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102 Recent Advances in Angiogenesis and Antiangiogenesis, 2009 Tozer and Kanthou
Table 1. Tubulin binding VDAs in clinical trial.
Drug Web-site Drug type
Zybrestat TM
OXl4503
ZD6126
AVE8062
ABT-751
TZT-1027
(soblidotin)
TM
Trisenox
NPl-2358
MPC-6827
TM
(Azixa )
BCN105
http://www.oxigene.com/
http://www.oxigene.com/
http://www.astrazeneca.com/
http://www.sanofi-aventis.com/
http://www.abbott.com/
http://www.aska-pharma.co.jp/
http://www.trisenox.com/
http://www.nereuspharm.com/
http://www.myriad.com/
http://www.bionomics.com.au/
structural similarity to the classic tubulin-binding
agent, colchicine, which itself disrupts tumor blood
vessels but is too toxic for clinical use, probably
because of its pseudo-irreversible binding to tubulin
[5, 7]. The combretastatins were originally isolated
from the Cape Bushwillow tree, Combretum caffrum
[8]. The lead compound is CA-4-P (disodium
combretastatin A-4 3-0-phosphate), which is a stable
pro-drug for the active compound, CA-4 [9]. Based on
pre-clinical data demonstrating selective tumor blood
flow shut-down (Fig. 1 [10-12], CA-4-P entered
clinical trial in the UK and USA in 1998 and is now
being developed as CA4 Prodrug/fosbretabulin/
Zybrestat TM by OXiGENE Inc. (http: //www.oxigene
.com/).
A Phase II/III trial of CA-4-P, in combination with
chemotherapy, for anaplastic thyroid cancer is ongoing.
Phase II trials are also running for CA-4-P, in
gynaecological tumor s and non-squamous cell nonsmall
cell lung cancer. The latter trial includes the
anti-angiogenic agent, bevacizumab (Avastin TM ), in
the standard chemotherapy arm. Interestingly, a Phase
I clinical study, in advanced solid tumor s, showed that
addition of bevacizumab helped sustain the vascular
shut-down observed for CA-4-P alone [13]. A sodium
phosphate pro-drug of combretastatin A-1, CA-1-P
CA-4-P, a combretastatin
prodrug
CA-1-P, a combretastatin
prodrug
colchicine analogue
prodrug
synthetic combretastatin
prodrug
sulfonamide b-tubulin
inhibitor
Synthetic derivative of
dolastatin-10, a marine
organism
arsenic trioxide
extract from marine
fungus
4-arylaminoquinazoline
b-tubulin inhibitor
CYT997 http://www.cytopia.com.au/ Orally active a-tubulin
inhibitor
Synthetic tubulin binding
agent
[14] (OXiGENE compound OXI4503) [15-18], is also
in Phase I clinical trial. This compound was more
potent than CA-4-P, in pre-clinical studies. In addition,
there are numerous synthetic analogues of the
combretastatins. For example, the Sanofi-Aventis
compound AVE8062, licensed from Ajinomoto Co.,
Inc., is a pro-drug for a combretastatin derivative,
which is cleaved by aminopeptidases, to form the
active drug [19-22]. AVE8062 is in Phase III clinical
trial for sarcoma and non-small cell lung cancer (http:
//en.sanofi-aventis.com/Aventis).
Apart from the combretastatins, other tubulin binding
agents have potential as VDAs. A pro-drug analogue
of colchicine, N-acetylcolchinol-O-phosphate
(ZD6126), has reached Phase II clinical trials [23]
(http: //www.angiogene.co.uk/) and other agents are at
earlier stages of development (Table 1).
4. JUNCTIONAL PROTEIN INHIBI-
TORS
Monoclonal antibodies targeted to the vascular cellcell
junction-associated protein, VE-cadherin, are
active against the established tumor vasculature [24].
N-cadherin is also involved with the structural
integrity of blood vessels and its down-regulation