dŚĞ EĂƚŝŽŶĂů ĂŶĐĞƌ /ŶƐƚŝƚƵƚĞ ĚĞĨŝŶĞƐ dŚĞ EĂƚŝŽŶĂů ĂŶĐĞƌ /ŶƐƚŝƚƵƚĞ ĚĞĨŝŶĞƐ ĐĂƌĚŝŽƚŽdžŝĐŝƚLJ ŝŶ ǀĞƌLJ ŐĞŶĞƌĂů ƚĞƌŵƐ ĂƐ

/ŵĞĐĐĂŶŝƐŵŝĚŝĐĂƌĚŝŽƚŽƐƐŝĐŝƚă

ůĞƐƐĂŶĚƌŽŽŶnjĂŶŽ͕D

^ĞƌǀŝnjŝŽĚŝĂƌĚŝŽůŽŐŝĂ͕

/Z^ĂŶĚŝŽůŽ

džĂĐƚůLJtŚĂƚŽĞƐĂƌĚŝŽƚŽdžŝĐŝƚLJDĞĂŶ͍

džĂĐƚůLJtŚĂƚŽĞƐĂƌĚŝŽƚŽdžŝĐŝƚLJDĞĂŶ͍

dŚĞ EĂƚŝŽŶĂů ĂŶĐĞƌ /ŶƐƚŝƚƵƚĞ ĚĞĨŝŶĞƐ dŚĞ EĂƚŝŽŶĂů ĂŶĐĞƌ /ŶƐƚŝƚƵƚĞ ĚĞĨŝŶĞƐ ĐĂƌĚŝŽƚŽdžŝĐŝƚLJ ŝŶ ǀĞƌLJ ŐĞŶĞƌĂů ƚĞƌŵƐ ĂƐ

͞ƚŽdžŝĐŝƚLJ ƚŚĂƚ ĂĨĨĞĐƚƐ ƚŚĞ ŚĞĂƌƚ͘͟

source: www.cancer.gov/dictionary/

ĨĨĞƚƚŝĚĞŝĐŚƚ ƐƵĐƵŽƌĞĞĐŝƌĐŽůŽ

• /ƉĞƌƚĞŶƐŝŽŶĞ

• ŝƐĨƵŶnjŝŽŶĞǀĞŶƚƌŝĐŽůĂƌĞƐŝŶŝƐƚƌĂ

• dƌŽŵďŽĞŵďŽůŝĂ

• ƌŝƚŵŝĞ;ĂůůƵŶŐĂŵĞŶƚŽYdĐͿ

• ƌŝƚŵŝĞ;ĂůůƵŶŐĂŵĞŶƚŽYdĐͿ

• /ƐĐŚĞŵŝĂ

• sĞƌƐĂŵĞŶƚŽƉĞƌŝĐĂƌĚŝĐŽ

• ZŝƐĐŚŝŽĚŝĞǀĞŶƚŝĐĂƌĚŝŽǀĂƐĐŽůĂƌŝŝŶƚĞƌĂƉŝĞ

ŽƌŵŽŶĂůŝ

DĞĐĐĂŶŝƐŵŝĚ͛ĂnjŝŽŶĞ

ŶƚƌĂĐŝĐůŝŶĞ

d</dƌĂƐƚƵnjƵŵĂď /ŵĂƚŝŶŝď

^ƵŶŝƚŝŶŝď

ĂƐĂƚŝŶŝď

ĂƐĂƚŝŶŝď

Ŷƚŝs'&ĞǀĂĐŝnjƵŵĂď

&ůƵŽƌŽƉŝƌŝŵŝĚŝŶĞ ϱ&K͕ĐĂƉĞĐŝƚĂďŝŶĂ

ůĐŚŝůĂŶƚŝŝƐƉůĂƚŝŶŽ

ŝĐůŽĨŽƐĨĂŵŝĚĞ

WĂĐůŝƚĂdžĞů ĞĂůĐĂůŽŝĚŝĚĞůůĂǀŝŶĐĂ

DŽĚƵůĂƚŽƌŝƌĞĐĞƚƚŽƌŝĞƐƚƌŽŐĞŶŝĐŝ

ĂƌĚŝŽƚŽdžŝĐŝƚLJ

ĂƌĚŝŽƚŽdžŝĐŝƚLJͲͲ ĂŵLJƌŝĂĚŽĨ ĂŵLJƌŝĂĚŽĨ

ŵĞĐŚĂŶŝƐŵƐ ŵĞĐŚĂŶŝƐŵƐ

Journal of the National Cancer Instiute JNCI, Jan 10 2010- Cardiotoxicity of Anticancer Drugs: The Need for

Cardio-Oncology and Cardio-Oncological Prevention

Adriana Albini , Giuseppina Pennesi , Francesco Donatelli , Rosaria Cammarota , Silvio De Flora , Douglas M. Noonan

ACE inhibitors Beta–blockers Anticancer drugs with possible

cardiotoxicity

Mechanisms of cardiotoxicity Potential protective agents

Doxorubicin and other anthracyclines

Mitochondrial dysfunction Apoptosis of cardiomyocytes

džĂŵƉůĞƐŽĨƉŽƚĞŶƚŝĂůůLJĐĂƌĚŝŽƚŽdžŝĐĂŶƚŝĐĂŶĐĞƌĚƌƵŐƐ͕ƚŚĞŝƌŵĞĐŚĂŶŝƐŵƐŽĨƚŽdžŝĐŝƚLJ͕ĂŶĚ

džĂŵƉůĞƐŽĨƉŽƚĞŶƚŝĂůůLJĐĂƌĚŝŽƚŽdžŝĐĂŶƚŝĐĂŶĐĞƌĚƌƵŐƐ͕ƚŚĞŝƌŵĞĐŚĂŶŝƐŵƐŽĨƚŽdžŝĐŝƚLJ͕ĂŶĚ

ŽĨƉŽƚĞŶƚŝĂůƉƌŽƚĞĐƚŝǀĞĂŐĞŶƚƐ ŽĨƉŽƚĞŶƚŝĂůƉƌŽƚĞĐƚŝǀĞĂŐĞŶƚƐ

Beta–blockers Statins

Dexrazoxane L–Carnitine Coenzyme Q10

N–Acetyl–L–Cysteine Glutathione

Erdosteine Selenium Zinc

Melatonin

Falvonoids and polyphenols Platelet antiaggregants anthracyclines

5–Fluorouracil, Capecitabine Paclitaxel and vinca alkaloids Cyclophosphamide

TK Inhibitors:

Trastuzumab Imatinib

Bevacizumab

Sorafenib, sunitinib etc COX–2 inhibitors

Estrogen receptor modulators Irradiation to the thorax

Apoptosis of cardiomyocytes ROS generation

DNA damage

Endothelial cell damage, spasms Antibody directed cellular cytotoxicity ATP block

Cell signaling, survival block Hypertension

Fibrosis

Sinus bradicardia

atrium-ventricular block ventricular tachycardia Arrythmias

thromboembolism

Cardiotoxicity of Anticancer Drugs: The Need for Cardio-Oncology and Cardio-Oncological Prevention. A Albini, et al., JNCI 2010

Examples of major mechanisms causing cardiotoxicity of anticancer treatments (black text), clinically used therapeutic agents (green text), and potential protective agents (blue cursive text)

ROS = reactive oxygen species; ACE = angiotensin-converting enzyme, NSAIDs = nonsteroidal anti-infl ammatory drugs.

