'Smarter' Drugs May Inhibit Tumor Growth By Blocking Angiogenesis or Matrix Metalloproteinase

TORONTO, Canada--Available cancer drugs have had little specificity,destroying both cancer cells and normal cells. Now, says RobertKerbel, PhD, of Sunnybrook Health Science Centre, University ofToronto, "we have the potential to design 'smarter' drugsto 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 whohave pioneered development of approaches to inhibit cancer developmentwithout harming normal cells.

These approaches are angiogenesis blockers that stop the developmentof blood vessels that feed tumors, and matrix metalloproteinaseblockers that suppress an enzyme that appears to play a key rolein tumor growth.

Judah Folkman, MD, of Harvard Medical School and Children's Hospital,Boston, first made the connection between blood vessels and tumorgrowth 25 years ago. Dr. Folkman, who chaired a session on thetopic at the AACR meeting, said that, like an invading army, growingtumors need supply lines, ie, blood vessels that give them accessto oxygen and nutrients.

Angiogenesis inhibitors turn off the production of those bloodvessels. Dr. Folkman's latest research on mice showed that dailydoses of these drugs not only slowed the growth of tumors butalso, in some cases, stopped metastatic spread of the tumor.

Dr. Folkman's team has identified angiogenesis inhibitors fromseveral sources, including fungi. But some of the most promisingagents occur naturally in the body. For example, he says, plateletfactor-4 is found in blood, while angiostatin is naturally secretedby primary tumors. "These proteins were hard to find becausethey occur only in parts per million," he said.

Angiostatin, for example, was painstakingly isolated from mouseurine--work performed by Michael O'Reilly, MD, in the Folkmanlaboratory. Once purified, the researchers identified all theamino acid constituents, and now efforts are underway to producehuman angiostatin from Escherichia coli bacteria, Dr. Folkmansaid.

He is particularly excited by the potential of angiostatin becauseit blocks only growing endothelial cells. The protein has beentested in mice and has shown no toxicity, even at high doses."It doesn't turn off bone marrow cells, doesn't turn offintestinal cells, and doesn't make hair fall out," he saidat the briefing.

Matrix Metalloproteinase Blockers

Utilizing another new approach, researchers at British BiotechPharmaceuticals Ltd of Oxford are working on drugs that subduea family of enzymes known as matrix metalloproteinases (MMP).

Scientists have discovered that levels of MMP are usually higherin a tumor than that in surrounding normal tissue in patientswith common solid tumors such as ovarian, lung, and prostate cancer.They have also found that normal cells can be made malignant bygenetically altering them to produce high levels of MMP.

Alan Drummond, PhD, who presented the company's findings at anAACR session, suggested that a tumor uses MMP as "excavatingequipment" to tunnel through connective tissue to make moreroom for itself. He also believes that MMP enzymes allow tumorsto form the blood vessels they need for growth.

Two drugs that show promise in suppressing MMP enzymes are batimastat(BB-94) and its second-generation cou-sin BB-2516. Both potentiallyslow cancer spread to a non-life-threatening crawl, Dr. Drummondsaid. When animals were treated with the inhibitor, new connectivetissue was laid down around the tumor, essentially walling itin and apparently preventing tumor growth.

Dr. Drummond said that these drugs do not kill the tumor, butonly keep it at bay. As a consequence, they would likely be usedas an adjunct with other chemotherapy.

British Biotech's research has been focused on making the drugspracticable for clinical use. Batimastat is currently given byinjection, Dr. Drummond said, but the second-generation compound,BB-2516, is well absorbed and well tolerated when given as a capsuleto human volunteers. It is currently being investigated in cancerpatients.