GreatWall International Cancer Center
Endostar - Antiangiogenesis Therapy


What is Endostar?


Endostar is an anti-angiogenic drug designed to stop cancer by nullifying a tumor’s ability to
obtain oxygen and nutrients for growth. Endostar works by inhibiting angiogenesis: the
proliferous formation of new blood vessels around in and around the tumoral tissue. Endostar’
s active constituent is a naturally occurring (and according to the latest evidence, harmless)
substance called endostatin. First discovered in the Folkman Laboratory (USA), isolated
samples of endostatin have been shown to inhibit the growth of cancerous tumors in humans
and to completely eradicate tumors in mice. Endostar is a soluble liquid delivered
intravenously and, in treatment procedures available in China, it is delivered in conjunction
with chemotherapy.


Current Clinical Status


Endostar has been approved by the SFDA (State Food and Drug Administration) for the
treatment of cancer. Since September, 2005, the Chinese government has allowed treatment
of non-small-cells lung carcinoma. Further experiments have been carried out on many other
types of cancer including lung, breast, pancreas and colorectal cancer. Endostar's parent
company has engaged in talks with U.S. pharmaceutical firms, although to date Endostar is not
licensed for use in the U.S.


What is angiogenesis?


Angiogenesis is the formation of new blood vessels. In order for any bodily organ or tissue to
survive, it requires a constant flow of blood to bring oxygen and nutrients, and to remove
metabolic waste. Any tissue with a readily available supply of nutrients is prone to rapid
growth. When angiogenesis occurs in the vicinity of a cancerous tumor, the tumor will rapidly
increase in size.

There is a critical size at which tumors require angiogenesis to grow. When the tumor is below
two cubic millimeters, it maintains a balance with its surrounding tissues - cell multiplication and
cell death keep the tumor at the same size (a malignant tumor). If the cell is bigger than two
cubic millimeters, angiogenesis may occur, resulting in the abundant supply of nutrients and
the proliferation of the tumor.

In addition to the rapid growth of the tumor, the passage of blood around the tumor can also
serve to spread cancerous cells to other parts of the body. Cancer cells, like many other cells,
secrete substances that encourage the formation of new blood vessels, and thus promote
their own multiplication. This process is called cancer angiogenesis.

Therefore, a possible solution to the proliferation of cancer within the body is to inhibit cancer
angiogenesis.


Alternative Angiogenesis Inhibitors Currently In Use or Under Trial


Bevacizumab (trade name Avastin)


Avastin is monoclonal antibody that binds to a single angiogenesis agent called VEGF
(Vascular Endothelial Growth Factor), thus keeping it from binding to its receptors and
inhibiting cancer angiogenesis. It was approved by the US FDA in February 2004 for the
treatment of colorectal cancers, and has since shown positive results. However it is potentially
inferior to Endostar in that it binds to only one angiogenesis promoting agent. Endostar
inhibits the action of at least sixteen.

Angiostatin


Angiostatin is a naturally occurring polypeptide of approximately 200 amino acids. It is
produced by the cleavage of plasminogen, a plasma protein that is important for dissolving
blood clots. Injections of angiostatin inhibit the metastasis of certain (mouse) primary tumors.
Angiostatin is still in the experimental stage.


Further Information

Standard therapies to combat cancer are usually aimed at interfering with the cellular
replication process which is accelerated in tumors. Despite the efforts made since 1971 to
fight cancer -- the year the United States declared war on the disease -- new cases of most
cancers have increased significantly. Ninety percent of all cancers are solid tumors and thus
depend on angiogenesis to support their growth.

Resistance to treatment is a major issue in oncology. In hormone-dependent cancer for
instance, after standard anti-hormonal therapy, it is common to see a recurrence of cancer.
This occurs when a malignant cell is transformed a second time, thus making its replication
independent of hormones. The same phenomenon takes place with cancers treated with
chemotherapy. Often a transformed cell exposed to a powerful chemical agent goes through a
mutation, giving it a selective advantage for growth, such as the production of a growth factor
or resistance to chemotherapeutic agents.

It has also been shown that the resection of a primary tumor is often accompanied by
metastases caused by a systemic disturbance of the angiogenic balance of the body. All these
standard therapies could profit from a concomitant treatment that would restrict latent tumors
in a prevascular phase.