Albini A et al, J Natl Cancer Inst. 2010 Jan 6;102(1):14-25

^h^dd//>/d͛'Ed/

,ĞŶŬ sŝƐƐĐŚĞƌ͕ŽůŝŶ:͘͘ZŽƐƐ͕^͘ZŽĚ ZĂƐƐĞŬŚ͕ŵŝŶĂĂƌŚĚĂĚŝ͕

DĂƌŝĞͲWŝĞƌƌĞƵďĞDz͕,ĞƐŚĂŵ ůͲ^ĂůŽŽƐ͕'ĞŽƌŐĞ^͘^ĂŶĚŽƌ͕,Ƶŝď E͘

ĂƌŽŶ͕ůǀŝƌĂ͘ǀĂŶĂůĞŶ͕>ĞŽŶƚŝĞŶ ͘<ƌĞŵĞƌ͕,ĞůĞŶĂ:͘ǀĂŶĚĞƌ

WĂů͕ŶĚƌĞǁ D͘<͘ƌŽǁŶ͕WĂƵů͘ZŽŐĞƌƐ͕DŝĐŚĂĞů^͘WŚŝůůŝƉƐ͕DŝĐŚĂĞů:͘

ZŝĞĚĞƌ͕ƌƵĐĞ͘ĂƌůĞƚŽŶ͕DŝĐŚĂĞů Z͘,ĂLJĚĞŶ͕ĂŶĚĂŶĂĚŝĂŶ

WŚĂƌŵĂĐŽŐĞŶŽŵŝĐƐ EĞƚǁŽƌŬĨŽƌƌƵŐ ^ĂĨĞƚLJ ŽŶƐŽƌƚŝƵŵ

ŝĨĨĞƌĞŶƚ ĐĂƌĚŝŽƚŽdžŝĐŝƚŝĞƐ

KŶƚĂƌŐĞƚ KĨĨƚĂƌŐĞƚ

dLJƉĞ /

dLJƉĞ //

KEdZ'd

• tŝƚŚŽŶͲƚĂƌŐĞƚƚŽdžŝĐŝƚLJ͕ƚŚĞŬŝŶĂƐĞƚŚĂƚŝƐƚĂƌŐĞƚĞĚŝŶƚŚĞĐĂŶĐĞƌĂůƐŽ

ƉƌŽǀŝĚĞƐĂŶŝŵƉŽƌƚĂŶƚĨƵŶĐƚŝŽŶŝŶƚŚĞŚĞĂƌƚĂŶĚͬŽƌǀĂƐĐƵůĂƚƵƌĞ͘

• /ŶŚŝďŝƚŝŶŐƚŚŝƐŬŝŶĂƐĞůĞĂĚƐƚŽĂĚǀĞƌƐĞĐŽŶƐĞƋƵĞŶĐĞƐŝŶƚŚĞŚĞĂƌƚ͘

• dž͗ƐŽƌĂĨĞŶŝď хŝŶŚŝďŝƚƐ ƌĂƉŝĚůLJ ĂĐĐĞůĞƌĂƚĞĚ ĨŝďƌŽƐĂƌĐŽŵĂ;Z&ͿͲϭĂŶĚ

Z&͘Z&ĨĂŵŝůLJŬŝŶĂƐĞƐĨƵŶĐƚŝŽŶŝŶƚŚĞƉƌŽͲƐƵƌǀŝǀĂůZ<;Žƌ

ŵŝƚŽŐĞŶͲĂĐƚŝǀĂƚĞĚƉƌŽƚĞŝŶŬŝŶĂƐĞͿĐĂƐĐĂĚĞ͘

• dŚĞŝŵƉŽƌƚĂŶĐĞŽĨZ&ͲϭŝŶƚŚĞŚĞĂƌƚŚĂƐďĞĞŶĚĞŵŽŶƐƚƌĂƚĞĚŝŶ

ŵŽƵƐĞŵŽĚĞůƐŝŶǁŚŝĐŚĐŽŶĚŝƚŝŽŶĂůĐĂƌĚŝĂĐͲƐƉĞĐŝĨŝĐĚĞůĞƚŝŽŶŽĨZ&Ͳ ϭƌĞƐƵůƚĞĚŝŶůĞĨƚǀĞŶƚƌŝĐƵůĂƌ;>sͿĚŝůĂƚŝŽŶĂŶĚƌĞĚƵĐĞĚĐŽŶƚƌĂĐƚŝůĞ

