Navigation Links
New oral angiogenesis inhibitor offers potential nontoxic therapy for a wide range of cancers
Date:7/1/2008

The first oral, broad-spectrum angiogenesis inhibitor, specially formulated through nanotechnology, shows promising anticancer results in mice, report researchers from Children's Hospital Boston. Findings were published online on June 29 by the journal Nature Biotechnology.

Because it is nontoxic and can be taken orally, the drug, called Lodamin, may be useful as a preventive therapy for patients at high risk for cancer or as a chronic maintenance therapy for a variety of cancers, preventing tumors from forming or recurring by blocking the growth of blood vessels to feed them. Lodamin may also be useful in other diseases that involve aberrant blood-vessel growth, such as age-related macular degeneration and arthritis.

Developed by Ofra Benny, PhD, in the Children's laboratory of the late Judah Folkman, MD, Lodamin is a novel slow-release reformulation of TNP-470, a drug developed nearly two decades ago by Donald Ingber, MD, PhD, then a fellow in Folkman's lab, and one of the first angiogenesis inhibitors to undergo clinical testing. In clinical trials, TNP-470 suppressed a surprisingly wide range of cancers, including metastatic cancers, and produced a few complete remissions. Trials were suspended in the 1990s because of neurologic side effects that occasionally occurred at high doses, but it remains one of the broadest-spectrum angiogenesis inhibitors known.

Lodamin appears to retain TNP-470's potency and broad spectrum of activity, but with no detectable neurotoxicity and greatly enhanced oral availability. While a number of angiogenesis inhibitors, such as Avastin, are now commercially available, most target only single angiogenic factors, such as VEGF, and they are approved only for a small number of specific cancers. In contrast, Lodamin prevented capillary growth in response to every angiogenic stimulus tested. Moreover, in mouse models, Lodamin reduced liver metastases, a fatal complication of many cancers for which there is no good treatment.

"The success of TNP-470 in Phase I and II clinical trials opened up anti-angiogenesis as an entirely new modality of cancer therapy, along with conventional chemotherapy, radiotherapy and surgical approaches," says Ingber, now co-interim director of the Vascular Biology Program at Children's.

TNP-470 was first reformulated several years ago by Ronit Satchi-Fainaro, PhD, a postdoctoral fellow in Folkman's lab, who attached a large polymer to prevent it from crossing the blood-brain barrier (Cancer Cell, March 2005). That formulation, Caplostatin, has no neurotoxicity and is being developed for clinical trials. However, it must be given intravenously.

Benny took another approach, attaching two short polymers (PEG and PLA) to TNP-470. Experimenting with polymers of different lengths, she found a combination that formed stable, "pom-pom"-shaped nanoparticles known as polymeric micelles, with TNP-470 at the core. The polymers (both FDA-approved and widely used commercially) protect TNP-470 from the stomach's acidic environment, allowing it to be absorbed intact when taken orally. The micelles reach the tumor, react with water and break down, slowly releasing the drug.

Tested in mice, Lodamin had a significantly increased half-life, selectively accumulated in tumor tissue, blocked angiogenesis, and significantly inhibited primary tumor growth in mouse models of melanoma and lung cancer, with no apparent side effects when used at effective doses. Subsequent tests suggest that Lodamin retains TNP-470's unusually broad spectrum of activity. "I had never expected such a strong effect on these aggressive tumor models," Benny says.

Notably, Lodamin accumulated in the liver without causing toxicity, preventing liver metastases and prolonging survival. "This was one of the most surprising things I saw," says Benny. "When I looked at the livers of the mice, the treated group was almost clean. In the control group you couldn't recognize the livers -- they were a mass of tumors."

TNP-470 itself has an interesting history. It was derived from fumagillin, a mold with strong anti-angiogenic effects that Ingber discovered accidentally while culturing endothelial cells (the cells that line blood vessels). Ingber noticed that in certain dishes -- those contaminated with the mold -- the cells changed their shape by rounding, a behavior that inhibits capillary cell growth. Ingber cultured the fungus, disregarding lab policy, which called for contaminated culture to be discarded immediately. He and Folkman later developed TNP-470, a synthetic analog of fumagillin, with the help of Takeda Chemical Industries in Japan (Nature, December 1990). It has shown activity against dozens of tumor types, though its mechanism of action is only partly known.

"It's been an evolution," says Benny, "from fumagillin to TNP-470 to Caplostatin to Lodamin."


'/>"/>

Contact: Bess Andrews
elizabeth.andrews@childrens.harvard.edu
617-919-3110
Children's Hospital Boston
Source:Eurekalert  

Related biology news :

1. Study finds blocking angiogenesis signaling from inside cell may lead to serious health problems
2. New inhibitor has potential as cancer drug
3. New research shows no link between aromatase inhibitors and cardiovascular problems
4. New partnership offers outsourced R&D in membrane biology
5. Census of protein architectures offers new view of history of life
6. NAS report offers new tools to assess health risks from chemicals
7. New class of drug offers hope to treatment-resistant AIDS patients
8. Darwin Symposium at Field Museum offers broad overview of his science and its impact
9. Conference on healthspan offers new opportunities for interdisciplinary collaboration
10. Protein controls blood vessel formation, offers new drug target
11. Genetic breakthrough offers promise in tackling kidney tumors
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
New oral angiogenesis inhibitor offers potential nontoxic therapy for a wide range of cancers
(Date:12/22/2016)... -- As part of its longstanding mission to improve genetic literacy ... released its latest children,s book, titled The One ... topics of inheritance and variation of traits that are part ... school classrooms in the US. The book ... Killoran , whose previous book with 23andMe, You ...
(Date:12/20/2016)... , Dec. 20, 2016 The rising ... rental and leasing is stoking significant interest in ... frequency technology, Bluetooth low energy (BLE), biometrics and ... the next wave of wireless technologies in the ... system to advanced access systems opens the market ...
(Date:12/19/2016)... España y TORONTO , 19 de diciembre de ... Biologics Inc. que permitirá el desarrollo acelerado de MSC-1, un anticuerpo ... varios tipos de tumor en 2017, con múltiples sitios previstos a ... ... con objetivo en el factor inhibidor de leucemia (LIF), una citoquina ...
Breaking Biology News(10 mins):
(Date:1/19/2017)... , Jan. 19, 2017 /PRNewswire -- WuXi AppTec, ... open-access capability and technology platform, today announced that ... biology focused preclinical drug discovery contract research organization ... become a wholly-owned subsidiary of WuXi, and will ... and providing greater services. The acquisition will further ...
(Date:1/19/2017)... and GAITHERSBURG, Md. , Jan. ... and Altimmune, Inc., a privately-held immunotherapeutics company targeting ... definitive agreement for the merger of PharmAthene and ... include Novartis Venture Fund, HealthCap, Truffle Capital and ... fully-integrated and diversified immunotherapeutics company with four clinical ...
(Date:1/19/2017)... Ca (PRWEB) , ... January 18, 2017 , ... ... events for tech innovators, engineers, and scientists from around the world, was today ... News. The awards program is based entirely on merit and decided upon by ...
(Date:1/19/2017)... BETHESDA, Md. , Jan. 18, 2017  Northwest ... company developing DCVax® personalized immune therapies for operable and ... Marnix Bosch , Chief Technical Officer of NW Bio, ... Thursday, January 19, 2017, at the Hyatt Regency Hotel ... Dr. Bosch will chair the session entitled "New Therapeutic ...
Breaking Biology Technology: