Scientists have developed a molecule that kills tumors by destroying the blood vessels that feed the cancer cells. In recent laboratory tests on mice, the cancer killing molecule, called icon, also caused the cancer cells to produce copies of icon that spread throughout the body and attacked other cancer cells.
The testing of icon molecules eradicated human melanoma and prostate cancers in tested mice.
The earlier drugs, which were intended to inhibit the growth of the blood vessels that feed cancer cells, have received wide attention and hope in recent years but showed little promise.
"Our study resulted in the eradication of injected tumors and also of other tumors in mice that had not been injected," said principal investigator Alan Garen, professor of molecular biophysics and biochemistry at Yale University. "This serves as a model of metastatic cancer. None of the normal tissues in the mouse appeared to be harmed by our procedure."
Zhiwei Hu, a researcher at Yale University worked with Alan Garen to develop the new therapy by taking a different approach of attacking the cells lining the blood vessels in tumors rather than trying to prevent the growth of new blood vessels.
"The result is that the tumor blood vessels are destroyed by the immune system and consequently the tumor cells die because they lack a blood supply," said Garen. "The normal blood vessels survive because they do not express tissue factor and therefore do not bind the icon."
Their findings are reported in the Oct. 2, 2001 issue of the Proceedings of the National Academy of Sciences.
"We're excited about it," Garen said. However, he also cautioned, "From mice to men, that is a big jump. Until the trial is done with patients you can't be sure."
The first trials of icon in humans are tentatively planned for next year. Dr. Albert Deisseroth of the Sidney Kimmel Cancer Center in San Diego is arranging clinical trials, which he hopes to launch next spring as soon as the approval is obtained from the Food and Drug Administration.
"This icon should work against all types of tumors that contain blood vessels," said Garen. "The icon that will be used in a clinical trial is derived entirely from human components and therefore should not be significantly immunogenic, which is an advantage over antibodies used in this kind of study."
Dr. Deisseroth also warned against jumping to conclusions about new possible cancer therapy.
"There are differences between animals and human beings." Deisseroth added, "when studies in animals are so reproducible and encouraging... then you feel justified to invite individuals who are not responding to other forms of therapy to participate" in trials.
Dr. Deisseroth said that the first trial will focus on people with melanoma, a type of skin cancer that spreads throughout the body. He also said that while the animal tests have worked on prostate cancer and melanoma, in theory the therapy should work on any solid cancer.
Garen said that cells lining the blood vessels in tumors have a receptor on their surface called TF (tissue factor), which is not present on the cells lining blood vessels in other parts of the body. His team found that a molecule circulating in the blood called fVII bonds strongly to TF.
The researchers created their new molecule by attaching an fVII molecule to a portion of a human antibody called Fc. Fc causes the breakdown of cells as it binds to and activates the body's immune system to attack those cells.
The new icon molecule was inserted in a harmless virus that was injected directly into a tumor. Once infected by the virus, the tumor cells produce more icon and secrete it into the blood, where the virus circulates. When the virus encounters a tumor, it binds to the TF in its blood vessels, destroying them.
In mice with human melanoma or prostate cancer that received the molecule, both the injected tumor and others that were not directly injected disappeared.
"The mice appeared to be free of the disease and in good health at the end of the experiments, which lasted up to 194 days," the researchers reported. Control mice with similar cancers that did not receive the molecule died within 63 days. Derrick Grant, a blood-vessel expert at Thomas Jefferson University in Philadelphia, called the findings "very exciting."
Grant said that the paper "puts a new and important spin on Judah Folkmans hypotheses that destroying the tumor vasculature can stop tumor growth."
Folkman, of Boston Children's Hospital, is a pioneer in efforts to battle cancer by attacking its blood supply. Transferring the molecule into a tumor in a virus that forces the tumor to make more of the anti-cancer molecule "is brilliant and deserves praise," Grant said.
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