ĨƵŶĐƚŝŽŶ͘

• ^K>hd/KE^͗ƚĂƌŐĞƚĞĚ ĚĞůŝǀĞƌLJŽĨĚƌƵŐ ƐƉĞĐŝĨŝĐĂůůLJƚŽƚŚĞĐĂŶĐĞƌ͕

ƐƉĂƌŝŶŐŶŽƌŵĂůƚŝƐƐƵĞ͕ŽƌŝŶŚŝďŝƚŝŶŐĐĞůůĚĞĂƚŚƉĂƚŚǁĂLJƐŝŶƚŚĞŚĞĂƌƚ

ƚŚĂƚĂƌĞĂĐƚŝǀĂƚĞĚďLJĂĐŽŵƉŽƵŶĚďƵƚƚŚĂƚĂƌĞŶŽƚŶĞĐĞƐƐĂƌLJĨŽƌ

ƚƵŵŽƌĐĞůůĚĞĂƚŚ͘

>Ăů ,͘:ϮϬϭϯ

K&&dZ'd

• KĨĨͲƚĂƌŐĞƚƚŽdžŝĐŝƚLJŝƐĚŝƌĞĐƚůLJƌĞůĂƚĞĚƚŽŶŽŶƐĞůĞĐƚŝǀŝƚLJ͘ /ŶƚŚŝƐ

ƐĐĞŶĂƌŝŽ͕ŝŶŚŝďŝƚŝŽŶŽĨĂƚĂƌŐĞƚŶŽƚŝŶƚĞŶĚĞĚƚŽďĞŝŶŚŝďŝƚĞĚďLJ

Ă</ŝƐƌĞƐƉŽŶƐŝďůĞĨŽƌƚŚĞĐĂƌĚŝŽƚŽdžŝĐŝƚLJ͘ůŵŽƐƚĂůůŽĨƚŚĞ

ĂƉƉƌŽǀĞĚ</ƐďŝŶĚƚŽŵƵůƚŝƉůĞŬŝŶĂƐĞƐ͕ĂůƚŚŽƵŐŚǁŝƚŚĚŝĨĨĞƌĞŶƚ

ĂĨĨŝŶŝƚŝĞƐ͘ĂƌĚŝŽƚŽdžŝĐŝƚLJ ǁŝƚŚ</ƐŝƐĚŝƌĞĐƚůLJĐŽƌƌĞůĂƚĞĚǁŝƚŚĂ

ĂĨĨŝŶŝƚŝĞƐ͘ĂƌĚŝŽƚŽdžŝĐŝƚLJ ǁŝƚŚ</ƐŝƐĚŝƌĞĐƚůLJĐŽƌƌĞůĂƚĞĚǁŝƚŚĂ

ůĂĐŬŽĨƚĂƌŐĞƚƐƉĞĐŝĨŝĐŝƚLJ͘

• dž͗ƐƵŶŝƚŝŶŝďͲŝŶĚƵĐĞĚĐĂƌĚŝŽƚŽdžŝĐŝƚLJ͘

• ^ƵŶŝƚŝŶŝď ǁĂƐĚĞƐŝŐŶĞĚĂƐĂŵƵůƚŝŬŝŶĂƐĞ ŝŶŚŝďŝƚŽƌƚŚĂƚƚĂƌŐĞƚĞĚ

s'&ƌĞĐĞƉƚŽƌϭ͕ƉůĂƚĞůĞƚͲĚĞƌŝǀĞĚŐƌŽǁƚŚĨĂĐƚŽƌ͕ĐŽůŽŶLJͲ

ƐƚŝŵƵůĂƚŝŶŐĨĂĐƚŽƌϭƌĞĐĞƉƚŽƌ͕ĂŶĚƐĞǀĞƌĂůŽƚŚĞƌƐ͘,ŽǁĞǀĞƌ͕ŝƚ

ƐĞĞŵƐƚŚĂƚ͕ĂƚƚŚĞƌĂƉĞƵƚŝĐƉůĂƐŵĂůĞǀĞůƐ͕ƐƵŶŝƚŝŶŝď ǁŽƵůĚ

ŝŶŚŝďŝƚĂƉƉƌŽdžŝŵĂƚĞůLJϵϬŬŝŶĂƐĞƐ͘

The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors

is correlated with lack of target specificity

Brian B. Hasinoff Toxicology and Applied Pharmacology 244 (2010) 190–195

EdZ/>/E

DĞĐĐĂŶŝƐŵŽĚ͛ĂnjŝŽŶĞŶƚƌĂĐŝĐůŝŶĞ

ĂƵŶŽƌƵďŝĐŝŶĂ͕ĚŽdžŽƌƵďŝĐŝŶĂ͕ĞƉŝƌƵďŝĐŝŶĂ͕ŝĚĂƌƵďŝĐŝŶĂ

• ŶƚŝďŝŽƚŝĐŝĐŝƚŽƐƚĂƚŝĐŝĐŚĞƐŝŝŶƐĞƌŝƐĐŽŶŽŶĞůůĂĚŽƉƉŝĂĐĂƚĞŶĂ

ĚĞůE

DĞĐĐĂŶŝƐŵŽĚ͛ĂnjŝŽŶĞĚĞůůĂĐĂƌĚŝŽƚŽƐƐŝĐŝƚă͗

ͲĨŽƌŵĂnjŝŽŶĞƌĂĚŝĐĂůŝůŝďĞƌŝ͕ĚŽǁŶƌĞŐƵůĂƚŝŽŶ ŵZE ĂͲdWĂƐŝ ͲĨŽƌŵĂnjŝŽŶĞƌĂĚŝĐĂůŝůŝďĞƌŝ͕ĚŽǁŶƌĞŐƵůĂƚŝŽŶ ŵZE ĂͲdWĂƐŝ

ƌĞƚŝĐŽůŽƐĂƌĐŽƉůĂƐŵĂƚŝĐŽ͕ĚĂŶŶŝEŵŝƚŽĐŽŶĚƌŝĂůĞ͕

ŝŶƚĞƌĨĞƌĞŶnjĂdŽƉŽŝƐŽŵĞƌĂƐŝ //ͲďĞƚĂ

ͲĐŽŶǀĞƌƐŝŽŶĞŝŶŵĞƚĂďŽůŝƚŝĂůĐŽŽůŝĐŝƉĞƌƐŝƐƚĞŶƚŝ͕ĐŚĞŝŶĂƚƚŝǀĂŶŽůĞ

ƉƌŽƚĞŝŶĞĐŚĞůĞŐĂŶŽŝůĐĂůĐŝŽŶĞůƉƌŽĐĞƐƐŽĚŝĂĐĐŽƉƉŝĂŵĞŶƚŽ

ĐŽŶƚƌĂnjŝŽŶĞƌŝůĂƐĐŝĂŵĞŶƚŽŽĨĂƚƚŽƌŝĐŚŝĂǀĞĚĞůŵĞƚĂďŽůŝƐŵŽ

ĐĞůůƵůĂƌĞĐŽŵĞů͛ĂĐŽŶŝƚĂƐŝ ĐŝƚŽƉůĂƐŵĂƚŝĐĂ

DĞĐĐĂŶŝƐŵŽĚ͛ĂnjŝŽŶĞŶƚƌĂĐŝĐůŝŶĞ

• ŶƚƌĂĐŝĐůŝŶĞĐƌĞĂŶŽĚŝƐĨƵŶnjŝŽŶĞĚŝĂƐƚŽůŝĐĂ

ĂƵŵĞŶƚĂŶĚŽŝůĐĂůĐŝŽĚŝĂƐƚŽůŝĐŽĞůĂƌŝŐŝĚŝƚă

ƉĂƌŝĞƚĂůĞхĂƵŵĞŶƚŽƉƌĞƐƐŝŽŶĞŝŶƚĞƌƐƚŝnjŝĂůĞх

ƌŝĚƵnjŝŽŶĞĐŽŶĚƵƚƚĂŶnjĂĐŽƌŽŶĂƌŝĐĂхĐĂƵƐĂĚŝ

ŝƐĐŚĞŵŝĂĚĞůŵŝĐƌŽĐŝƌĐŽůŽ ŝƐĐŚĞŵŝĂĚĞůŵŝĐƌŽĐŝƌĐŽůŽ

• ^ƵĐĐĞƐƐŝǀĂĞǀŽůƵnjŝŽŶĞǀĞƌƐŽůĂĚŝƐĨƵŶnjŝŽŶĞ

ƐŝƐƚŽůŝĐĂĐŽŶůĂƌŝĚŽƚƚĂĞƐƉƌĞƐƐŝŽŶĞĞůĂ

ĚŝƐŽƌŐĂŶŝnjnjĂnjŝŽŶĞĚĞůůĞŵŝŽĨŝďƌŝůůĞхĂƉŽƉƚŽƐŝ͘

• /ƉĞƌƚƌŽĨŝĂs^хĚŝůĂƚĂnjŝŽŶĞĞĂƐƐŽƚƚŝŐůŝĂŵĞŶƚŽх

ĞǀŽůƵnjŝŽŶĞĚŝůĂƚĂƚŝǀĂ

DŽůĞĐƵůĂƌŵĞĐŚĂŶŝƐŵƐŽĨĐĂƌĚŝŽƚŽdžŝĐŝƚLJ DŽůĞĐƵůĂƌŵĞĐŚĂŶŝƐŵƐŽĨĐĂƌĚŝŽƚŽdžŝĐŝƚLJ

ůďŝŶŝĞƚů͘

/E//dKZ/>>d/ZK^/E,/E^/

;d</Ϳ

dŚĞĐŚĞŵŽƚŚĞƌĂƉĞƵƚŝĐĂŐĞŶƚƐƚĂƌŐĞƚŝŶŐ,ZϮŽǀĞƌ

dŚĞĐŚĞŵŽƚŚĞƌĂƉĞƵƚŝĐĂŐĞŶƚƐƚĂƌŐĞƚŝŶŐ,ZϮŽǀĞƌͲͲĞdžƉƌĞƐƐŝŶŐ ĞdžƉƌĞƐƐŝŶŐ

ƚƵŵŽƌƐ ƚƵŵŽƌƐ

Albini A et al, Future Cardiol. 2011; 7 (5)

