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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
2
3
2
1
Baudelet , Vincent Grégoire , Bernard Gallez , Olivier Feron
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
([email protected])
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.
AIMS
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.
RESULTS
1. Specific tumor vascular reactivity: Endothelin Receptor A antagonist
2. ET-A antag. decreases blood flow
heterogeneities
Co-opted tumor arteriole
Saline
ET-A antag.
ET-A antag.
Saline
50µm
ETA receptors
3. ET-A antag. improves « global» tumor
perfusion (DCE-MRI)
Saline (I.P.)
0,035
0,03
[P792] (mM)
[P792] (mM)
0,04
0,025
0,02
0,015
0,01
0,005
0
0
10
20
30
40
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
50
ET-A antag.
(I.P. 1mg/kg)
Time (min)
0,045
0,035
After
0,03
[P792] (mM)
[P792] (mM)
0,04
0,025
0,02
0,015
Before
0,01
0,005
0
0
10
20
30
40
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
50
4. ET-A antag. «qualitatively» improves
tumor perfusion (DCE-MRI)
Vascular smooth muscle cells
Endothelial cells
ns
25
Before ET-A antag.
Changes in Tumor Voxels (%)
0,045
Hoechst 33342 labeling (blue) and CD31-immunostained
tumor vasculature (red)
Laser Doppler Needle
Isolated tumor and size-matched arterioles (myography)
50µm
Blood flow
ET-1
Before
After
ET-A antag.
*
After ET-A antag.
constriction
*
20
15
10
5
0
-5
-10
-15
Blood flow
Saline
Before
After
ET-A antag.
Tumor perfused voxels
Time (min)
Tumor contrast agent concentration
5. ET-A antag. increases IFP
Saline
ET-A antag.
*
80
Tumor
IFP (mmHg)
Tumor
Muscle
Muscle
60
50
40
30
***
20
10
0
250
225
225
200
200
175
175
150
150
*
125
25-nm fluorescent microspheres (red) and CD-31immunostained tumor/muscle vasculature (green)
ta
g.
0
an
« Wick-in-Needle »
*
Saline
Cyclophosphamide
ET-A antag. (1mg/kg)
125
100
2
4
6
8
10
12
14
16
Cyclophos.+ET-A antag.
0
1
Time (Days)
ET
-A
Sa
lin
e
an
ET
-A
Tumor
ta
g.
100
Sa
lin
e
Tumor
250
Tumor Diameter (%)
200-250 mm3
800-1000 mm3
70
6. ET-A antag. improves the efficacy of
conventional chemotherapy
2
3
4
5
6
7
8
9
Time (Days)
Chemotherapy, Cyclophos. I.P. (100mg/kg, d0 and d6; 25mg/kg,
d0 and d1) co-injected with ET-A antag.
CONCLUSIONS
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
2
3
2
1
Baudelet , Vincent Grégoire , Bernard Gallez , Olivier Feron
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
([email protected])
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.
AIMS
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.
RESULTS
1. Specific tumor vascular reactivity: Endothelin Receptor A antagonist
2. ET-A antag. decreases blood flow
heterogeneities
Co-opted tumor arteriole
Saline
ET-A antag.
ET-A antag.
Saline
50µm
Hoechst 33342 labeling (blue) and CD31-immunostained
tumor vasculature (red)
Laser Doppler Needle
Isolated tumor and size-matched arterioles (myography)
3. ET-A antag. improves « global» tumor
perfusion (DCE-MRI)
Saline (I.P.)
0,035
0,03
[P792] (mM)
[P792] (mM)
0,04
0,025
0,02
0,015
0,01
0,005
0
0
10
20
30
40
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
50
ET-A antag.
(I.P. 1mg/kg)
Time (min)
0,045
0,035
After
0,03
[P792] (mM)
[P792] (mM)
0,04
0,025
0,02
0,015
Before
0,01
0,005
0
0
10
20
30
40
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
50
4. ET-A antag. «qualitatively» improves
tumor perfusion (DCE-MRI)
ns
Before ET-A antag.
ET-A antagonist
Treatment:
Consequences
Before
After
After ET-A antag.
*
Before
After
Implications
for drugs delivery
ET-A antag.
*
80
IFP (mmHg)
Tumor
60
50
40
30
***
20
10
0
5
0
-5
-10
25-nm fluorescent microspheres (red) and CD-31immunostained tumor/muscle vasculature (green)
225
225
200
200
175
175
150
150
*
125
ta
g.
0
an
« Wick-in-Needle »
*
Saline
Cyclophosphamide
ET-A antag. (1mg/kg)
125
100
2
4
6
8
10
12
14
16
Cyclophos.+ET-A antag.
0
1
Time (Days)
ET
-A
Sa
lin
e
ta
g.
an
ET
-A
Tumor
ET-A antag.
250
100
Sa
lin
e
Tumor
10
6. ET-A antag. improves the efficacy of
conventional chemotherapy
250
Tumor Diameter (%)
200-250 mm3
800-1000 mm3
70
Muscle
15
Tumor perfused voxels
5. ET-A antag. increases IFP
Muscle
20
Saline
Tumor contrast agent concentration
Tumor
*
-15
Time (min)
Saline
25
Changes in Tumor Voxels (%)
0,045
50µm
2
3
4
5
6
7
8
9
Time (Days)
Chemotherapy, Cyclophos. I.P. (100mg/kg, d0 and d6; 25mg/kg,
d0 and d1) co-injected with ET-A antag.
CONCLUSIONS
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.