http://www.medicalnewstoday.com/medi...33753&nfid=mnf#
Treatment of Brain Tumors, Discovery and Development of Blood-Brain Barrier (BBB) Penetrating Anthracyclines
Category:
Cancer/Oncology News
Article Date: 21 Nov 2005
A major deterrent in treating malignant brain tumors is that systemic chemotherapy effective against other types of tumors is limited because most drugs can not penetrate the blood-brain barrier effectively. But now, researchers at The University of Texas M. D. Anderson Cancer Center have developed an agent that not only gains entry into the brain, but also targets topoisomerase II , a protein associated with malignant gliomas, the most aggressive form of brain tumors. The drug, WP744, has entered a phase I clinical trial, which will enroll up to 30 patients with advanced brain cancer.
A research team led by Waldemar Priebe, Ph.D., professor of Medicinal Chemistry in the Department of Experimental Therapeutics, developed the dual-purpose agent, which targets topoisomerase II and avoids transport proteins found in both the blood-brain barrier and glioma tumor cells. These proteins,known as ABC-binding cassette transporters like MRP1, LRP, and P-gp, control which molecules can pass through a membrane (such as the "blood-brain barrier") and are also part of a cellular defense that is associated with a cancer cell's ability to become resistant to multiple drugs.
Priebe, working with, Charles Conrad, M.D., associate professor of Neuro-Oncology, Timothy Madden, Pharm.D., associate professor of Pharmacology, and Izabela Fokt, Ph.D., Instructor of Medicinal Chemistry, designed and synthesized DNA-binding agents using a modular approach and searched for topoisomerase II poisons that could circumvent transport proteins efflux, hypothesizing that this will allow entry into both the blood-brain barrier and glioma tumor cells.
Out of 400 DNA binding agents, they selected two compounds for evaluation in vivo. Both of these compounds resemble the well-known anticancer chemotherapy drug doxorubicin, but have properties that are also unique, according to Priebe. In mice studies, one of the compounds, WP744 entered the brain and effectively treated cancer, increasing the survival time of the animals. This compound, now called RTA744, was licensed by Reata Pharmaceuticals in Dallas and is undergoing phase I studies at the M. D. Anderson Cancer Center.
The researchers say the agent may prove to be effective in treating brain tumor patients because, in contrast to doxorubicin, it can cross the blood-brain barrier and hone in on these cancers when delivered systemically. RTA744 (WP744) may represent a treatment not only for tumors that originate in the brain, but also for other cancers that tend to metastasize to the brain as well, the researchers say.
(Abstract 3384)
Founded in 1907, the American Association for Cancer Research is a professional society of more than 24,000 laboratory, translational, and clinical scientists engaged in cancer research in the United States and in more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication, and advocacy. This work is carried out through five major peer-reviewed scientific journals and high-quality scientific programs focusing on the latest developments in all areas of cancer research.
The National Cancer Institute, founded in 1971, is the principal United States government agency charged with coordinating the National Cancer Program. It facilitates international cooperation in clinical trials involving U.S. and foreign collaborating institutions.
The European Organisation for Research and Treatment of Cancer was organized in 1962 to conduct, develop, coordinate and stimulate laboratory and clinical research in Europe, and to improve the management of cancer and related problems by increasing the survival and quality of life for patients.
Warren R. Froelich
froelich@aacr.org
American Association for Cancer Research
aacr.org
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