DE/^DK͛/KE/E//dKZ/,ZϮ

1. ERBB2 signaling in breast cancer and 1. ERBB2 signaling in breast cancer and

cardiomyocytes cardiomyocytes

Force et al., Nature Rev Cancer, 2007

</>^^/&/d/KE&KZ/&&ZEd/E/E'dK</E^^

>Ăů :ϮϬϭϯ

>Ăů :ϮϬϭϯ

YƵĂůĞĐĂƌĚŝŽƚŽƐƐŝĐŝƚă͍

• ĂŶŶŽƉĞƌŵĂŶĞŶƚĞ

ŝƌƌĞǀĞƌƐŝďŝůĞ

• ŽƐĞĐŽƌƌĞůĂƚŽ

• ĂŶŶŽƌĞǀĞƌƐŝďŝůĞŝŶϮͲϰ

ŵĞƐŝ

• EŽŶĚŽƐĞĐŽƌƌĞůĂƚŽ

Z/KdK^^//d͛ϭ

;EdZ/>/EͿ

Z/KdK^^//d͛Ϯ

;dZ^dhhDͿ

• ŽƐĞĐŽƌƌĞůĂƚŽ

• ZĂĚŝĐĂůŝůŝďĞƌŝͬƐƚƌĞƐƐ

ŽƐƐŝĚĂƚŝǀŽ

• sĂĐƵŽůŝ͕ĚŝƐŐƌĞŐĂnjŝŽŶĞĞ

ƉĞƌĚŝƚĂŵŝŽĨŝďƌŝůůĂƌĞ

• EŽŶĚŽƐĞĐŽƌƌĞůĂƚŽ

• ůŽĐĐŽ,ZͲϮ

• EŽŶĚĂŶŶŽƵůƚƌĂƐƚƌƵƚƚƵƌĂůĞ

• /ŶĐŝĚĞŶnjĂĚŝ,&ŝŶ

ĂĚŝƵǀĂŶƚĞĚĞůϬ͘ϲй

YƵĂůĞĐĂƌĚŝŽƚŽƐƐŝĐŝƚă͍

• ZŝĚƵnjŝŽŶĞ͘&͘

• ůƚĂƉƌŽďĂďŝůŝƚăĚŝƌĞĐŝĚŝǀĂх

• ZŝĚƵnjŝŽŶĞ͘&͘

• ŝŵŽƐƚƌĂnjŝŽŶĞƐŝĐƵƌĞnjnjĂ

Z/KdK^^//d͛Ϯ

;dZ^dhhDͿ

Z/KdK^^//d͛ϭ

;EdZ/>/EͿ

• ůƚĂƉƌŽďĂďŝůŝƚăĚŝƌĞĐŝĚŝǀĂх

,&ŝŶƚƌĂƚƚĂďŝůĞхĚĞĐĞƐƐŽ

• ůƚĂƉƌŽďĂďŝůŝƚăĚŝƐĨƵŶnjŝŽŶĞ

ĐĂƌĚŝĂĐĂĐŽƌƌĞůĂƚĂĂĚĂŶŶŽ

ƐĞƋƵĞŶnjŝĂůĞ

• ŝŵŽƐƚƌĂnjŝŽŶĞƐŝĐƵƌĞnjnjĂ

ƌĞůĂƚŝǀĂĚĞůƌĞĐŚĂůůĞŶŐĞ

• ĂƐƐĂƉƌŽďĂďŝůŝƚăĚŝƐĨƵnjŝŽŶĞ ĐĂƌĚŝĂĐĂĐŽƌƌĞůĂƚĂĂĚĂŶŶŽ

ƐĞƋƵĞŶnjŝĂůĞ

&ŽƌĐĞ͕EĂƚZĞǀĂŶĐĞƌ͘ϮϬϬϳ

/ŵĂƚŝŶŝď ĐĂƌĚŝŽƚŽdžŝĐŝƚLJ

'ŽŽĚ ƉƌŽĨŝůĞ ŽĨĐĂƌĚŝĂĐ ƐĂĨĞƚLJ

ĂƌĚŝŽƚŽdžŝĐŝƚLJ ŝĨ ƉƌĞĞdžŝƐƚĞŶƚ ĐĂƌĚŝĂĐ ĚĂŵĂŐĞ

;dƵƌƌŝƐŝ /Ŷƚ͘:ĂƌĚŝŽů͘ϮϬϭϬͿ EŽĐĂƌĚŝŽƚŽdž͘ďƵƚ ƚƌĞĂƚ &Ěƌ EŽĐĂƌĚŝŽƚŽdž͘ďƵƚ ƚƌĞĂƚ &Ěƌ

;dƌĞŶƚ ͘ĂŶĐĞƌ ϮϬϭϬͿ;WĞƌŝŬ W͘^͘ŶŶ͘KĨKŶĐŽů͘

ϮϬϬϴͿ

dĂƌŐĞƚZͲ>ĂŶĚĐͲ</d

;dŚĂŶŽƉƵŽůŽƵ ͘ƌĐŚ͘dŽdžŝĐŽů͘ϮϬϭϮͿ

^ƵŶŝƚŝŶŝď ĐĂƌĚŝŽƚŽdžŝĐŝƚLJ

ĂƌĚŝŽŵLJŽĐLJƚĞ ŝŶũƵƌLJ ŝŶǀŝǀŽĂŶĚ

ůŽƐƐ ŝŶŵŽƵƐĞƐ х

ĐĂƵƐĞĚ ďLJĚŝƌĞĐƚ ;ŽĨĨͲƚĂƌŐĞƚͿ

ŝŶŚŝďŝƚŝŽŶ ŽĨDW<ŝŶĂƐĞ х

ŵŝƚŚŽĐŽŶĚƌŝĂů ĚĂŵĂŐĞ х

ĐĂƌĚŝŽŵLJŽĐLJƚĞ ĚĞĂƚŚ͖

ŝŶŚŝďŝƚŝŽŶ ĂůƐŽ ŽĨDdϬZϭďLJƚŚĞ

ŝŶŚŝďŝƚŝŽŶ ĂůƐŽ ŽĨDdϬZϭďLJƚŚĞ

ƌĞĐƌƵŝƚŵĞŶƚ ŽĨĂŶĂůƚĞƌŶĂƚŝǀĞ

ƉĂƚŚǁĂLJхĞ&ϮƉŚŽƐƉŚŽƌLJůĂƚŝŽŶх

ƌĞĚƵĐĞĚ ƉƌŽƚĞŝŶ ƚƌĂƐůĂƚŝŽŶ͘

EŽƌĞĚƵĐƚŝŽŶ ŽĨĐĂƉŝůůĂƌLJ ĚĞŶƐŝƚLJ

;<ĞƌŬĞůĂ Z͘ůŝŶ͘dƌĂƐů͘^Đŝ͘ϮϬϭϬͿ

^ƵŶŝƚŝŶŝď ĐĂƌĚŝŽƚŽdžŝĐŝƚLJ

ƵƚŽƉŚĂŐLJ ƌĂŝƐĞĚ ŝŶ,ϵϮĐĂƌĚŝŽŵLJŽĐŝƚĞƐ

;ŚĂŽzdŽdž͘ƉƉů͘WŚ͘ϮϬϭϬͿ

ϯĚĞŶŽƐŝŶ ƌĞĐĞƉƚŽƌ ĂŐŽŶŝƐƚ хĐĂƌĚŝŽƉƌŽƚĞĐƚŝǀĞ ĞĨĨĞĐƚ ;^ĂŶĚŚƵ ,͘,ĞĂƌƚ ϮϬϭϰͿ

ĞĨĨĞĐƚ ;^ĂŶĚŚƵ ,͘,ĞĂƌƚ ϮϬϭϰͿ

ĞǀĞůŽƉŵĞŶƚŽĨŚLJƉĞƌƚƌŽƉŚLJ ŝŶĨůƵĞŶĐĞĚ ďLJƚŚĞ

ĂƌLJů ŚLJĚƌŽĐĂƌďŽŶ ƐŝŐŶĂůŝŶŐ ƉĂƚŚǁĂLJ хƌĞƐǀĞƌĂƚƌŽů хƉƌŽƚĞĐƚŝǀĞ ĞĨĨĞĐƚ ;DĂĂLJĂŚ ,͕͘ƌĐŚ͘dŽdžŝĐŽů͘

ϮϬϭϰͿ

WĞƌŝĐLJƚĞƐ

ĞůůƚLJƉĞƐ ĚĞƉĞŶĚĞŶƚ ŽŶŝŶƚĂĐƚ W'&ZƐŝŐŶĂůŝŶŐ

^ƵŶŝƚŝŶŝď ŝŶĚƵĐĞƐ ƉĞƌŝĐLJƚĞƐ ĚĞƉůĞƚŝŽŶ ĂŶĚĐŽƌŽŶĂƌLJ ĚĞƉůĞƚŝŽŶ ĂŶĚĐŽƌŽŶĂƌLJ ŵŝĐƌŽǀĂƐĐƵůĂƌ ĚĂŵĂŐĞ dŚĂůŝĚŽŵŝĚĞ ƉƌĞǀĞŶƚƐ