Anti-angiogenesis as a strategy against cancer

As early as the 1970s, Dr. Judah Folkman of the Harvard Medical School suggested inhibiting
new blood vessel formation as a way to fight cancer. The malignant tissue would be deprived
of its ability to obtain oxygen and nutrients as well as eliminate metabolic wastes. This in turn
would inhibit tumor progression and metastatic progression that accompanies most advanced
cancers. These are the main steps of the angiogenic process that can be interrupted:

Inhibiting endogenous angiogenic factors, such as bFGF (basic Fibroblast Growth Factor) and
VEGF (Vascular Endothelial Growth Factor)
Inhibiting degradative enzymes (Matrix Metalloproteinases) responsible for the degradation of
the basement membrane of blood vessels
Inhibiting endothelial cell proliferation
Inhibiting endothelial cell migration
Anti-angiogenesis Chemotherapy

Timothy Browder in the Folkman lab was the first to demonstrate this novel concept: by
optimizing the dosing schedule of conventional cytotoxic chemotherapy to achieve more
sustained apoptosis of endothelial cells in the vascular bed of a tumor, it is possible to achieve
more effective control of tumor growth in mice, even if the tumor cells are drug-resistant.
Conventional chemotherapy is administered at maximum tolerated doses followed by off-
therapy intervals of 2–3 weeks to allow the bone marrow and gastrointestinal tract to recover.
In contrast, anti-angiogenic chemotherapy is administered more frequently at lower doses,
without long interruptions in therapy, and with little or no toxicity. During anti-angiogenic
chemotherapy, endothelial cell apoptosis and capillary dropout precede the death of tumor
cells that surround each capillary. Durable tumor regression and sometimes eradication occur
even in drug-resistant tumors. Cyclophosphamide, 5-fluorouracil, 6-mercaptopurine ribose
phosphate, and Doxil (the pegylated liposomal formulation of doxorubicin) inhibit angiogenesis
when administered on an anti-angiogenic dose schedule. Two other labs confirmed Browder’s
findings. Kerbel et al. subsequently showed that continuous administration of
cyclophosphamide in the drinking water inhibited tumor growth in mice by 95% and
significantly increased circulating levels of thrombospondin-1. Angiogenesis and tumor growth
were not inhibited in thrombospondin-1-null mice.

This suggests that continuous exposure of vascular endothelium to low concentrations of
cyclophosphamide induces increased expression of the angiogenesis inhibitor
thrombospondin-1 by endothelium (and perhaps by stromal fibroblasts) in the tumor bed. Anti-
angiogenic chemotherapy is also called metronomic chemotherapy. The former term
emphasizes that chemotherapy dose and schedule are optimized to target endothelial cells
instead of tumor cells. The latter term emphasizes how chemotherapy dose and schedule are
optimized for endothelial cells, i.e., administration at close, regular intervals. The lesson from
these studies is that drug-resistant tumors can be converted to drug-sensitive tumors by
optimizing the dose and schedule of conventional cytotoxic chemotherapy for its anti-
angiogenic activity.

Since Avastin received FDA approval for the treatment of colorectal cancer in February 2004,
other angiogenesis inhibitors have also been approved in the United States and other
countries. Avastin is also being studied in numerous clinical trials for patients with other types
of cancer, and it is being administered in combination with Tarceva. Anti-angiogenic therapy
has recently been reported to significantly increase survival in lung cancer and breast cancer,
in addition to colorectal cancer.

A lesson from this experience is that when an angiogenesis inhibitor is approved for one type
of cancer, it may be prudent to test it in clinical trials for other types of cancer. Another lesson
from clinical studies is that patients may continue to take angiogenesis inhibitors for prolonged
periods of time. For example, thalidomide was approved in Australia for the treatment of
advanced multiple myeloma in 2003 and is now used as a first-line therapy. Many patients
have been on the drug for 3–5 years without evidence of drug resistance. Thalidomide
suppresses production of endothelial cell precursors and downregulates circulating VEGF.
Endostatin is another example. Four patients at the Dana Farber Cancer Institute, who have
carcinoid or islet cell carcinoma with metastases to the liver, have been on daily endostatin for
3.5 years at this writing. They show stable disease or slow tumor regression, without drug
resistance and without toxicity. Another lesson is that certain drugs previously approved by the
FDA for another function, and subsequently discovered to be anti-angiogenic, are being used
successfully to treat refractory recurrent cancers. For example, doxycycline, a chemically
modified tetracycline, is a mild antibiotic that has recently been demonstrated to inhibit
angiogenesis by increasing thrombospondin-1 and to successfully regress a life-threatening
hemangioendothelioma of both lungs. Also, low-dose daily interferon-α has been used for the
past six years to successfully treat life-threatening hemangiomas and recurrent refractory high-
grade giant cell tumor. Anti-angiogenic chemotherapy (metronomic chemotherapy) is being
used in clinical trials of advanced breast cancer as well as for tumors of the central nervous
system and other cancers. UFT, an orally available prodrug of 5-fluorouracil made by Taiho, is
being used in Japan as long-term anti-angiogenic (metronomic) chemotherapy.

