Jan. 21, 2003 NASHVILLE, Tenn. -- A team of Vanderbilt-Ingram Cancer Center scientists shrunk tumors or delayed their growth in animal studies by using radiation to enable a drug to "zero in" and block the tumor blood vessels.
The work, reported in the January issue of the journal Cancer Cell, is a model for what might be achieved in patients by using radiation to activate drug targets in tumors. "We can now use combinations of chemotherapy and radiation to improve the anti-cancer effect for many of our patients, but the side effects can be great," said Dr. Dennis Hallahan, chair of Radiation Oncology at Vanderbilt- Ingram. "With this approach, we hope we can ultimately deliver drugs directly and selectively to the tumor alone, and reduce side effects."
This paper describes work by investigators in Vanderbilt's departments of Radiation Oncology, Radiology, Biochemical Engineering and Cancer Biology to identify receptors in tumor blood vessels that are activated by radiation and then to demonstrate that these receptors can be selectively targeted.
To identify the radiation-induced targets, the scientists treated tumor- bearing animals with radiation and then injected them with a peptide library. The peptides (portions of proteins) that correspond to the radiation-induced receptors bind, or stick, and can then be recovered. By identifying which peptides stick to radiation-treated tumor cells compared to untreated cells, the scientists can identify what receptors are activated by radiation.
A particular protein portion, the amino acid sequence RGDGSSV, was recovered from several tumor models and was found to bind within the tumor blood vessels. It was found to bind to two types of fibrinogen receptors that are important to angiogenesis, the development of blood vessels. Tumor blood vessels are an attractive therapeutic target because tumor cells depend on the blood vessels for vital oxygen and nutrients necessary for their growth and spread.
The scientists then coated liposomes (fatty molecules that can be used to deliver drugs) with an antibody that binds to these fibrinogen receptors. These liposomes were tagged with a fluorescent marker so they could be tracked in the body and were injected into mice with tumors on both hind legs. The right tumors were treated with radiation, while the left tumors were left untreated as controls. The fluorescent marker, indicating the presence of the antibody-coated liposomes, was seen in the treated tumors but not in the untreated tumors. The finding suggests that anti-cancer drugs might be attached to these antibody-coated liposomes and targeted specifically to tumors.
The scientists next tested whether they could affect tumor growth by targeting these radiation-induced receptors with nanoparticles designed to obstruct the blood flow within the vessels. They compared effects of radiation combined with nanoparticles coated with the fibrinogen antibody versus radiation alone and radiation combined with uncoated nanoparticles.
Sonographic measurement of microscopic blood flow found that radiation alone or used with uncoated nanoparticles achieved virtually no change in tumor blood flow. However, blood flow was reduced by 85 percent in tumors treated with coated nanoparticles and radiation.
In addition, tumor growth was significantly delayed in tumors treated with radiation and coated nanoparticles, compared to those treated with uncoated nanoparticles or radiation alone.
Hallahan and his colleagues have begun pilot studies in cancer patients to test the feasibility of this approach. Current trials are designed to demonstrate that radiation can activate receptors in these patients that can then be targeted with the antibodies. Among the factors being explored are whether the type of radiation -- traditional external radiation, internally delivered radiation (brachytherapy) or stereotactically delivered radiation -- makes a difference in the ability to target therapy.
Hallahan estimates that clinical trials using this approach to test treatments are still several years away.
In addition to Hallahan, authors on the paper were Ling Geng, Shimian Qu, Christopher Scarfone, Todd Giorgio, Edwin Donnelly, Xiang Gao and Jeff Clanton.
The work was funded by the National Institutes of Health, including support from Vanderbilt-Ingram's SPORE (Specialized Program Of Research Excellence) in Lung Cancer grant from the National Cancer Institute; the American Society for Therapeutic Radiation Oncology; and Vanderbilt's department of Radiation Oncology.
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