^hEƉĞƌŝĐLJƚĞƐ ĐĞůů ĚĞĂƚŚ

;ŚŝŶƚĂůŐĂƚƚƵ s͕͘^Đŝ dƌĂƐů͘DĞĚ͘ϮϬϭϯͿ

^hE/d/E//Es/dZKdKy//dz

ZĞĚƵĐƚŝŽŶ ǀŝƚĂůŝƚLJ ŽĨĐĂƌĚŝŽŵLJŽĐŝƚĞƐ͕/ŶŝďŝƚŝŽŶ ŽĨDW<͕ZĂŝƐĞ ŝŶ

ůŝƉŝĚƐ͕dWĚĞƉůĞƚŝŽŶ ŽŚĞƌƚLJEZ;dŽdžŝĐŽů͘ƉƉů͘WŚ͘ϮϬϭϯͿ

EŽƉƌŽƚĞĐƚŝŽŶ ǁŝƚŚĚĞdžƚƌĂnjŽdžĂŶĞ

;ĚŽdžŽƌƵďŝĐŝŶĞ ĐĂƌĚŝŽƉƌŽƚĞĐƚŝǀĞ ĂŐĞŶƚͿ EŽƉƌŽƚĞĐƚŝŽŶ ǁŝƚŚŵĞƚĨŽƌŵŝŶ ;DW<

ĂĐƚŝǀĂƚŽƌͿ

^ƵŶŝƚŝŶŝď ĐĂƵƐĞŵŝŽĐLJƚĞ ĚĂŵĂŐĞ ǁŝƚŚƌŝƐĞŽĨ>,;,ĂƐŝŶŽĨĨ͘ϮϬϬϴͿ

>ĂƉĂƚŝŶŝď

Basic & Clinical Pharmacology & Toxicology, 107, 614–618

ĂƐĂƚŝŶŝď ĂŶĚƉůĞƵƌŽƉĞƌŝĐĂƌĚŝĂů ĞĨĨƵƐŝŽŶ

d</ǁŝƚŚƉůĞƵƌĂů ĂŶĚƉĞƌŝĐĂƌĚŝĂů ŝŶĨůĂŵŵĂƚŝŽŶ /ŶŝďŝƚŝŽŶ ŽĨW'&

džƉĂŶƐŝŽŶŽĨĐLJƚŽƚŽdžŝĐ dĂŶĚŶĂƚƵƌĂů ŬŝůůĞƌĐĞůůƐ ŝƚĐĂŶŶŽƚďĞƉƌĞĚŝĐƚĞĚ͕

ŝƚĐĂŶŶŽƚďĞƉƌĞĚŝĐƚĞĚ͕

ƚŝŵĞŽĨŽŶƐĞƚǀĂƌŝĂďůĞ͕

ŵĂŶĂŐĞŵĞŶƚĨƌĞƋƵĞŶƚůLJƌĞƋƵŝƌĞƐƌĞƉĞĂƚŝŶǀĂƐŝǀĞ

ƉƌŽĐĞĚƵƌĞƐ͘

<ĞůůLJ<dĂƌŐĞƚKŶĐŽů͘ϮϬϬϵ

Ed/s'&

DƵůƚŝƉůĞĨƵŶĐƚŝŽŶƐŽĨs'&

ƌƵŐ/ŶĨŽƌŵĂƚŝŽŶƐƐŽĐŝĂƚŝŽŶ ǁǁǁ͘ĚŝĂŚŽŵĞ͘ŽƌŐ 38

Ferrara N The Oncologist 2004;9:2-10

ŚĞŶ͕EĂƚƵƌĞZĞǀŝĞǁƐʹ ůŝŶŝĐĂůKŶĐŽůŽŐLJϮϬϬϵ

s'&ƐŝŐŶĂůŝŶŐƉĂƚŚǁĂLJŝŶŚŝďŝƚŽƌƐ

ƌƵŐ/ŶĨŽƌŵĂƚŝŽŶƐƐŽĐŝĂƚŝŽŶ ǁǁǁ͘ĚŝĂŚŽŵĞ͘ŽƌŐ 40

Nazer, Circulation 2011, 124:1687-1691

^LJƐƚĞŵŝĐĨĨĞĐƚƐŽĨŶƚŝ

^LJƐƚĞŵŝĐĨĨĞĐƚƐŽĨŶƚŝͲͲs'&dŚĞƌĂƉLJ s'&dŚĞƌĂƉLJ

Normal Tissues

(VEGF constitutively expressed)

Tumor Tissues

(VEGF upregulated)

Lung cancer (bevacizumab) Inhibition of tumor growth, tumor cavitation

Hypertensive remodeling Microvascular rarefaction

Cardiomyopathy (sunitinib and sorafenib)

Hepatocellular carcinoma (sorafenib) Tumor necrosis

Renal cell carcinoma (sunitinib) Tumor shrinkage, tumor cell necrosis

Colorectal cancer (bevacizumab) Deceleration of tumor growth efficient chemotherapy delivery

1 2 3

Microcirculation: 1. normal arteriole, 2. functional rarefaction (endothelial dysfunction,vasoconstriction), 3. anatomic rarefaction

Thrombotic microangiopathy Glomerulopathy / glomerulonephritis Proteinuria

Hypertensive nephropathy

Vaklavos, et al Oncologist 2010, p 130.

ĂƌĚŝŽǀĂƐĐƵůĂƌƚŽdžŝĐŝƚŝĞƐ

•Pulmonary hemorrhage and edema

• gastrointestinal tract bleeding

•Hypertension

•Venous thromboembolism bevacizumab

sorafenib bevacizumab

ƌƵŐ/ŶĨŽƌŵĂƚŝŽŶƐƐŽĐŝĂƚŝŽŶ ǁǁǁ͘ĚŝĂŚŽŵĞ͘ŽƌŐ 42

•Arterial thrombotic event (stroke, myocardial infarction)

•Atrial fibrillation

•Cardiomyocites toxicity

•Symptomatic heart failure

•Decreased left ventricular ejection fraction

sorafenib, sunitinib sorafenib

sunitinib

DdE>/^/^KZ&E/^hE/d/E/

WZsEd/dZKDKd//

ŚŽƵĞŝƌŝ͕:KϮϬϭϬ

ĞǀĂĐŝnjƵŵĂďͲƌĞůĂƚĞĚŚLJƉĞƌƚĞŶƐŝŽŶĂŶĚŵŝĐƌŽĐŝƌĐƵůĂƚŝŽŶĚĂŵĂŐĞŝŶƉĂƚŝĞŶƚƐǁŝƚŚ

ŵĞƚĂƐƚĂƚŝĐĐŽůŽƌĞĐƚĂůĐĂŶĐĞƌƚƌĞĂƚĞĚǁŝƚŚďĞǀĂĐŝnjƵŵĂď

Scatter plot of systolic blood pressure (SBP) and diastolic blood pressure (DBP) at baseline and after 6 months of treatment with bevacizumab.

Mourad JJ et al. Annals of Oncology 2008; 19: 927-934

ƌƵĐŝĂůƌŽůĞĨŽƌŵŝĐƌŽĐŝƌĐƵůĂƚŝŽŶŝŶƚŚĞƌŝƐŝŶŐŽĨďůŽŽĚƉƌĞƐƐƵƌĞĨŽůůŽǁŝŶŐ

ĂŶŐŝŽŐĞŶĞƐŝƐŝŶŚŝďŝƚŝŽŶďLJďĞǀĂĐŝnjƵŵĂď

Typical video microscopic image of capillaries in the phalanx skin during venous occlusion. The blue rectangle represents a calibrated 1-mm²surface.

The structural capillary density is the number of capillary structures in this surface area.

Typical examples of laser Doppler recordings before (upper figure, before treatment) and after a 6-month bevacizumab treatment (lower figure, altered

response). Vertical lines indicate the successive administrations of pilocarpine. The red line represents the skin temperature maintained at 33°C

during baseline and pilocarpine administrations and heated at 44°C for recording of the maximal skin flow under local vasodilation.

Mourad JJ et al. Annals of Oncology 2008; 19: 927-934

ĂƉŝůůĂƌLJĚĞŶƐŝƚLJĂŶĚǀĂƐŽůĚŝůĂƚĂƚŽƌLJƌĞƐƉŽŶƐĞĂĨƚĞƌϲŵŽŶƚŚƐ

ŽĨƚƌĞĂƚŵĞŶƚǁŝƚŚĞǀĂĐŝnjƵŵĂď

Scatter plot of maximal capillary density (during

venous occlusion) at baseline and after a 6-month treatment with bevacizumab.

