The effectiveness of most drugs used for treating cancer is limited because they spread throughout the body, killing off normal dividing cells as well as those of tumors. And to make matters worse, the tumor cells themselves often become resistant to the drugs. Now scientists report in today's issue of Science a way to target cancer drugs to the new blood vessels that nourish a tumor. Such drugs may not only spare other tissues, but tumor vessel cells are much less likely to develop resistance to them than are highly mutable cancer cells.
Cancer researchers have been trying for several years to use other molecules to ferry chemotherapeutic drugs to tumors. But the standard vehicle, large proteins such as antibodies, has had mixed success. Erkki Ruoslahti at the Burnham Institute in La Jolla, California, decided to combine that idea with another strategy that has shown promise in animal tests: blocking tumor growth by inhibiting the formation of the new blood vessels that tumors need. Indeed, such work has made angiogenesis, as new blood vessel growth is called, a red-hot research area in recent years (Science, 24 January 1997, p. 482). Progress has been slowed, however, because the best angiogenesis inhibitors are expensive and laborious to produce in bacteria.
Because of the problems with large molecules, Ruoslahti wanted to find small peptides that could deliver drugs specifically to tumors. To do this, his team turned to a technique called phage display. This involves engineering bacterial viruses called phages so that each phage displays a different random peptide on its surface. The technique had been used to find peptides that stick to particular proteins, by exposing a mix of peptide-displaying phages to a surface coated with the protein. Ruoslahti reasoned that if the phages were injected into an animal, the technique may be able to identify peptides that stick to tumor blood vessels.
After identifying several such peptides, the team chose two and hooked them individually to the anticancer drug doxorubicin. When given to mice that had large tumors derived from human breast cancer cells, even tiny amounts of the peptide-linked drug were better at stunting tumor growth than was free doxorubicin, the effects of which were limited by its toxicity. Indeed, some of the mice treated with the doxorubicin-peptide blend lived for 6 months after the treatment, while those treated with doxorubicin alone died either of tumors or doxorubicin poisoning at the high doses. The tumors don't disappear completely, he notes, but what remains seems to be inactive scar tissue. "The mice live very long, so it doesn't seem to bother them."
What's more, the technique the Ruoslahti team used to identify peptides that home in on tumor vessels is able to identify peptides that bind specifically to the blood vessels of other organs. This means peptides could be found to carry drugs to many different tissues to treat conditions other than cancer. "Ruoslahti can address drugs wherever he wants to in a nontoxic way," enthuses angiogenesis pioneer Judah Folkman of Harvard Medical School. "A few years from now this will be the basis of a new pharmacology."