Targeting the vascular tone of microarterioles with an endothelin-1 (ET-1) antagonist selectively modulates tumor blood flow and promotes response to treatment

(1)

Mature tumor vessels exhibit

an ET-1-dependent myogenic tone. This reserve of vasodilation

can be mobilized

using a selective ET_A antagonist. ET-1 inhibition selectively radio-

and chemosensitizes tumors.

CONCLUSIONS

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.

Targeting the vascular tone of tumor microarterioles

with an endothelin-1 (ET-1) antagonist selectively modulates tumor blood flow

and promotes response to treatment.

Philippe Martinive

1

, Pierre Sonveaux

1

, Chantal Dessy

1

, Vincent Grégoire

2

, Olivier Feron

1

UCL Medical School, 1Pharmacology & Therapeutics Unit (FATH 5349), 2Radiobiology and Radioprotection

Unit, Ave E. Mounier 53, B-1200 Brussels, Belgium (feron@mint.ucl.ac.be)

1. To characterize the effects of tumor cell-secreted ET-1 on the tumor vascular tone.

2. To modulate the ET-1 pathway to improve tumor response to radio- and chemotherapy.

AIMS

INTRODUCTION

1. In tumors, ET-1 is known as a potent autocrine and paracrine growth-factor produced by tumor cells. 2. In the vascular field, ET-1 is also known as a potent vasoconstrictor acting through ET_A receptors.

Immunohistolocalization of ET-1 (red)

1. Various tumor models produce ET-1

normal heart

LLc (Lewis lung carc.)

TLT (hepatocarcinoma) FSA-II (fibrosarcoma) coronary lumen muscle necrotic core 100 µm

2. Increased ET-1/ET_A expression

and reactivity in tumor arterioles

healthy

tumor-coopted

Isolated tumor and size-matched arterioles

10-13 ₁₀-12 ₁₀-11 ₁₀-10 ₁₀-9 ₁₀-8 ₁₀-7 -25 0 25 50 75 100 125 [ET-1] (M) ve s se l d ia m e te r (% ) EC₅₀ 0.4 nM EC₅₀ 2 nm healthy tumor ET_A 50 kDa

3. Tumor arterioles exhibit a myogenic

tone sensitive to an ET_A antagonist

V es se l d ia m et er Mean pressure no Ca2+_{= passive diameter} + Ca2+_{= active diameter} myogenic tone 0 20 40 60 80 100120140 90 100 110 120 130 140 150 160 Mean Pressure (mmHg) V es se l d ia m e te r (% ) 0 20 40 60 80 100120140 90 100 110 120 130 140 150 160 Mean Pressure (mmHg) V es se l d ia m e te r (% )

Isolated tumor and size-matched arterioles (myography) passive active 1 µM BQ123 healthy tumor-coopted BQ123 1 mg/kg i.p. 0’ 30’ 60’ saline

5. ET_A antagonism triggers a

tumor-specific increase in blood flow

basal saline BQ123 0 1 2 3 4 5 6 ** tu m o r p O2 ( m m H g )

EPR before and 45 min after BQ123 IP injection (1 mg/kg) charcoal O₂ probe, 1.1 GHz)

4. ET_A antagonism triggers an

increase in tumor oxygenation

0 10 20 30 40 80 90 100 110 120 130 time (min) tu m e u r p e rf u s io n ( % )

Surface Laser Doppler in TLT tumor-bearing mice

Invasive Laser Doppler (oxyflow) 1 mg/kg BQ123 saline *

6. ET_A inhibition radio- and chemosensitizes tumors

0 2 4 6 8 10 12 14 100 125 150 175 200 225 time (days) tu m o r d ia m e te r (% ) 0 5 10 15 20 25 100 125 150 175 200 225 250 time (days) tu m o r d ia m e te r (% ) 0 Gy 5 x BQ123 5x2 Gy 5x2 Gy + BQ123 0 Gy 2 x BQ123 2x6 Gy 2x6 Gy + BQ123

Local irradiation (days 0-1 or 0-4) or chemotherapy (cyclophosphamide IP, days 0-1) were delivered daily, BQ123 (1 mg/kg IP) was delivered 45 min before each dose of conventional therapy

0 1 2 3 4 5 6 7 8 9 10 100 125 150 175 200 225 250 275 300 Cyclophosphamide (25 mg/kg) cyclo + BQ123 BQ123 alone saline Days T u m o r % D 0

Vascular smooth muscle cells Endothelial cells ET_A receptors Blood flow constriction ET-1 ET_A antagonist Blood flow muscle = BQ123 pO₂ pO₂ (P<0.01) (P<0.01) (P<0.01)