Scatter plot of vasodilatory response to pilocarpine, marker of endothelium function, at baseline after 6 months of treatment with bevacizumab.

Mourad JJ et al. Annals of Oncology 2008; 19: 927-934

ĚǀĞƌƐĞĞĨĨĞĐƚƐŽĨĂŶƚŝĐĂŶĐĞƌĂŐĞŶƚƐƚŚĂƚƚĂƌŐĞƚƚŚĞ

s'&ƉĂƚŚǁĂLJ

ƌƵŐ/ŶĨŽƌŵĂƚŝŽŶƐƐŽĐŝĂƚŝŽŶ ǁǁǁ͘ĚŝĂŚŽŵĞ͘ŽƌŐ 47

Chen, H. X. & Cleck, J. N. Nat. Rev. Clin. Oncol. 6, 465–477 (2009);

&>hKZKW/Z/D//E

ĨůƵŽƌŽƉLJƌŝŵŝĚŝŶĞ

ůƚŚŽƵŐŚĂĐƵƚĞ,&͕ĂƌƌŚLJƚŚŵŝĂ͕ĂŶĚ'ĐŚĂŶŐĞƐŚĂǀĞďĞĞŶĂƐƐŽĐŝĂƚĞĚ

ǁŝƚŚϱͲ&hƚƌĞĂƚŵĞŶƚ͕ƚŚĞŵŽƐƚĐŽŵŵŽŶůLJĚĞƐĐƌŝďĞĚĂŶĚƐĞǀĞƌĞ

ĐĂƌĚŝĂĐƐŝĚĞͲĞĨĨĞĐƚŝƐŵLJŽĐĂƌĚŝĂůŝƐĐŚĞŵŝĂ͕ǁŚŝĐŚĐůŝŶŝĐĂůůLJǀĂƌŝĞƐĨƌŽŵ

ĂŶŐŝŶĂƚŽĂĐƵƚĞŵLJŽĐĂƌĚŝĂů ŝŶĨĂƌĐƚŝŽŶ͘

/ƚŚĂƐďĞĞŶƐŚŽǁŶƚŚĂƚƚŚĞĨƌĞƋƵĞŶĐLJŽĨĐĂƌĚŝĂĐĞǀĞŶƚƐ͕ŝŶĐůƵĚŝŶŐ

ĂĐƵƚĞĐŽƌŽŶĂƌLJƐLJŶĚƌŽŵĞƐŝƐϳ͘ϲйĂŶĚƚŚĞŵŽƌƚĂůŝƚLJƌĂƚĞŝƐϮ͘ϮйĂĨƚĞƌ

ĐŽŶƚŝŶƵŽƵƐŝŶĨƵƐŝŽŶŽĨŚŝŐŚĚŽƐĞƐŽĨϱͲ&h͘WĂƚŝĞŶƚƐǁŝƚŚĂŚŝƐƚŽƌLJŽĨ

ĐŽŶƚŝŶƵŽƵƐŝŶĨƵƐŝŽŶŽĨŚŝŐŚĚŽƐĞƐŽĨϱͲ&h͘WĂƚŝĞŶƚƐǁŝƚŚĂŚŝƐƚŽƌLJŽĨ

ĐŽƌŽŶĂƌLJĂƌƚĞƌLJĚŝƐĞĂƐĞŚĂĚĂŚŝŐŚĞƌŝŶĐŝĚĞŶĐĞŽĨŝƐĐŚĞŵŝĐĂĚǀĞƌƐĞ

ĞǀĞŶƚƐ͘ůƚŚŽƵŐŚƚŚĞĞƚŝŽůŽŐLJŝƐƐƚŝůůƵŶŬŶŽǁŶ͕ĐĂƌĚŝŽƚŽdžŝĐŝƚLJ ƐĞĞŵƐƚŽ

ďĞƌĞůĂƚĞĚƚŽĞŶĚŽƚŚĞůŝĂůĚLJƐĨƵŶĐƚŝŽŶĂŶĚǀĂƐŽƐƉĂƐŵŽĨĐŽƌŽŶĂƌLJ

ĂƌƚĞƌŝĞƐ΀ϱϯ͕ϱϰ΁͘ĂƉĞĐŝƚĂďŝŶĞ ŵĂLJĂůƐŽĞůŝĐŝƚŵLJŽĐĂƌĚŝĂůŝƐĐŚĞŵŝĂĂŶĚ

ǀĞŶƚƌŝĐƵůĂƌĂƌƌŚLJƚŚŵŝĂƐ͕ĂůƚŚŽƵŐŚŝƚĂƉƉĞĂƌƐƚŽŚĂǀĞůĞƐƐƚŽdžŝĐŝƚLJ ƚŚĂŶ ϱͲ&h΀ϱϱ΁͘

ĞƌĂƌĚŝZƌŝƚŝĐĂůZĞǀŝĞǁƐŝŶ

KŶĐŽůŽŐLJͬ,ĞŵĂƚŽůŽŐLJϴϴ;ϮϬϭϯͿϳϱʹϴϲ

D,E/^DK&d/KE

• ĂƉĞĐŝƚĂďŝŶĞ ŝƐĐŽŶǀĞƌƚĞĚƚŽϱͲ&hŝŶĂƚŚƌĞĞͲ ƐƚĞƉŵĞƚĂďŽůŝĐƉƌŽĐĞƐƐ͘tŚĞŶϱͲ&hŝƐ

ĂŶĂďŽůŝnjĞĚ ƚŽƚŚĞŶƵĐůĞŽƚŝĚĞůĞǀĞů͕ŝƚĞdžĞƌƚƐŝƚƐ

ĐLJƚŽƚŽdžŝĐĞĨĨĞĐƚƐƚŚƌŽƵŐŚŝŶĐŽƌƉŽƌĂƚŝŽŶŝŶƚŽ

ĐLJƚŽƚŽdžŝĐĞĨĨĞĐƚƐƚŚƌŽƵŐŚŝŶĐŽƌƉŽƌĂƚŝŽŶŝŶƚŽ

ďŽƚŚŶƵĐůĞĂƌĂŶĚĐLJƚŽƉůĂƐŵŝĐZEƐƉĞĐŝĞƐĂŶĚ

ŝŶƚŽE͘,ŽǁĞǀĞƌ͕ƚŚĞŵŽƐƚŝŵƉŽƌƚĂŶƚ

ŵĞĐŚĂŶŝƐŵŽĨƚŚĞĂŶƚŝͲƚƵŵŽƌĞĨĨĞĐƚŽĨϱͲ&hŝƐ

ƚŚĞŝŶŚŝďŝƚŝŽŶŽĨƚŚĞŶƵĐůĞŽƚŝĚĞƐLJŶƚŚĞƚŝĐ

ĞŶnjLJŵĞd^ ;ŵƐƚƵƚnj͕&ƵƚƵƌĞDĞĚĞĐŝŶĞ ϮϬϭϭͿ

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ůŬLJůĂƚŝŶŐ ĂŐĞŶƚƐ

• ŝĐůŽƉŚŽƐĨĂŵŝĚĞ ϳͲϮϴй͕ŝƉŚŽƐĨĂŵŝĚĞ ϭϳй

• ŶĚŽƚŚĞůŝĂů ĚŝƐĨƵŶĐƚŝŽŶ ƉĞƌƐŝƐƚĞŶƚ͘

• /DŽŶůLJ ŝŶфϲй;sĂŶĚĞƌ ĞůƚͲƵƐĞďŽƵƚ ϮϬϬϲͿ

• &Z͗ƉƌĞǀŝŽƵƐ dŚ͘ŶƚƌĂĐ͕͘ŝƌƌĂĚ ŵĞĚŝĂƐƚ͘

WĞƌŝĐĂƌĚŝĂů ĞĨĨƵƐŝŽŶ ĂƐLJŵƉƚŽŵĂƚŝĐ͕,&͕DLJŽ

• WĞƌŝĐĂƌĚŝĂů ĞĨĨƵƐŝŽŶ ĂƐLJŵƉƚŽŵĂƚŝĐ͕,&͕DLJŽ ƉĞƌŝĐĂƌĚŝƚŝƐ͕

• ϭͲϭϬĚĂLJƐ ĨƌŽŵƚŚĞďĞŐŝŶŶŝŶŐ ƐƉŽƚƚLJŵLJŽĐĂƌĚŝĂů

ŚĞŵŽƌƌŚĂŐĞĂŶĚŵLJŽĐĂƌĚŝĂůĨŝďƌŽƐŝƐǁŝƚŚ

ĚŝƐƌƵƉƚŝŽŶĂŶĚĂŐŐƌĞŐĂƚŝŽŶŽĨŵŝƚŽĐŚŽŶĚƌŝĂů

ĐƌŝƐƚĂĞ͘

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ĂĨƚĞƌ W͖ƉƌŽƚĞĐƚŝǀĞ ĞĨĨĞĐƚ ŽĨĂĐĞƚLJůͲ ĂĨƚĞƌ W͖ƉƌŽƚĞĐƚŝǀĞ ĞĨĨĞĐƚ ŽĨĂĐĞƚLJůͲ

