; 25mg/kg, d0 and d1) co-injected with ET-A antag.
1.Endogenous ET-1 production largely participates in the tumor blood flow heterogeneities.
2.ET-A antag. may wipe out such heterogeneities and improves the delivery of chemotherapeutic drugs.
ET-A antagonist Treatment:
Consequences
Implications for drugs delivery