Anti-angiogenesis Therapies Available in China

Anti-angiogenic agents combined with mild chemotherapy not only produce tumor shrinking
but also overcome prior chemotherapy resistance in many types of advanced cancer patients.
Endostar (recombinant human endostatin) is the most potent anti-angiogenesis agent known
today, due to its effective interaction with a wide range of angiogenesis promoters. Unlike
Avastin, its U.S. equivalent, Endostar is now actively used in lung, breast, pancreas and
colorectal cancers. In colorectal and pancreatic cancer, targeting at COX-2 not only through
the anti-angiogenesis pathway, but also through interruption of PI3K-AKT-mTOR signaling
pathways has clearly shown benefits, such as tumor regression, chemotherapy sensitization
and symptomatic improvement in many advanced breast, colorectal and pancreatic cancer
patients.



References

1. Endostar Combined with Chemotherapy on the Multiple Kinds of Advanced Malignancies,
LIU Xiu-feng, Qin She-kui, et al., Chinese Clinical Oncology, 2007, 12: 241  

2. Clinical Study of Endostar Combined with Chemotherapy for the Multiple Kind of Advanced
Malignancies except Lung Cancer, QIN Shu-kui, LIU Xiu-feng, et al., Chinese Clinical
Oncology, 2007, 12: 728-35    

3. Endostar Combined with Chemotherapy in the Treatment of HER-2 Negative Breast Cancer,
YUAN Xia, ZHANG Dongsheng, et al., Oncology Progress, 2007, 5: 604-607   

4. Intrahepatic Arterial Infusion of Endostar Combined with Transcatheter Arterial
Chemoembolization for Treatment of Advanced Hepatocellular Carcinoma, QI Xiuheng, WU
Zhenming, et al., Chinese Journal of Clinical Oncology, 2008, 35: 5-7

5. Result of Randomized, Multicenter, Double-blined Phase III Trail of rh-endostatin (YH-16) in
Treatment of Advanced Non-Small Cell Lung Cancer Patients, WANG Jinwan, SUN Yan, et al.,
Chin J Lung Cancer, 2005, 8: 283-90  

6. The Efficacy of NP plus ENDOSTAR and Chemotherapy in the Treatment of Non-small Cell
Lung Cancer, HUANG Guosheng, Henan Journal of Surgery, 2007, 13: 1-2  

7. Clinical Analysis of Advanced NSCLC Treated by Endostar in Combination with NP, HUANG
Chun, LI Kai, Chin J Cancer Prev Treat, 2008, 15: 283-85  

8. Observation of Short-Term Effects of YH-16 Combined with GP Regimen for Non-Small Cell
Lung Cancer, SONG Ziyan, BIAN Baoxiang, et al., Journal of Basic and Clinical Oncology,
2007, 20: 506-507  

9. Epidermal Growth Factor Receptor Antibody Plus Recombinant Human Endostatin in
Treatment of Hepatic Metastases after Remnant Gastric Cancer Resection. Sun L, Ye HY, et
al. World J Gastroenterol, 2007 Dec 7, 13(45):6115-8

10. Inhibitory Effect of Angiogenesis Inhibitor YH-16 on Liver Metastases from Colorectal
Cancer. Zhou Zhiwei, Wan Desen, et al. Chinese Journal of Cancer, 2006, 25(7):818-822

11. Inhibitory Effects of Endostatin on Melanoma Microcirculation. Liu Yanqing, Zhang Shiwu,
et al. Acta Academiae Medicinae CPAPF. 2007, 16(3):262-267.

12.Endostar, a Novel Recombinant Human Endostatin, Exerts Antiangiogenic Effect via
Blocking VEGF-induced Tyrosine Phosphorylation of KDR/Flk-1 of Endothelial Cells. Ling Y,
Yang Y, et al., Biochem Biophys Res Commun.2007.361(1):79-84  




Last Updated ( Tuesday, 02 September 2008 21:30 )