>ĐĂƌŶŝƚŝŶĞ͕>ͲɲͲůŝƉŽŝĐ ĂĐŝĚĂŶĚ

ƐŝůLJŵĂƌŝŶ ĂŐĂŝŶƐƚƚŽdžŝĐŝƚLJ

'Z/WZ>͛ddE/KE

'Z/WZ>͛ddE/KE

YEH JACC 2009

¾Coronary vasospams and subsequent ischaemia

¾Direct toxic effects on endothelial and/or cardiac cells

¾Release of vasoactive substances

¾Arterial thrombosis

WŽƐƐŝďůĞĐĂƵƐĞƐŽĨĚƌƵŐ

WŽƐƐŝďůĞĐĂƵƐĞƐŽĨĚƌƵŐͲͲŝŶĚƵĐĞĚĐĂƌĚŝĂĐƚŽdžŝĐŝƚLJ ŝŶĚƵĐĞĚĐĂƌĚŝĂĐƚŽdžŝĐŝƚLJ

¾Decrease of the oxygen levels in blood

¾Reduction of antioxidant defense capacities

¾Interference with cardiac myocyte metabolism

¾5FU and 5FU metabolites accumulation-related-cardiotoxicity

• ^ƵŶŝƚŝŶŝďÆ ĚĞĐůŝŶĞŽĨĞũĞĐƚŝŽŶĨƌĂĐƚŝŽŶďLJϭϬй;ƉŝǀŽƚĂůƉŚĂƐĞ///ƚƌŝĂůƐƵŶŝƚŝŶŝďǀƐ

ĂůĨĂ/&EͿͲхƵƉĚĂƚĞĚϮͬϮϬϬϳ͗Ϯϭй;ƌĞǀĞƌƐŝďůĞĂĨƚĞƌĚŽƐĞŵŽĚŝĨŝĐĂƚŝŽŶŽƌ

ĚŝƐĐŽŶƚŝŶƵĂƚŝŽŶͿ

• ^ŽƌĂĨĞŶŝďůĞĚƚŽĐĂƌĚŝĂĐŝƐĐŚĞŵŝĂŝŶϯйŽĨƉĂƚŝĞŶƚƐ

• dŚĞƉƌĞĐŝƐĞƌĂƚĞŽĨĐĂƌĚŝŽƚŽdžŝĐŝƚLJĂƐƐŽĐŝĂƚĞĚǁŝƚŚd</ƐĂŶĚŝƚƐƌĞǀĞƌƐŝďŝůŝƚLJŝƐ

ƵŶŬŶŽǁŶ

• ,/&ͲϭʹƌĞůĂƚĞĚŐĞŶĞƉƌŽĚƵĐƚƐĂƌĞƉŚLJƐŝŽůŽŐŝĐŵĞĚŝĂƚŽƌƐŽĨŵLJŽĐĂƌĚŝĂůƌĞƐƉŽŶƐĞƚŽ

ĂƌĚŝŽƚŽdžŝĐŝƚLJ͗ǀĞŶƚƌŝĐƵůĂƌĚŝƐĨƵŶĐƚŝŽŶĂŶĚ

ĐŽŶŐĞƐƚŝǀĞŚĞĂƌƚĨĂŝůƵƌĞ

• ,/&ͲϭʹƌĞůĂƚĞĚŐĞŶĞƉƌŽĚƵĐƚƐĂƌĞƉŚLJƐŝŽůŽŐŝĐŵĞĚŝĂƚŽƌƐŽĨŵLJŽĐĂƌĚŝĂůƌĞƐƉŽŶƐĞƚŽ

ĂĐƵƚĞŽƌĐŚƌŽŶŝĐŝƐĐŚĞŵŝĂ͕ŵLJŽĐĂƌĚŝĂůƌĞŵŽĚĞůŝŶŐ͕ƉĞƌŝͲŝŶĨĂƌĐƚǀĂƐĐƵůĂƌŝnjĂƚŝŽŶĂŶĚ

ǀĂƐĐƵůĂƌƉĞƌŵĞĂďŝůŝƚLJ

• WƚƐǁŝƚŚƉŽŽƌůLJĐŽŶƚƌŽůůĞĚŚLJƉĞƌƚĞŶƐŝŽŶĂƌĞĂƚƌŝƐŬŽĨĐŽŶƚƌĂĐƚŝůĞĚLJƐĨƵŶĐƚŝŽŶ͕

ĨŝďƌŽƐŝƐ͕ĂŶĚŚĞĂƌƚĨĂŝůƵƌĞ

• sĞƌLJĨĞǁĐůŝŶŝĐĂůƚƌŝĂůƐŚĂǀĞĞdžĂŵŝŶĞĚĐĂƌĚŝŽƚŽdžŝĐŝƚŝĞƐŽĨd</ƐŝŶĂƉƌŽƐƉĞĐƚŝǀĞ

ĨĂƐŚŝŽŶǁŝƚŚƉƌĞĚĞĨŝŶĞĚĐĂƌĚŝĂĐĞŶĚƉŽŝŶƚƐ͕ŝŶĐůƵĚŝŶŐůĞĨƚǀĞŶƚƌŝĐƵůĂƌĨƵŶĐƚŝŽŶ

^ĐŚŵŝĚŝŶŐĞƌ:KϮϬϬϴ

^ƵŶŝƚŝŶŝď

• ^ƵŶŝƚŝŶŝďŝƐŵĞƚĂďŽůŝnjĞĚƉƌŝŵĂƌŝůLJďLJĐLJƚŽĐŚƌŽŵĞWϰϱϬ;zWͿϯϰƚŽƉƌŽĚƵĐĞŝƚƐ

ƉƌŝŵĂƌLJĂĐƚŝǀĞŵĞƚĂďŽůŝƚĞ;^hϭϮϲϲϮͿÆ ŵĞƚĂďŽůŝnjĞĚďLJzWϯϰ;ŝŶĂĐƚŝǀĞŵĞƚĂďŽůŝƚĞͿ

• ^ƚƌŽŶŐzWϯϰŝŶŚŝďŝƚŽƌƐŵĂLJŝŶĐƌĞĂƐĞƐƵŶŝƚŝŶŝďƉůĂƐŵĂĐŽŶĐĞŶƚƌĂƚŝŽŶƐ;ĐŽŶĐŽŵŝƚĂŶƚ

ŵĞĚŝĐĂƚŝŽŶǁŝƚŚŶŽŽƌŵŝŶŝŵĂůzWϯϰŝŶŚŝďŝƚŝŽŶƉŽƚĞŶƚŝĂůŝƐƌĞĐŽŵŵĞŶĚĞĚͿ

• ĚŽƐĞƌĞĚƵĐƚŝŽŶŽĨƐƵŶŝƚŝŶŝďƚŽϯϳ͘ϱŵŐĚĂŝůLJƐŚŽƵůĚďĞĐŽŶƐŝĚĞƌĞĚŝĨĂƐƚƌŽŶŐ

zWϯϰŝŶŚŝďŝƚŽƌŵƵƐƚďĞƵƐĞĚ;ŝ͘Ğ͘<ĞƚŽĐŽŶĂnjŽůĹ ϱϬйͿ

• zWϯϰŝŶĚƵĐĞƌƐŵĂLJĚĞĐƌĞĂƐĞƐƵŶŝƚŝŶŝďƉůĂƐŵĂĐŽŶĐĞŶƚƌĂƚŝŽŶƐ;ƌŝĨĂŵƉŝŶ↓ϱϬйͿĂŶĚ

• zWϯϰŝŶĚƵĐĞƌƐŵĂLJĚĞĐƌĞĂƐĞƐƵŶŝƚŝŶŝďƉůĂƐŵĂĐŽŶĐĞŶƚƌĂƚŝŽŶƐ;ƌŝĨĂŵƉŝŶ↓ϱϬйͿĂŶĚ

ƐŚŽƵůĚďĞĂǀŽŝĚĞĚ

• ƐƵŶŝƚŝŶŝďĚŽƐĞŝŶĐƌĞĂƐĞƚŽĂŵĂdžŝŵƵŵŽĨϴϳ͘ϱŵŐĚĂŝůLJƐŚŽƵůĚďĞĐŽŶƐŝĚĞƌĞĚŝĨ

ĐŽĂĚŵŝŶŝƐƚƌĂƚŝŽŶǁŝƚŚĂzWϯϰŝŶĚƵĐĞƌŝƐŶĞĐĞƐƐĂƌLJ;ƉĂƚŝĞŶƚƐƐŚŽƵůĚďĞŵŽŶŝƚŽƌĞĚ

ĐĂƌĞĨƵůůLJĨŽƌƚŽdžŝĐŝƚŝĞƐͿ

• /ŶŚƵŵĂŶůŝǀĞƌŵŝĐƌŽƐŽŵĞƐĂŶĚŚĞƉĂƚŽĐLJƚĞƐ͕ƐƚƵĚŝĞƐŝŶĚŝĐĂƚĞĚƚŚĂƚƐƵŶŝƚŝŶŝďĚŽĞƐ

ŶŽƚŝŶĚƵĐĞŽƌŝŶŚŝďŝƚƚŚĞŵĂũŽƌzWĞŶnjLJŵĞƐ

Drugs that block matrix breakdown Dalteparin A low molecular weight, synthetic heparin. (Fragmin® by Pfizer, Inc.) 3

Suramin A polysulphonated naphthylurea 2

