TORONTO, Canada--Available cancer drugs have had little specificity, destroying both cancer cells and normal cells. Now, says Robert Kerbel, PhD, of Sunnybrook Health Science Centre, University of Toronto, "we have the potential to design 'smarter' drugs to help circumvent the problems of toxicity and resistance." At a media conference at the American Association for Cancer Research (AACR) annual meeting, Dr. Kerbel introduced two researchers who have pioneered development of approaches to inhibit cancer development without harming normal cells.
These approaches are angiogenesis blockers that stop the development of blood vessels that feed tumors, and matrix metalloproteinase blockers that suppress an enzyme that appears to play a key role in tumor growth.
Judah Folkman, MD, of Harvard Medical School and Children's Hospital, Boston, first made the connection between blood vessels and tumor growth 25 years ago. Dr. Folkman, who chaired a session on the topic at the AACR meeting, said that, like an invading army, growing tumors need supply lines, ie, blood vessels that give them access to oxygen and nutrients.
Angiogenesis inhibitors turn off the production of those blood vessels. Dr. Folkman's latest research on mice showed that daily doses of these drugs not only slowed the growth of tumors but also, in some cases, stopped metastatic spread of the tumor.
Dr. Folkman's team has identified angiogenesis inhibitors from several sources, including fungi. But some of the most promising agents occur naturally in the body. For example, he says, platelet factor-4 is found in blood, while angiostatin is naturally secreted by primary tumors. "These proteins were hard to find because they occur only in parts per million," he said.
Angiostatin, for example, was painstakingly isolated from mouse urine--work performed by Michael O'Reilly, MD, in the Folkman laboratory. Once purified, the researchers identified all the amino acid constituents, and now efforts are underway to produce human angiostatin from Escherichia coli bacteria, Dr. Folkman said.
He is particularly excited by the potential of angiostatin because it blocks only growing endothelial cells. The protein has been tested in mice and has shown no toxicity, even at high doses. "It doesn't turn off bone marrow cells, doesn't turn off intestinal cells, and doesn't make hair fall out," he said at the briefing.