Drugs that inhibit endothelian cells directly ABT-510 A nonapeptide thrombospondin analogue 2

Combretastatin A4 Phosphate A water-soluble prodrug 3

Lenalidomide (Revlimid® by Celgene) 23

LY317615 (Enzastaurin) The hydrochloride salt of enzastaurin 7

Soy Isoflavone (Genistein; Soy Protein Isolate) 6

Thalidomide A synthetic derivative of glutamic acid. (Thalomid by Celgene) 68

6RPH$FWLYH&OLQLFDO7ULDOVRQ$QWLDQJLRJHQLF

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Thalidomide A synthetic derivative of glutamic acid. (Thalomid by Celgene) 68

Drugs that block activators of angiogenesis AMG-706 An orally bioavailable multiple-receptor tyrosine kinase inhibitor 7 Anti-VEGF Antibody (Bevacizumab. Avastin by Genentech and by Roche ) 179

AZD2171 An indole ether quinazoline derivative 25

Bay 43-9006 Tosylate salt of Sorafenib (Nexavar by Bayer) 51

PI-88 A sulfated oligosaccharide 3

PTK787/ZK 222584 (Vatalanib) An orally bioavailable anilinophthalazine 19 SU11248 (Sunitinib malate) An orally bioavailable malate salt 20 VEGF-Trap A protein combining the Fc portion of human IgG1 with VEGFR1 and

VEGFR2

8

XL184 An orally bioavailable small molecule RTK inhibitor 1

ZD6474 An orally bioavailable 4-anilinoquinazoline 6

Drugs that inhibit endothelial-specific integrin/survial signaling

ATN-161 A small peptide antagonist of integrin alpha5beta1 2

EMD 121974 (Cilenigtide) A cyclic Arg-Gly-Asp peptide 5

Albini A et al, Future Cardiol. 2011; 7 (5)

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ŶnjŝŵĂĂƚƚŝǀĂƚŽĚĂƐƚŝŵŽůŝĞdžƚƌĂĐĞůůƵůĂƌŝ;ĨĂƚƚ͘Ěŝ

ĐƌĞƐĐŝƚĂs'&W'&ͿŽŝŶƚƌĂĐĞůůƵůĂƌŝ;ƐƚƌĞƐƐ

ŽƐƐŝĚĂƚŝǀŽͿхĐĂƚĂůŝnjnjĂƚƌĂƐĨĞƌŝŵĞŶƚŽĚŝƵŶĨŽƐĨĂƚŽ

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ŝŶƚƌĂĐĞůůƵůĂƌŝ

ϭ͘ ZĞĐĞƚƚŽƌŝZd<ƐхŵĞŵďƌĂŶĂĐĞůůƵůĂƌĞ Ϯ͘ EŽŶƌĞĐĞƚƚŽƌŝEZd<Ɛ хŝŶƚƌĂĐĞůůƵůĂƌŝ WŽƐƐŽŶŽŵĞĚŝĂƌĞƐĞŐŶĂůŝƐŝĂŝŶƚƌĂ ĐŚĞ

ĞdžƚƌĂĐĞůůƵůĂƌŝхƌƵŽůŽĐƌŝƚŝĐŽŶĞůů͛ŽŵĞŽƐƚĂƐŝĐĞůů͘

ŶŐŝŽŐĞŶĞƐŝƐŝƐĂŶĞĐĞƐƐĂƌLJĐŽŶĚŝƚŝŽŶĨŽƌƐƵƐƚĂŝŶĞĚ

ƚƵŵŽƌŐƌŽǁƚŚ͘

ƌƵŐ/ŶĨŽƌŵĂƚŝŽŶƐƐŽĐŝĂƚŝŽŶ ǁǁǁ͘ĚŝĂŚŽŵĞ͘ŽƌŐ 66

Ferrara N The Oncologist 2004;9:2-10

dĂƌŐĞƚƐŝŶĐůŝŶŝĐĂůƚƌŝĂů͘

ƌƵŐ/ŶĨŽƌŵĂƚŝŽŶƐƐŽĐŝĂƚŝŽŶ ǁǁǁ͘ĚŝĂŚŽŵĞ͘ŽƌŐ Vakalvas, The Oncologist 2010;15:130–14167

DĞĐŚĂŶŝƐŵƐŽĨŚLJƉĞƌƚĞŶƐŝŽŶƐĞĐŽŶĚĂƌLJƚŽĂŶƚŝͲ ĂŶŐŝŽŐĞŶŝĐƚŚĞƌĂƉLJ

VEGF VEGFR-2

Tumor

eNOS vascular permeability vasodilation

ƌƵŐ/ŶĨŽƌŵĂƚŝŽŶƐƐŽĐŝĂƚŝŽŶ ǁǁǁ͘ĚŝĂŚŽŵĞ͘ŽƌŐ 68

eNOS Anti-Angiogenesis

Therapy

HYPERTENSION vascular permeability vasodilation

microvascular rarefaction endothelial

disfunction

aortic stiffness